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Current Practices and Controversies
in Assisted Reproduction
Report of a meeting on“Medical, Ethical and Social Aspects of Assisted Reproduction”
held at WHO Headquarters in Geneva, Switzerland17–21 September 2001
Edited byEFFY VAYENA
PATRICK J. ROWEP. DAVID GRIFFIN
World Health OrganizationGeneva
2002
WHO Library Cataloguing-in-Publication Data
Medical, Ethical and Social Aspects of Assisted Reproduction (2001: Geneva, Switzerland)Current practices and controversies in assisted reproduction : report of a WHO meeting / editors,Effy Vayena, Patrick J. Rowe and P. David Griffin.
1. Reproductive techniques, Assisted – trends 2. Infertility 3. Bioethical issues 4. Pregnancyoutcome 5. Social environment I. Vayena, Effy II. Rowe, Patrick J. III. Griffin P. David. IV. Title.
ISBN 92 4 159030 0 (NLM classification: WQ 208)
© World Health Organization, 2002
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Copy-edited and typeset by Byword Editorial Consultants, New Delhi, India
Participants and contributors vii
Foreword xv
Glossary xix
Introduction
Current challenges in assisted reproductionMAHMOUD FATHALLA 3
1. Infertility and assisted reproductive technologies in the developing world
Infertility and social suffering: the case of ART in developing countriesABDALLAH S. DAAR, ZARA MERALI 15
ART in developing countries with particular reference to sub-Saharan AfricaOSATO F. GIWA-OSAGIE 22
2. Infertility and assisted reproductive technologies from a regional perspective
Assisted reproductive technology in Latin America: some ethical and sociocultural issuesFLORENCIA LUNA 31
Attitudes and cultural perspectives on infertility and its alleviation in the Middle East areaGAMAL I. SEROUR 41
Social and ethical aspects of assisted conception in anglophone sub-Saharan AfricaOSATO F. GIWA-OSAGIE 50
ART and African sociocultural practices: worldview, belief and value systems withparticular reference to francophone AfricaGODFREY B. TANGWA 55
Sociocultural attitudes towards infertility and assisted reproduction in IndiaANJALI WIDGE 60
Sociocultural dimensions of infertility and assisted reproduction in the Far EastREN-ZONG QIU 75
Contents
iv Contents
3. Recent medical developments and unresolved issues in ART
Gamete source, manipulation and disposition
Gamete source and manipulationHERMAN TOURNAYE 83
Ovarian stimulation for assisted reproductive technologiesJEAN-NOEL HUGUES 102
Intracytoplasmic sperm injection: technical aspectsHENRY E. MALTER, JACQUES COHEN 126
Intracytoplasmic sperm injection: micromanipulation in assisted fertilizationANDRÉ VAN STEIRTEGHEM 134
Cryopreservation of oocytes and ovarian tissueHELEN M. PICTON, ROGER G. GOSDEN, STANLEY P. LEIBO 142
Cryopreservation of human spermatozoaSTANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN 152
Gamete and embryo donationCLAUDIA BORRERO 166
Embryo selection methods and criteria
Embryo culture, assessment, selection and transferGAYLE M. JONES, FATIMA FIGUEIREDO, TIKI OSIANLIS, ADRIANNE K. POPE,LUK ROMBAUTS, TRACEY E. STEEVES, GEORGE THOUAS, ALAN O. TROUNSON 177
Preimplantation genetic diagnosisLUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI 210
Multiple pregnancies and multiple births
Multiple pregnancy in assisted reproduction techniquesOZKAN OZTURK, ALLAN TEMPLETON 220
Outcome of multiple pregnancy following ART: the effect on the childORVAR FINNSTROEM 235
Multiple birth children and their families following ARTJANE DENTON, ELIZABETH BRYAN 243
4. Social and psychological issues in infertility and ART
Consumer perspectivesSANDRA DILL 255
Gender, infertility and ARTELLEN HARDY, MARIA YOLANDA MAKUCH 272
Contents v
Family networks and support to infertile peoplePIMPAWUN BOONMONGKON 281
Parenting and the psychological development of the child in ART familiesSUSAN GOLOMBOK 287
5. Ethical aspects of infertility and ART
Patient-centred ethical issues raised by the procurement and use of gametes andembryos in assisted reproductionHELGA KUHSE 305
When reproductive freedom encounters medical responsibility: changing conceptions ofreproductive choiceSIMONE BATEMAN 320
Ethical issues arising from the use of assisted reproductive technologiesBERNARD M. DICKENS 333
6. National and international surveillance of ART and their outcomes
The Swedish experience of assisted reproductive technologies surveillanceKARL NYGREN 351
The Latin American Registry of Assisted ReproductionFERNANDO ZEGERS-HOCHSCHILD 355
Assessment of outcomes for assisted reproductive technology: overview of issuesand the U.S. experience in establishing a surveillance systemLAURA A. SCHIEVE, LYNNE S. WILCOX, JOYCE ZEITZ, GARY JENG, DAVID HOFFMAN,ROBERT BRZYSKI, JAMES TONER, DAVID GRAINGER, LILY TATHAM, BENJAMIN YOUNGER 363
International registries of assisted reproductive technologiesKARL NYGREN 377
Recommendations 381
List of participants and contributors
Dr SIMONE BATEMAN
Centre de Recherche Sens Ethique, Société59 Rue Pouchet75849 Paris Cedex 17FranceE-mail: [email protected]
Dr PIMPAWUN BOONMONGKON
Center for Health Policy StudiesFaculty of Social Sciences and HumanitiesMahidol UniversitySalaya, 73170 KanornpathomThailandE-mail: [email protected]
Dr CLAUDIA BORRERO
Latin American Network of Assisted Reproduction(CONCEPTUM)
Carrera 16 # 82-29BogotáColombiaE-mail: [email protected]
Dr ELIZABETH BRYAN
The Multiple Births FoundationLevel 4 Hammersmith HouseQueen Charlotte’s and Chelsea HospitalDu Cane RoadLondon W12 OHSUnited KingdomE-mail: [email protected]
Dr ROBERT BRZYSKI
Society for Assisted Reproductive Technology1209 Montgomery HighwayBirmingham, AL 35216USAE-mail: [email protected]
Dr JACQUES COHEN
Institute for Reproductive Medicine and ScienceSaint Barnabas Medical CenterOld Short Hills Road East WingSuite 403, Livingston, New Jersey 07039USAE-mail: [email protected]
Dr FRANK COMHAIRE
Department of EndocrinologyResearch Laboratory of AndrologyState University Hospital185 de Pintelaar, B-9000 GhentBelgiumE-mail: [email protected]
Dr IAN D. COOKE
80 Grove Road, MillhousesSheffield, S7 2GZUnited KingdomE-mail: [email protected]
Dr ABDALLAH S. DAAR
Joint Centre for BioethicsUniversity of Toronto88 College StreetToronto M5G 1L4CanadaE-mail: [email protected]
Mrs JANE DENTON
The Multiple Births FoundationLevel 4 Hammersmith HouseQueen Charlotte’s and Chelsea HospitalDu Cane RoadLondon W12 OHSUnited KingdomE-mail: [email protected]
viii List of participants and contributors
Dr BERNARD DICKENS
Faculty of Medicine and Joint Centre for BioethicsUniversity of Toronto84 Queen’s Park CrescentToronto, Ontario M5S 2C5CanadaE-mail: [email protected]
Ms SANDRA DILL
ACCESS Australia Infertility NetworkBox 959Parramatta, NSW 2124AustraliaE-mail: [email protected]
Dr Mahmoud F. FathallaP.O. Box 30AssiutEgyptE-mail: [email protected]
Dr Anna P. FerrarettiSISMER, Reproductive Medicine UnitVia Mazzini 1240138 BolognaItalyE-mail: [email protected]
Ms FATIMA FIGUEIREDO
Centre for Early Human DevelopmentInstitute of Reproduction and DevelopmentMonash UniversityMonash Medical Centre, Level 5246 Clayton RoadClayton, VIC 3168Australia
Dr ORVAR FINNSTROEM
Department of PaediatricsUniversity Hospital58185 LinkoepingSwedenE-mail: [email protected]
Dr JAMES GALLAGHER
Council for International Organizations of MedicalSciences (CIOMS)
c/o World Health OrganizationCH-1211 Geneva 27SwitzerlandE-mail: [email protected]
Dr LUCA GIANAROLI
SISMER, Reproductive Medicine UnitVia Mazzini 1240138 BolognaItalyE-mail: [email protected]
Dr OSATO F. GIWA-OSAGIE
Department of Obstetrics and GynaecologyCollege of Medicine of the University of LagosP.O. Box 12003LagosNigeriaE-mail: [email protected]
Dr SUSAN GOLOMBOK
Family and Child Psychology Research CentreCity UniversityNorthampton SquareLondon EC1V OHBUnited KingdomE-mail: [email protected]
Dr ROGER GOSDEN
Division of Reproductive BiologyDepartment of Obstetrics and GynecologyMcGill UniversityWomen’s Pavilion (F3.38)Royal Victoria Hospital687 Pine Avenue WestMontreal H3A 1A1, QuebecCanadaE-mail: [email protected]
Dr DAVID GRAINGER
Society for Assisted Reproductive Technology1209 Montgomery HighwayBirmingham, AL 35216USAE-mail: [email protected]
Dr KERSTIN HAGENFELDT
Department of Women and Child HealthDivision of Obstetrics and GynaecologyKarolinska HospitalBox 140S-171 76 StockholmSwedenE-mail: [email protected]
List of participants and contributors ix
Dr ELLEN HARDY
Department of Obstetrics and GynecologySchool of Medical SciencesState University of CampinasCEMICAMPCaixa Postal 6181Campinas 13081 - 970Sao PauloBrazilE-mail: [email protected]
Dr ROBERT F. HARRISON
International Federation of Fertility Societies (IFFS)Department of Obstetrics and GynaecologyRotunda HospitalParnell StreetDublin 1IrelandE-mail: [email protected]
Dr AUCKY HINTING
Reproductive Health Research CentreAirlangga UniversityJalan Prof. Moestopo 47Surabaya 60131IndonesiaE-mail: [email protected]
Dr DAVID HOFFMAN
Society for Assisted Reproductive Technology1209 Montgomery HighwayBirmingham, AL 35216USAE-mail: [email protected]
Dr JEAN-NOEL HUGUES
Reproductive Medicine UnitJean Verdier HospitalBondy 93143FranceE-mail: [email protected]
Ms ORIO IKEBE
Division of the Ethics of Science andTechnology
UNESCO1, rue Miollis75732 Paris Cedex 15FranceE-mail: [email protected]
Dr GARY JENG
Division of Reproductive HealthCenters for Disease ControlMailstop K-204770 Buford Highway, NEAtlanta, GA 30341-3724USAE-mail: [email protected]
Dr ELOF D.B. JOHANSSON
The Population Council1 Dag Hammarskjold PlazaNew York, NY 10017USAE-mail: [email protected]
Dr GAYLE JONES
Centre for Early Human DevelopmentInstitute of Reproduction and DevelopmentMonash UniversityMonash Medical Centre, Level 5246 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
Dr HELGA KUHSE
Centre for Human BioethicsMonash UniversityClayton, VIC 3168AustraliaE-mail: [email protected]
Dr REGINA KULIER
International Federation of Gynaecology andObstetrics (FIGO)
30 Boulevard de la Cluse1211 Geneva 14SwitzerlandE-mail: [email protected]
Dr STANLEY P. LEIBO
ACRES, 14001 River RoadNew OrleansLA 70131USAE-mail: [email protected]
x List of participants and contributors
Dr BORIS V. LEONOV
Laboratory of Clinical EmbryologyScientific Center for Obstetrics and Gynaecology4 Oparin StreetMoscow117815 RussiaE-mail: [email protected]
Dr FLORENCIA LUNA
University of Buenos AiresFLACSOUgarteche 3050487, Capital Federal (1425)ArgentinaE-mail: [email protected]
Dr RUTH MACKLIN
Department of Epidemiology and Social MedicineAlbert Einstein College of Medicine1300 Morris Park AvenueBronx, NY 10461USAE-mail: [email protected]
Ms MARIA CRISTINA MAGLI
SISMER, Reproductive Medicine UnitVia Mazzini 1240138 BolognaItalyE-mail: [email protected]
Dr MARIA YOLANDA MAKUCH
Centro de Pesquisas Materno-Infantis de CampinasCaixa Postal 6181-CEP 13084-971Campinas-SPBrazilE-mail: [email protected]
Dr HENRY MALTER
Institute for Reproductive Medicine and ScienceSaint Barnabas Medical CenterOld Short Hills Road East WingSuite 403, LivingstonNew Jersey 07039USAE-mail: [email protected]
Ms ZARA MERALI
77 Park Avenue, Apt 1408Hoboken, NJUSA 07030E-mail: [email protected]
Dr JACQUES DE MOUZON
INSERM U292Hôpital de Bicêtre82, rue du Général Leclerc94276 Le Kremlin Bicetre CedexFranceE-mail: [email protected]
Dr KARL-C. NYGREN
IVF-Unit, Sophia HospitalBox 5605, S-114-86 StockholmSwedenE-mail: [email protected]
Dr TIKI OSIANLIS
Monash IVF, Monash Private Surgical Hospital252–254 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
DR OZKAN OZTURK
Department of Obstetrics and GynaecologyUniversity of AberdeenForesterhillAberdeen AB24 3DBUnited KingdomE-mail: [email protected]
Dr HELEN PICTON
Department of Obstetrics and GynaecologyLeeds General InfirmaryBelmont Grove, Leeds LS2 9NSUnited KingdomE-mail: [email protected]
Dr ADRIANNE POPE
Monash IVFMonash Private Surgical Hospital252–254 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
Dr REN-ZONG QIU
Institute of PhilosophyChinese Academy of Social Sciences5 Jianguomennei DajieBeijing 100732ChinaE-mail: [email protected]
List of participants and contributors xi
Dr LUK ROMBAUTS
Monash IVFMonash Private Surgical Hospital252–254 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
Dr LAURA SCHIEVE
Division of Reproductive HealthCenters for Disease ControlMailstop K-204770 Buford Highway, NEAtlanta, GA 30341-3724USAE-mail: [email protected]
Dr MARKKU SEPPALA
Department of Obstetrics and GynecologyHelsinki University HospitalP.O.B. 20FIN-00014 HelsinkiFinlandE-mail: [email protected]
Dr GAMAL I. SEROUR
International Islamic Center for Population Studies andResearch
Al-Azhar UniversityCairoEgyptE-mail: [email protected]
Dr TRACEY STEEVES
Monash IVFLevel 4 Epworth Hospital89 Bridge RoadRichmond, VIC 3121AustraliaE-mail: [email protected]
Dr GODFREY B. TANGWA
University of YaoundéP.O. Box 13597YaoundéCameroonE-mail: [email protected]
Dr LILY TATHAM
Division of Reproductive HealthCenters for Disease ControlMailstop K-204770 Buford Highway, NEAtlanta, GA 30341-3724USAE-mail: [email protected]
Dr Allan TempletonDept. of Obstetrics and GynaecologyUniversity of AberdeenAberdeen Maternity HospitalForesterhillAberdeen, AB25 2ZDUnited KingdomE-mail: [email protected]
Dr GEORGE THOUAS
Centre for Early Human DevelopmentInstitute of Reproduction and DevelopmentMonash UniversityMonash Medical Centre, Level 5246 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
Dr MAHMOUD A. TOLBA
Galaa Assisted Reproduction and IVF Unit(GARU)
Galaa Maternity HospitalCairoEgyptE-mail: [email protected]
Dr JAMES TONER
Society for Assisted Reproductive Technology1209 Montgomery HighwayBirmingham, AL 35216USAE-mail: [email protected]
Dr HERMAN TOURNAYE
Center for Reproductive MedicineBrussels Free UniversityLaarbeeklaan 1011090 BrusselsBelgiumE-mail: [email protected]
xii List of participants and contributors
Dr ALAN TROUNSON
Centre for Early Human DevelopmentInstitute of Reproduction and DevelopmentMonash UniversityMonash Medical Centre, Level 5246 Clayton RoadClayton, VIC 3168AustraliaE-mail: [email protected]
Dr ANDRÉ VAN STEIRTEGHEM
Centre for Reproductive MedicineUniversity of BrusselsLaarbeeklaan 101B-1090 BrusselsBelgiumE-mail: [email protected]
Ms LISA VERON
Bertarelli Foundation18 rue du Rhone1204 GenevaSwitzerlandE-mail: [email protected]
Dr ANJALI WIDGE
The Population CouncilRegional Office for South and East AsiaZone 5A, GF, India Habitat CentreLodi RoadNew Delhi-110003IndiaE-mail: [email protected]
Dr LYNNE S. WILCOX
Division of Reproductive HealthCenters for Disease ControlMailstop K-204770 Buford Highway, NEAtlanta, GA 30341-3724USAE-mail: [email protected]
Dr BENCHA YODDUMNERN-ATTIG
Institute for Population and Social ResearchMahidol UniversitySalaya, Nakornpathom 73170ThailandE-mail: [email protected]
Dr BENJAMIN YOUNGER
American Society for Reproductive Medicine1209 Montgomery HighwayBirmingham, AL 35216-2809USAE-mail: [email protected]
Dr FERNANDO ZEGERS-HOCHSCHILD
Clinica Las CondesLa Fontecilla 441SantiagoChileE-mail: [email protected]
Ms JOYCE ZEITZ
Society for Assisted Reproductive Technology1209 Montgomery HighwayBirmingham, AL 35216-2809USAE-mail: [email protected]
List of participants and contributors xiii
Mr P. DAVID GRIFFIN
ScientistDepartment of Reproductive Health and ResearchE-mail: [email protected]
Ms CHRISTINE M. KLEKR
SecretaryDepartment of Reproductive Health and ResearchE.mail: [email protected]
Mrs LYNDA PASINI
SecretaryDepartment of Reproductive Health and ResearchE.mail: [email protected]
Dr PATRICK J. ROWE
Medical OfficerDepartment of Reproductive Health and ResearchE-mail: [email protected]
Dr PAUL F. A. VAN LOOK
DirectorDepartment of Reproductive Health and ResearchE-mail: [email protected]
Dr EFFY VAYENA
Technical OfficerDepartment of Reproductive Health and ResearchE-mail: [email protected]
WHO Secretariat
Foreword
The last quarter of the 20th century has witnessedseveral major advances in reproductive medicine. Oneof the most widely publicised, celebrated and, at thetime, controversial medical landmarks in this area wasthe birth, in 1978, of the first human baby resultingfrom in vitro fertilization (IVF). Since then, IVF hasbecome a routine and widely accepted treatment forinfertility. However, IVF is but one of many proceduresin the increasingly complex and sophisticated field ofbiomedicine known as assisted reproduction. Since1978, nearly one million babies have been bornworldwide as the result of assisted reproductivetechnology (ART) of one form or another. It has beenestimated that in some European countries up to fiveper cent of all births are now due to ART. It is clearthat ART has made a significant impact on the livesof many infertile and subfertile couples. However, ithas also been the source of great disappointment tothose couples for whom ART has proven unsuccessfuland to many more infertile people around the worldwho have no access to these technologies.
It is commonly accepted that infertility affectsmore than 80 million people worldwide. In general, onein ten couples experiences primary or secondaryinfertility, but infertility rates vary amongst countriesfrom less than 5% to more than 30%. Most of thosewho suffer from infertility live in developing countrieswhere infertility services in general, and ART inparticular, are not available. Malaria, tuberculosis andinfection with the human immunodeficiency virus(HIV) among other diseases which have significantmorbidity and mortality and adversely affect deve-loping country economies, are, justifiably, the centreof public health attention. In many developingcountries, infertility is the result of genital tractinfection which includes sexually transmitted infec-tions (STIs), postpartum or postabortal infection andpelvic tuberculosis or schistosomiasis. Tubal
blockage is responsible for infertility in up to two-thirds of infertile nulliparous women in sub-SaharanAfrica and between one-quarter and one-third ofinfertile women in developed and developingcountries, respectively. It is often argued that thesolution to the problem of infertility in developingcountries can only be found in prevention of infertilitythrough prevention of STIs and unsafe abortion.Therefore, the use of ART to manage infertility is acontested issue in the context of the cause of theproblem, the attitude to overpopulation and theavailability of scarce health resources in developingcountries. Even in developed countries, however ,where infertility patients stand a better chance ofreceiving infertility treatment, access to ART islimited. The generally high cost of ART proceduresand national policies regarding accessibility andreimbursement leave many infertile people without theoption of treatment.
Although infertility may not be a public healthpriority in many countries, it is a central issue in thelives of the individuals who suffer from it. It is asource of social and psychological suffering for bothmen and women and can place great pressures onthe relationship within the couple. While the role andstatus of women in society should not be definedsolely by their reproductive capacity, in somesocieties womanhood is defined through mother-hood. In these situations, the personal suffering ofthe infertile woman is exacerbated and can lead tounstable marriage, domestic violence, stigmatizationand even ostracism. Although peer and socialpressures to have children vary from country tocountry, what remains common in all is the desperateneed of infertile people to give birth to a healthychild. Many infertility consumer groups consider thisto be a human right based on the following note fromthe UN Declaration of Human Rights, Article 16.1:
xvi
Men and women of full age, without anylimitation due to race, nationality or religion,have the right to marry and to found a family.
In the past decade, developments in the field ofART have intensified the hopes and the wishes ofinfertile people to resolve their infertility and haveresulted in an increasing demand for such servicesin both developed and developing countries. Whiledevelopments in ART have evolved rapidly, so havethe ethical, social and political controversies whichsurround nearly all aspects of ART. Few other areasin medicine have posed so many social and ethicalquestions and have attracted so much publicattention as ART.
International concerns about ART and its socialand ethical implications were raised at the 52nd WorldHealth Assembly in 1999, which requested the WorldHealth Organization (WHO) to review recent develop-ments in the field of ART as well as their social andethical implications. In response to this request, theWHO Department of Reproductive Health andResearch convened a meeting on the medical, ethicaland social aspects of assisted reproduction on 17–21September 2001.
WHO had previously dealt with the issue of ARTin the context of other work on the subject of infertility.In 1990, a similar meeting was convened by WHOwhich resulted in a technical report entitled Recentadvances in medically assisted conception (TechnicalReport Series No. 820, 1992). At that time, the empha-sis was on technical aspects of ART. The meeting inSeptember 2001 was organized to provide a forum forinterdisciplinary discussion involving as manyinterested parties as possible. More than 40 parti-cipants from 22 countries took part in the meeting;they included clinicians, embryologists, socialscientists, ethicists and consumer representatives.The objectives of the meeting were (a) to review andassess recent developments in ART; (b) to identifyunresolved issues in the field; and (c) to providerecommendations for future research.
To permit in-depth analysis and discussion, themeeting did not cover the whole field of ART. Instead,it focused on a selected number of topics that eitherwere too recent in their development to have beendiscussed at the previous WHO meeting in this area,or considered to present particularly difficult andpressing problems at the present time. These topicsincluded national and international surveillance ofART, intracytoplasmic sperm injection (ICSI), mani-
pulation and cryopreservation of gametes, multiplepregnancy, techniques of ovarian stimulation,preimplantation genetic diagnosis, psychosocialissues, ethical aspects in relation to the individual, tothe couple and to the offspring, as well as issues ofequitable access, the role of consumers and the placeof ART in developing countries. The issue of cloningwas not reviewed and discussed as it has been thesubject of previous meetings held by WHO. Also,artificial insemination was not considered since it wascovered in-depth by the WHO Technical Reportpublished in 1992 and an update was not deemednecessary.
Background papers were commissioned frominvited speakers and peer-reviewed prior to themeeting. The papers were briefly presented withemphasis being given to discussion and the deli-neation of recommendations for practice and futureresearch. All of the meeting sessions were plenary toallow full interaction among the different disciplines.A wide variety of views and approaches waspresented in an intense, dynamic and rich debate.
This publication comprises 6 sections, consistingof the background papers and the recommendationsagreed to by the meeting participants. The papers aregrouped by subject in an order similar to that of themeeting programme but also in a way that the differentviews are juxtaposed or complementary. Despite thediverse opinions on ART voiced at the meeting, therewere many points upon which consensus wasreached. These are reflected in the corresponding setsof recommendations, which appear in the last sectionof this report. These recommendations include somethat are directed towards those responsible for healthpolicy, some for those who are concerned with clinicalpractice and some to the research community. Themeeting also agreed on a list of working definitionsfor ART for the purposes of the meeting’s discussions.These definitions are included as a glossary in thereport for consistency and clarity. However, it needsto be emphasized that these are not definitions thathave been adopted by WHO, but they can be used tofacilitate the standardization of language in the fieldand in national and international registries.
Over the past years, WHO has received severalrequests from developing countries for advice on howto handle the introduction of ART in their, oftenresource-poor, settings. On the other hand, the numberof ART clinics in such settings is increasing andinfertility consumer groups have become an estab-lished and outspoken force in several developing
Foreword
xvii
EFFY VAYENAPATRICK ROWEDAVID GRIFFIN
PAUL VAN LOOKTOMRIS TÜRMEN
countries. At the same time, there has been consi-derable international debate on related topics such asstem cell research, claims for successful humancloning and vigorous condemnations thereof.Inevitably, ART has ramifications beyond thetreatment of infertility as it is related to the currentresearch on molecular reproductive biology offertilization and implantation, as well as on stem celland cloning research. Progress in this area can onlybe achieved through informed debate among all thoseinvolved in ART. This, the most recent WHO meetingin this area, provided one opportunity for such debate.The meeting and this report are not meant to providesolutions to the many problems encountered in thecomplex subject of assisted reproduction. Rather, theyare intended to stimulate further debate among allthose interested in the scientific, social and ethicalaspects of ART and to provide some guidance andclarification for ongoing discussion.
Acknowledgements
In addition to the participants and other contributorswho made the meeting such a success, we would alsolike to thank the Department of Health of Canada forits generous contribution to the cost of this meeting,the members of the Planning Committee (FrankComhaire, Ian Cooke, Sandra Dill, Kerstin Hagenfeldt,Ruth Macklin, Bencha Yoddumnern-Attig andFernando Zegers-Hochschild) for their tireless effortsto develop a comprehensive and coherent programmeand for reviewing the background documents, IanCooke who so ably and productively chaired themeeting, and Mrs Lynda Pasini and Ms ChristineKlekr for their excellent organizational and adminis-trative support throughout the planning and conductof the meeting.
Foreword
Aspiration cycle: initiated ART cycle in which one ormore follicles are punctured and aspirated irrespectiveof whether or not oocytes are retrieved.
Assisted hatching: an in vitro procedure in which thezona pellucida of an embryo (usually at 8-cell stageor a blastocyst) is perforated by chemical, mechanicalor laser-assisted methods to assist separation of theblastocyst from the zona pellucida.
Assisted reproductive technology (ART): all treat-ments or procedures that include the in vitro handlingof human oocytes and sperm or embryos for thepurpose of establishing a pregnancy. This includes,but is not limited to, in vitro fertilization and trans-cervical embryo transfer, gamete intrafallopiantransfer, zygote intrafallopian transfer, tubal embryotransfer, gamete and embryo cryopreservation, oocyteand embryo donation and gestational surrogacy. ARTdoes not include assisted insemination (artificialinsemination) using sperm from either a woman’spartner or sperm donor.
Birth defect: Structural, functional or developmentalabnormalities present at birth or later in life, due togenetic or nongenetic factors acting before birth.
Blastocyst: an embryo with a fluid-filled blastocelecavity (usually developing by five or six days afterfertilization).
Cancelled cycle: an ART cycle in which ovarianstimulation or monitoring has been carried out withthe intent of undergoing ART but which did notproceed to follicular aspiration, or in the case of athawed embryo, to transfer.
Glossary
Clinical abortion: an abortion of a clinical pregnancywhich takes place between the diagnosis of pregnancyand 20 completed weeks’ gestational age.
Clinical pregnancy: evidence of pregnancy byclinical or ultrasound parameters (ultrasound visual-ization of a gestational sac). It includes ectopic preg-nancy. Multiple gestational sacs in one patient arecounted as one clinical pregnancy.
Clinical pregnancy rate: number of clinical preg-nancies expressed per 100 initiated cycles, aspirationcycles or embryo transfer cycles. When clinicalpregnancy rates are given, the denominator (initiated,aspirated or embryo transfer cycles) must be specified.
Controlled ovarian hyperstimulation (COH): medicaltreatment to induce the development of multipleovarian follicles to obtain multiple oocytes at follicularaspiration.
Cryopreservation: freezing and storage of gametes,zygotes or embryos.
Delivery rate: number of deliveries expressed per 100initiated cycles, aspiration cycles or embryo transfercycles. When delivery rates are given, the denomi-nator (initiated, aspirated or embryo transfer cycles)must be specified. It includes deliveries that resultedin a live birth and/or stillbirth. The delivery of asingleton, twin or other multiple pregnancy isregistered as one delivery.
Early neonatal death: death occurring within the firstseven days after delivery.
Ectopic pregnancy: a pregnancy in which implantationtakes place outside the uterine cavity.
xx
Embryo: product of conception from the time offertilization to the end of the embryonic stage eightweeks after fertilization (the term “pre-embryo” ordividing conceptus has been replaced by embryo).
Embryo donation: the transfer of an embryo resultingfrom gametes that did not originate from the recipientand/or her partner.
Embryo transfer (ET): procedure in which embryo(s)are placed in the uterus or fallopian tube.
Embryo transfer cycle: ART cycle in which one ormore embryos are transferred into the uterus orfallopian tube.
Fertilization: the penetration of the ovum by thespermatozoon and fusion of genetic materialsresulting in the development of a zygote.
Fetus: the product of conception starting fromcompletion of embryonic development (at eightcompleted weeks after fertilization) until birth orabortion.
Full-term birth: a birth that takes place at 37 or morecompleted weeks of gestational age. This includesboth live births and stillbirths.
Gamete intrafallopian transfer (GIFT): ART proce-dure in which both gametes (oocytes and sperm) aretransferred to the fallopian tubes.
Gestational age: age of an embryo or fetus calculatedby adding 14 days (2 weeks) to the number ofcompleted weeks since fertilization.
Gestational carrier: a woman in whom a pregnancyresulted from fertilization with third-party sperm andoocytes. She carries the pregnancy with the intentionor agreement that the offspring will be parented byone or both of the persons that produced the gametes.
Gestational sac: a fluid-filled structure containing anembryo that develops early in pregnancy usuallywithin the uterus.
Hatching: it is the process that precedes implantationby which an embryo at the blastocyst stage separatesfrom the zona pellucida.
Host uterus: see gestational carrier.
Implantation: the attachment and subsequent pene-tration by the zona-free blastocyst (usually in theendometrium) which starts five to seven daysfollowing fertilization.
In vitro fertilization (IVF): an ART procedure whichinvolves extracorporeal fertilization.
Infertility: failure to conceive after at least one yearof unprotected coitus.
Initiated cycles: ART treatment cycles in which thewoman receives ovarian stimulation, or monitoring inthe case of spontaneous cycles, irrespective ofwhether or not follicular aspiration is attempted.
Intracytoplasmatic (intracytoplasmic) sperm injec-tion (ICSI): IVF procedure in which a single spermato-zoon is injected through the zona pellucida into theoocyte.
Live birth: a birth in which a fetus is delivered withsigns of life after complete expulsion or extraction fromits mother, beyond 20 completed weeks of gestationalage. (Live births are counted as birth events, e.g. atwin or triplet live birth is counted as one birth event.)
Live-birth delivery rate: number of live-birth deliveriesexpressed per 100 initiated cycles, aspiration cyclesor embryo transfer cycles. When delivery rates aregiven, the denominator (initiated, aspirated or embryotransfer cycles) must be specified. It includesdeliveries that resulted in at least one live birth. Thedelivery of a singleton, twin or other multiple birth isregistered as one delivery.
Malformation rate: includes all structural, functional,genetic and chromosomal abnormalities identified inaborted tissue or diagnosed before or subsequent tobirth.
Medically assisted conception: conception broughtabout by noncoital conjunction of the gametes.Includes ART procedures and intrauterine, intra-cervical and intravaginal insemination with semen ofhusband/partner or donor.
Micromanipulation (also referred to as assisted fertili-zation): the use of special micromanipulative technol-
Glossary
xxi
ogy that allows operative procedures to be performedon the oocyte, sperm or embryo.
Microscopic epididymal sperm aspiration (MESA):procedure in which spermatozoa are obtained from theepididymis, by either aspiration or surgical excision.
Missed abortion: a clinical abortion where theproducts of conception are not expelled spon-taneously from the uterus.
Neonatal death: death within 28 days of birth.
Newborns or infants born: the number of live birthsplus stillbirths.
Oocyte donation: an ART procedure performed withthird-party oocytes.
Preclinical abortion: an abortion that takes placebefore clinical or ultrasound evidence of pregnancy.
Preclinical pregnancy (biochemical pregnancy):evidence of conception based only on biochemicaldata in the serum or urine before ultrasound evidenceof a gestational sac.
Preimplantation genetic diagnosis (PGD): screeningof cells from preimplantation embryos for thedetection of genetic and/or chromosomal disordersbefore embryo transfer.
Preterm birth: a birth which takes place after at least
20, but less than 37, completed weeks of gestation.This includes both live births and stillbirths. Birthsare counted as birth events (e.g. a twin or triplet livebirth is counted as one birth event).
Recipient: in an ART cycle refers to the woman whoreceives an oocyte or an embryo from another woman.
Spontaneous abortion: spontaneous loss of a clinicalpregnancy before 20 completed weeks of gestation or,if gestational age is unknown, a weight of 500 g or less.
Stillbirth: a birth in which the fetus does not exhibitany signs of life when completely removed or expelledfrom the birth canal at or above 20 completed weeksof gestation. Stillbirths are counted as birth events(e.g. a twin or triplet stillbirth is counted as one birthevent).
Surrogate mother: see gestational carrier.
Testicular sperm aspiration (TESA): procedure inwhich spermatozoa are obtained directly from thetesticle, by either aspiration or surgical excision oftesticular tissue.
Zygote intrafallopian transfer (ZIFT): procedure inwhich the zygote, in its pronuclear stage of deve-lopment, is transferred into the fallopian tube.
Zygote: is the diploid cell, resulting from the fertiliza-tion of an oocyte by a spermatozoon, which subse-quently develops into an embryo.
Glossary
This glossary was generated by the International Working Group for Registers on Assisted Reproduction and was furtherdeveloped and used during this meeting.
Current challenges in assisted reproduction 1
Introduction
Current challenges in assisted reproduction
MAHMOUD F. FATHALLA
And God blessed them, and God said untothem, Be fruitful, and multiply, and replenishthe earth and subdue it.
—Holy Bible: Genesis 1:28 (1)
Our human species is not exactly known for itswillingness to comply with divine instruction. Butwhen God said unto them “Be fruitful and multiply”,they were more than eager to comply. They took thetask to heart. They turned a duty into a pleasure. Themajority of couples had no problem. A minority,however, were distressed because of delay or inabilityto conceive and bring forth children. Medicine triedto help them to conceive naturally. There remained,however, a group who could not reproduce naturallywithout assistance.
When the first baby conceived in vitro was born(2), a completely new frontier was opened up inreproductive medicine, and new hope was given toinfertile couples. The new technology brought happi-ness and harmony to many families.
Since 1978, the field of assisted reproductivetechnology (ART) has witnessed spectacular scien-tific advances and additional medical applications.With the introduction of intracytoplasmic sperminjection (ICSI) (3), ART can now help infertilecouples with a male factor, a condition for whichresults of traditional treatment have not beensatisfactory. The potential of ART is now not limited
to infertile couples. It can help fertile couples as wellto conceive healthy children through the applicationof the new technologies of preimplantation geneticdiagnosis and embryo selection (4). Further into thefuture, ART allowed a much better understanding ofthe early stages of human development and differen-tiation, and opened up a new field of stem cell research,bringing a new hope for the treatment of certainserious diseases, for which no effective treatment iscurrently available (5).
With all these advances, challenges are still to befaced. There are challenges which scientists have todeal with. There are challenges to the health services.There are challenges for which the health profession,as a group, has to take responsibility. And last butnot least, society has to cope with new challengesbrought to the forefront by this technologicalrevolution and its social implications.
One challenge that cuts across all others is howto make ART more widely available and affordable forall who need it, particularly in developing countries.
We live in a world of rich cultural diversity. Thishas to be taken into account when these challengesare discussed.
Scientific challenges
Tremendous scientific progress has been made in the
4 MAHMOUD F. FATHALLA
field of assisted reproduction. Important challengesstill remain. Three of these challenges are worthy ofspecial mention.
Improving success rates
Success rates have so far been fairly constant, ataround 25% live births per cycle, until the age of 34years, when there is steep decline (6). This successrate sounds good enough. But it also means a failurerate of around 75%, that is distressing for those whowent through the financial and heavy psychologicalcost of the procedure.
Can we bring happiness to more couples? Or, canwe have better predictors of the outcome, to savethose unfortunate couples from going through theheavy burden of the procedure if they have no chanceof success?
There is room for improving the success rates ofassisted reproduction. Success rates have beenimproved by simply increasing the chances for implan-tation through transfer of more than one embryo tothe uterus. The drawback is an increased risk ofmultiple gestation. The introduction of better criteriafor embryo assessment and selection, before transfer,is likely to improve implantation rates. This will allowwider use of elective single embryo transfer. Recentadvances in molecular biology are also bringing newinsights into our understanding of the complex anddelicate mechanism of implantation, which again mayincrease the success rate of implantation (7).
Shortage of gametes
ART depends on the availability of an adequatenumber of healthy gametes to allow successfulmanipulation. Three approaches are currently beingpursued: increasing the production, cryopreservationand donation from a third party. The applicability andsuccess have been different for female and malegametes. Oocytes are scarce and are more difficult toobtain. But the ovary can be hyperstimulated to yieldenough ova. Sperm is normally more than plentiful infertile men, but can be very scarce in infertile men.There is, however, no way to increase the supply frominfertile men, though sperm can now be obtaineddirectly from the epididymis or testis. The relative easeand the success of cryopreservation of sperm andembryos contrast markedly with the problemsassociated with freezing of oocytes. Sperm donationhas been in use for decades. Oocyte donation is
possible, but is more difficult and raises differentconcerns. Shortage of gametes is still a challenge inART. More research is needed to develop innovativeapproaches.
Multiple gestation
Improving success rates and overcoming shortage ofgametes are important challenges on which scientistsneed to work. The pressing problem that challengesscientists is, however, the prevalence of multiplegestation, twins and higher-order births, as a resultof assisted reproduction.
A world collaborative report on in vitro fertiliza-tion (IVF) recorded a multiple birth rate of 29%, themajority of which are twins (8) . The large scaleSwedish retrospective cohort study reported a 20-foldincreased risk of multiple pregnancy following ARTcompared with the general population (9) . Withincreasing resort to and utilization of assistedreproduction, we may soon be facing a public healthproblem.
Regardless of whether they originate from assistedor nonassisted reproduction, multiple gestation isassociated with an increased risk of preterm delivery,low birth weight, congenital malformations, fetal andinfant deaths and long-term morbidity and mortalityas survivors (10).
The risks of multiple gestation are often expressedin terms of perinatal and infant morbidity and mortality.The impact on the woman often takes second placeor is completely ignored. First, there are the compli-cations of pregnancy and labour that are morefrequently encountered with multiple gestation.Second, there is the psychosocial impact (includingthe impact of multifetal pregnancy reduction) and theheavy burden on the mother of caring for more thanone immature baby. Third, perinatal morbidity andmortality should be appropriately counted as part ofthe burden of disease on women, rather than on thechild, as it is often counted. It is women who havemade a major investment of themselves in thepregnancy, and who have the responsibility of caringfor a disabled baby.
Controlled ovarian hyperstimulation and intra-uterine insemination (IUI) and transferring multipleembryos account for the high incidence of multiplegestation. Controlled ovarian hyperstimulation withIUI is associated with the higher orders of multiplepregnancy. Transferring multiple embryos is astandard practice to increase the chances of success.
Current challenges in assisted reproduction 5
Monozygotic twinning has been reported to be higherfollowing assisted reproduction (11).
Health service challenges
The introduction of assisted reproduction in main-stream medical practice posed a number of challengesto health care services, particularly in relativelyresource-poor settings. Three such challenges facehealth administrators and policy-makers: deciding onwhat resources can be allocated to ART services,defining who can have access to such services, andstriking the right balance between investment inprevention and in cure.
Equitable allocation of resources
And when Rachel saw that she bare Jacobno children, Rachel envied her sister; andsaid unto Jacob, Give me children or else Idie.—Holy Bible: Genesis: 30:1 (1)
Infertility is not a disease. In fact, in many cases ofinfertility no evidence of any disease may be found.Per se, infertility does not threaten life or endangerphysical health. But this is not how we define health.Health, as defined in the constitution of the WorldHealth Organization, is not merely the absence ofdisease or infirmity. It is a state of complete physical,mental and social well-being. Patients do perceive thesuffering from infertility as very real.
With the population problem on our hands, is itappropriate that we continue to worry about theproblem of infertility? The answer is that we shouldworry even more. The adoption of a small family norm,through voluntary infertility, which is a desired targetat country and at global levels, makes the issue ofinvoluntary infertility more pressing. If couples areurged to postpone and to widely space pregnancies,it is imperative that they should be helped to achievea pregnancy when they so decide, in the more limitedtime they have available.
Resources are finite. Allocation of relativelyscarce resources is difficult. There is always an oppor-tunity cost. If resources are used for one purpose, theopportunity is lost for using the same resources todeal with another important disease condition. TheWorld Bank attempted to prioritize health problems onthe basis of a quantitative assessment of thedisability-adjusted life years (DALYs) lost as a result
of the health problem (12). The problem is in thedefinition of disability. The World Bank study triedto quantify disability from a disease condition bymultiplying the expected duration of the condition (toremission or to death) by a severity weight thatmeasured the severity of the disability in comparisonwith loss of life. Diseases were grouped into sixclasses of severity of disability. The World Bank reportInvesting in health published tables quantifying theburden of disease in females by cause. In a list of 96causes, infertility is conspicuous by its absence.
If DALYs are substituted with QUALYs (quality-adjusted life years), the priority ranking of healthproblems will differ. If ranking is based, not just onthe basis of productivity loss but on how peopleperceive the disability, infertility will rank high on thelist. The physical and psychological burden theinfertile couples are willing to go through, and thefinancial cost couples are willing to pay if they canafford it, attest to the high ranking of infertility as aperceived burden of disease.
Access to services
The States Parties to the present Conventionrecognize the right of everyone to the enjoy-ment of the highest attainable standard ofphysical and mental health.
The States Parties to the present Conven-tion recognize the right of everyone . . . toenjoy the benefits of scientific progress andits applications.
—International Covenant on Economic,Social and Cultural Rights,
Article 12. 1; 15.1.b (13)
The Human Rights Treaty, the International Covenanton Economic, Social and Cultural Rights (known asthe Economic Covenant) (13), adopted by the UnitedNations General Assembly in December 1966, andentered into force in January 1976, recognized the rightof everyone to enjoy the benefits of scientific progressand its applications, and the right of everyone toenjoy the highest standard of physical and mentalhealth.
In its general comment 14, the United NationsCommittee on Economic, Social and Cultural Rightsexpanded on the right to health, stating that: “The rightto health is not to be understood as a right to behealthy. The right to health contains both freedomsand entitlements” (14).
6 MAHMOUD F. FATHALLA
Entitlements depend on the availability ofresources from public funding. There is a legitimateneed to rationalize the allocation of scarce resources.The important point is that resources are allocatedwith equity and transparency, with more to those whoare more in need.
Freedoms in the pursuit of the right to healthmeans that people are not denied access to services.In the area of assisted reproduction, access to servicesis often restricted, legally or medically, in one way oranother. This raises human rights concerns. Anyrestrictions on access have to be justifiable anddefensible, and have to be shown as not violatingpeople’s human right to health.
In some countries, access to ART is often limitedto certain procedures or to certain consumers. Thefollowing procedures are subject to restrictions incertain countries: sperm donation, ovum donation,embryo donation and surrogacy. Restriction may beabsolute or related to commercialization of theseprocedures. Preimplantation genetic manipulation andselection is also subject to certain restrictions.
Certain consumers are denied access to assistedreproduction for widely different reasons. Theseinclude single women, lesbians and homosexualcouples. A concept of fitness to parent is sometimesinvoked, including no outstanding criminal charges,no history of an offense that was sexual or violent innature, and no disease or disability which couldinterfere with the capacity to parent. Assistedreproduction has been denied to women with HIVinfection, on the basis of concern over the lifeexpectancy of the infected parent and the risk of viraltransmission to the offspring. This has recently beenchallenged (15). The best interest of the child is oftenmade as an argument. The implication is that it maybe in the best interest of the child not to be born at all.
Because of the inconsistency of restrictiveregulations in different countries, the situation inviteswhat may be called “reproductive tourism”. This hasbeen a topic that attracted media attention in Europe,such as the following recent extensive report inL’Hebdo magazine (16) :
La quête du bébé a tout prixEn Europe, le paysage des pratiques et deslois sur la PMA (Procréation médicalementassistée) est bien contrasté. Cette situationencourage, de façon modeste, un tourismeprocréatif des pays les plus réglementés versles pays les plus libéraux.
Balance between preventive and curativeservices
The allocation of resources does not only depend onthe magnitude and severity of a health problem. It alsodepends on the availability of cost-effective inter-ventions. Health services need to balance theutilization of their resources between preventive andcurative services. Preventive services may be morecost-effective and benefit more people than expensivecurative services. In a sense, assisted reproductionis not a curative treatment. The couple remains infertileafter the success of the procedure. Prevention ofinfertility, particularly infection-related infertility,should not be ignored in the enthusiasm for assistedreproduction. Prevention of sexually transmittedinfections, particularly among adolescents, may savetheir fertility potential. Sexually active adolescent girlsare appropriately advised to use the condom if theywant to have a child in the future. It should berecognized, however, that infertility is not alwayspreventable. Preventive services will also not help themany couples who already suffer from the problem.
Professional challenges
The introduction of assisted reproduction as a noveltechnology poses a number of significant challengesfor the health profession as a whole. The professionis challenged to ensure transparency about theoutcome and risks of these new procedures. Theprofession is challenged to assume the role of self-regulation and to provide quality control. The profes-sion has a responsibility to put proper surveillance inplace as a follow-up after the introduction of thesecompletely novel technologies. Last, but not least, thehealth profession is challenged to partner withconsumers, and not to deal with them as passiverecipients.
Transparency
As with many other novel technologies in medicine,unjustified claims can be made by enthusiasts of newprocedures. This does not mean that they may presentfalse data. However, data can be presented in waysthat can be misleading to potential clients. Random-ized, double-blind, controlled trials are difficult todesign in this field except to compare certainmodifications or changes in the procedure. One of the
Current challenges in assisted reproduction 7
professional challenges is to ensure that benefits andrisks are presented in an objective and transparentway that allows potential consumers to make informeddecisions.
Success of assisted reproduction procedures hasvariously been reported as a positive beta-hCG test14 days after treatment, ultrasound diagnosis of agestation sac, pulsating heart on ultrasound examina-tion, or a take-home baby. Success has been expressedper transfer or per cycle commenced.
A standardized way of presenting results is oftenadvocated, but it can also be misleading if used tocompare the performance in different centres withouttaking into consideration variables that may influencethe outcome. The selection of clients influences thesuccess rate. Success can be expected to be higher inyounger women. Success is also generally higher inthe first cycles, and so may be higher in centresreceiving more new clients. The procedure used alsoinfluences the success rate. Ovarian hyperstimulationand transfer of more than one embryo carry a highersuccess rate, but also a higher risk of multiplepregnancy.
When results of different centres are compiled andpublished by professional bodies, lack of anonymitymay influence centres to project their publishedresults in a more positive light. Anonymity andcollective analysis and presentation of the results isan alternative that would still be helpful to potentialclients.
Self-regulation
Medical and surgical procedures are more difficult toregulate than new drugs or new devices. New drugsand devices are subjected to vigorous testing inanimals and in human volunteers before they arefinally approved for general medical use, for specificindications and under specific instructions.
The challenge to the profession is to take over thisresponsibility. The experience with ReproductiveTechnology Accreditation Committees in Australiahas demonstrated that self-regulation can work.Committees accredit practitioners who are qualified toperform the procedures and have adequate facilitiesto perform them. They also try to ensure that theaccredited centres maintain the quality of theirservices and regularly report their results in anobjective, unbiased way.
Benefits of self-regulation include its flexibility. Itcan respond to new developments in a rapidly
advancing field. If the profession does not fulfil thisresponsibility, it is likely that law-makers or policy-makers may be persuaded by the public to imposeregulation, which may restrict access and hinderprogress.
Surveillance
Although scientists, regulatory authorities andservice providers all do their best to ensure that drugsand devices are safe for the consumers before theyare introduced, postmarketing surveillance hasbecome an established practice and a professionalresponsibility. It is only through surveillance that rareevents and distant events can be discovered.Methodologies for surveillance are well established.They include systematic reporting of adverse effects,case–control studies and longitudinal cohort studiesin which subjects and matched controls are followedfor years.
The same principles should apply to new medicalprocedures. In the field of assisted reproduction,surveillance presents the profession with new anddifferent challenges, in terms of methodology and interms of targets. The methodology should not belimited to medical surveillance, but has to includepsychosocial studies. Also, the follow-up has to belong term, and not just short term. The targets forsurveillance should include not only the child, butalso the woman and the family.
The child
The follow-up of babies is not to be confined to theshort-term health consequences of mortality, morbidityand clinically recognizable congenital anomalies.Follow-up is needed to provide assurance of psycho-logical and mental development. Follow-up is neededto continue for the period of adolescent development.Surveillance is still needed to ensure potential futurefertility. The direct injection of a single spermatozooninto the mature oocyte eliminates the process ofnatural sperm selection. Of particular concern is thefuture fertility of babies born to infertile men after thisICSI procedure. The finding that hypospadias is morefrequent in ICSI children may be related to paternalsubfertility with a genetic background (17).
8 MAHMOUD F. FATHALLA
Women
Controlled ovarian hyperstimulation is a standardcomponent of assisted reproduction, to ensure anadequate supply of oocytes. Women exposed toovarian hyperstimulation need to be followed up toensure that they will not be exposed to an increasedrisk of epithelial ovarian cancer. Incessant ovulationhas been postulated as a factor in the pathogenesisof common epithelial ovarian tumours (18). Thesurface epithelium of the ovary is subjected to traumaat every occurrence of ovulation. The repair processinvolves repeated cell division with an increasedchance for DNA damage. The protective effect of oralcontraceptive use lent support to this hypothesis.Bamford and Steele (19) reported the first case ofovarian carcinoma in a patient receiving gonado-trophin therapy. Some studies have shown thatinfertile women using infertility drugs are three timesmore at risk for invasive ovarian cancer than womenwithout history of infertility (20) . A cohort studyreported a relative risk of 11.1 (confidence interval [CI]1.5 to 82.3) for women who received clomiphene for12 or more monthly cycles (21). It may also be notedthat assisted reproduction not only involves excessiveovulation, but also repeated minor trauma for ovumpick-up.
The jury is still out on the risk of ovarian cancer inwomen who are superovulated. Some studies havebeen reassuring (22,23). Large prospective andretrospective studies will be necessary before the riskcan be excluded (24).
Families
Families need to be followed up for the impact ofassisted reproduction, particularly if assisted repro-duction involves a third party in the way of gamete orembryo donation. Questions can be raised as towhether parenting in these families is different fromparenting in families with natural reproduction.Surveillance should include the quality of parenting,family functioning and child psychological develop-ment (25).
Surveillance, particularly its psychosocialcomponent, needs to be carried out in different regionsof the world. It is quite possible that the psychosocialoutcome of assisted reproduction may be influencedby the cultural context in which the technologies areused.
Consumers as partners and not passiverecipients
Dealing with consumers as partners and not aspassive recipients is not always easy for the medicalprofession. The profession has to adopt new atti-tudes, and has to abandon a lot of strongly entrenchedpatronizing attitudes. Partnership between consumersand providers is needed at three levels. At the levelof the individual patient–doctor relationship, it meansthe active participation of the infertile couple in makingthe decisions about treatment. To make informeddecisions, consumers are entitled to factual andobjective information about all alternatives. Theyshould know the chances of success, and the risksinvolved.
At the level of the profession as a group, there isa need for a constructive dialogue with consumergroups in which both sides can listen to each otherand talk to each other. Mutual trust is crucial to build.Consumer groups can be represented on appropriatescientific and professional committees. The WHOSpecial Programme of Research, Development andResearch Training in Human Reproduction realized theneed for this dialogue and convened, in collaborationwith the International Women’s Health Coalition, ameeting that included both women’s health advocatesand scientists. The report of the meeting waspublished under the title Creating common ground(26). This was followed by a series of regionalmeetings, and by institutionalizing the participationof consumers in the advisory bodies of the Programme.
At a third and equally important level, there ispower in partnership and this power can be used inadvocacy. In the late 1980s, a coalition of consumersand physicians successfully lobbied the Australianfederal government for recognition of fertility as amedical condition and for reimbursement for ARTtreatment.
Social challenges
Assisted reproduction introduced a number ofchallenges with which society has to cope. Threechallenges need to be addressed. The first challengeis rather generic: the public trust in science. Thesecond challenge is specific to human reproduction:ethical and cultural concerns. The third challenge isthat assisted reproduction has brought the issue ofgender to the forefront, and society is being
Current challenges in assisted reproduction 9
challenged to re-think the way it views the role ofwomen.
Public trust in science
In recent years, a question often crops up in thepublic mind and in public media: Is science a solutionor a problem?
There are probably more scientists alive andworking today than all scientists who have livedthroughout human history. Scientists never imaginedthat they would be able to explore the new frontiersof science that have now opened up. On the positiveside, the promise of science to improve the quality oflife has never been so great. On the negative side,there are unmistakable signs of public mistrust. Thearea of assisted reproduction is one such area, wherescience is rapidly advancing and public mistrust isalso growing. Scientists are suspected of trying to playGod, and to mess in what has always been God’s act:procreation.
Public mistrust in science can result in givingscience a bad image, can endanger the flow of publicfunding for science, and is likely to raise pressure toenact restrictive regulation, which impedes theutilization of the fruits of science or impedes thefurther progress of science.
What can scientists do to help build and maintainpublic trust in science?
First, scientists need to engage the public in aninformed debate. This involves more than just makingscientific information freely available. The role ofscientists is no longer to preach enlightenment to theignorant masses. The role of scientists is to presentthe case objectively to an enlightened citizen jury toallow them to make an informed judgement. Scientistsmust accept that they are no more qualified than thegeneral public to make value judgements as to the usesto which science shall be put.
Second, scientists should avoid giving the publica perception of being arrogant. Time and again, thelimits of science are being exposed. With the recentcrisis of the bovine spongiform encephalopathy (madcow disease), people may feel justified if theyquestion whether they can really trust scientists withtheir supper.
Third, scientists should be careful in communi-cating scientific data to the public media. The media,in its presentation of science, aims first to engage andentertain, and only second to inform. Scientists shouldresist the temptation of publicity.
Cultural and ethical concerns
No society, primitive or advanced, no culture, noreligion, and no legal code has been neutral aboutreproductive life. Even in societies which do notinterfere with fertile individuals making reproductivedecisions, infertile couples are often subject to publicattention and scrutiny. In addition, assisted reproduc-tion has brought new issues to the forefront. Societalinstitutions have been slow to cope with the newdevelopments.
Cultural and ethical concerns cannot be lumpedall in one basket. First, there is what may be called“moral panic” reaction. On a completely differentlevel, there are concerns based on ideology andreligious belief. Third, there are concerns based onutilitarian considerations.
The term “moral panic” describes the reactionwhen traditional moral beliefs about the family andreproduction appear to be threatened by perceiveddangers. The reaction is often unjustified or exag-gerated. This may be a transient phase before theprocedures get accepted. The reaction tends to movefrom horrified negation to negation without horror,then gradual understanding and finally a slow but finalacceptance. Included in this moral panic is the fear ofa “slippery path”—if science is not reined in now, itwill cross red lines in the future.
Concerns based on ideology and religious beliefinclude the status of the embryo as a person, withinterests and rights, in the Catholic religion. Theyinclude also the sanctity of the family’s geneticlineage in Islamic faith. Ideological concerns areentitled to respect, but cannot be forced on others whodo not uphold them.
Ethical concerns, based on utilitarian principles,are about what is best for society and what is in thebest interests of the child. Different conclusions canbe reached through different ethical approaches andare generally tolerated. One example is the concernabout donation of human gametes and embryos.People may accept such procedures if there are nocommercial transactions involved, or if payment is notconsidered for a commodity but for a servicetransaction.
In principle, societies have had to cope with tworevolutionary concepts in human reproduction:separation of sex from reproduction, and reproductionwith involvement of a third party.
10 MAHMOUD F. FATHALLA
Separation of sex from reproduction
Sex without reproduction
The controversy about contraception may now belargely something of the past, but the days are stillremembered when there was a moral outrage andstrong opposition on ideological grounds. WhenMargaret Sanger, her sister Ethel, and a social workerFania, opened the first contraceptive clinic inBrooklyn, the clinic was soon raided and the threewomen arrested (27) . Released on bail, they promptlyreopened the clinic and were arrested again andcharged with maintaining a public nuisance. TheRoman Catholic Church still rejects any acts thatseparate the procreative aspects of human intercoursefrom the unitive love-making aspect of the sexual act.But contraception has become a way of life. In theworld, as a whole, it has been estimated that about58% of couples in the reproductive age group arecurrently using contraception, to separate the sex actfrom the act of procreation, with a range between 55%in less developed regions and 70% in more developedregions (28).
Reproduction without sex
The other side of the coin, reproduction without sex,is relatively more recent, with the introduction ofassisted reproduction. There was less moral outrageprobably because it responded to a limited need ofinfertile couples, it did not contradict pronatalistattitudes, and particularly that it allowed infertile men,and not only women to reproduce. Controversy arosewith the expansion of applications that allowedreproduction outside the social frame of a traditionallymarried man and woman.
Reproduction with the involvement ofa third party
And she said, Behold my maid Bil-hah, go inunto her, and she shall bear upon my knees,that I may also have children by her.
—Holy Bible: Genesis 30:3 (1)
Gamete and embryo donation raised more ethical andcultural concerns. The act of reproduction is an actof a couple; a third party is considered one too many.Partial surrogacy is mentioned in the old testament.
Illicit relationships of married partners exist and havebeen more tolerated than assisted reproduction withdonation of gametes.
Gender issues
Sex is biologically determined; gender is a socialconstruct. Gender is related to how we are perceivedand expected to think and act as women and menbecause of the way society is organized, not becauseof our biological differences.
Responsibility for infertility is commonly sharedby the couple. Analysis of data compiled in a largeWHO multinational study showed that a major factorin the female with no demonstrable cause in the malewas diagnosed in only 12.8% of cases, and a majorfactor in the male with no demonstrable cause in thefemale was diagnosed in only 7.5% of cases (29). Forbiological and social reasons, however, the burden ofinfertility is unequally shared.
The psychological and social burden of infertilityin most societies is much heavier on the woman. Awoman’s status is often identified with her fertility, andfailure to have children can be seen as a social disgraceor a cause for divorce. The suffering of the infertilewoman can be very real.
The burden and risks of assisted reproduction areby no means equally shared between men and women.Women bear the physical and psychological burden.The incidence of severe ovarian hyperstimulationsyndrome has been estimated at 0.2%–1% of allassisted conception cycles (30). The burden ofassisted reproduction for male infertility falls largelyon the woman. It has been reported that 27% of ARTin the UK is carried out for severe male infertility (31).
The noble task of reproducing our species has notbrought societal awards to women. On the contrary,it has often led to their subordination. Women insociety are subject to both pronatalist and paternalistattitudes. The introduction of assisted reproductionis a challenge to societies to re-examine these attitudes.
Pronatalist attitudes
But first we must ask: what is a woman? ‘Totamulier in utero’, says one, ‘woman is awomb’.—Simone de Beauvoir (32)
Women have been identified with their role as mothers.A woman is reduced to a mobile womb walking on two
Current challenges in assisted reproduction 11
legs, and with a human face on top. In many societieswomen are coerced to be mothers. The Declaration ofNicolae Ceausescu that the fetus is the socialistproperty of the whole society, that giving birth is apatriotic duty, determining the fate of the country, andthat those who refuse to have children are deserters,escaping the law of natural continuity, may have beenan extreme example of coerced motherhood (33) . Butcoerced motherhood or “compulsory” childbearing,broadly defined, is a major problem in the world today.It does not take place by directly forcing women to bemothers. Women are coerced into childbearing whenthey are denied the choice, when they are denied themeans to avoid unwanted pregnancy, and whensociety makes children the only goods a woman candeliver and is expected to deliver. In many societiesin the world today, women are left with no choice inlife except to pursue a reproductive career. It is a validquestion to ask whether women resort to assistedreproduction of their own free will, or whether theyare being coerced by society to be mothers.
Paternalist attitudes
A woman can claim as her own her head, her hair, herhands, her arms, her upper body, her legs and her feet.She cannot claim the same right to the remaining areaof her body, which appears to belong more to certainmales of the species, moralists, politicians, lawyersand others, all of whom try to decide on how the areais best utilized.
The paternalistic attitude towards women restrictstheir reproductive freedom in natural reproduction.Women in need of assisted reproduction are evenmore subject to paternalistic subjective decisions.Decisions, which women can make and should be ableto make, are often made on their behalf by others.Because of the subordination of women, societies maysee fit to make decisions on who should be mothersand who should not. This does not have a parallelabout who should be a father and who should not.Egg donation is treated differently from spermdonation. A postmenopausal woman is treateddifferently from an elderly man, or a man with a diseasewhich may shorten the lifespan.
The challenges and the reward
The challenges to assisted reproduction cannot beunderestimated. But the reward is also great. What
reward can be better than a happy mother, a proudfather, a healthy child and a harmonious family?
References
1. Holy Bible. Genesis 1:28: 30:1.2. Steptoe PC, Edwards RG. Birth after the reimplantation
of a human embryo. Lancet, 1978, 366.3. Palermo G et al. Pregnancies after intracytoplasmic
injection of single spermatozoon into an oocyte.Lancet , 1992, 340 :17–18.
4. Handyside AH et al . Pregnancies from biopsied humanpreimplantation embryo sexed by Y-specific DNAamplification. Nature , 1990, 344 :768–770.
5. Reubinoff BE et al. Embryonic stem cell lines fromhuman blastocysts: somatic differentiation in vitro.Nature Biotechnology, 2000, 18:399–404.
6. Society for Assisted Reproductive Technology and TheAmerican Society for Reproductive Medicine, AssistedReproductive Technology in the United States andCanada: 1995 results generated from the AmericanSociety for Reproductive Medicine/Society for AssistedReproductive Technology Registry . Fer tility andSterility, 1998, 69:389–398.
7. Cooke ID, Lim KJH. Implantation. In: O’Brien PMS,ed. The year book of obstetrics and gynaecology .London, RCOG Press, 2000, 8:206–222.
8. de Mouzon J, Lancaster P. World Collaborative reporton in-vitro fertilization. Preliminary data for 1995.Journal of Assisted Reproduction and Genetics, 1997,14:S251–S265.
9. Bergh T et al. Deliveries and children born after in-vitro fertilization in Sweden 1982–95: a retrospectivecohort study. Lancet, 1999, 354 :1579–1585.
10. Olivennes F. Avoiding multiple pregnancies in ART.Double trouble: yes a twin pregnancy is an adverseoutcome. Human Reproduction, 2000, 15:1663–1665.
11. Edwards RJ, Mettler L, Walter DE. Identical twins andin-vitro fertilization. Journal of In Vitro Fer tilisationand Embryo Transfer, 1986, 3:114–117.
12. World Bank. World Development Repor t: investing inhealth. New York, Oxford University Press, 1993:215.
13. International Covenant on Economic, Social, andCultural Rights. Adopted and opened for signature,ratification, and accession by United Nations GeneralAssembly Resolution 2200 A (XXI) on 16 December1966. Entered into force on 3 January 1976 inaccordance with article 27.
14. Committee on Economic, Social and Cultural Rights,General Comment 14: The right to the highestattainable standard of health (Article 12). CESCR,General Comment 14, United Nations Document E/C.12/2000/4. 11 August 2000.
15. Gilling-Smith C, Smith JR, Semprini AE. HIV andinfertility: time to treat [Editorial]. Lancet, 2001,322 :566–567.
12 MAHMOUD F. FATHALLA
16. L’Hebdo. La quête du bébé a tout prix. No 26. Semainedu 28 Juin 2001, 38–45.
17. Ericson A, Kallen B. Congenital malformations ininfants born after IVF: a population-based study. HumanReproduction, 2001, 16:504–509.
18. Fathalla MF. Incessant ovulation—a factor in ovarianneoplasia? Lancet, 1971:163.
19. Bamford PN, Steele SJ. Uterine and ovarian carcinomain a patient receiving gonadotrophin therapy. BritishJournal of Obstetrics and Gynaecology, 1992, 89:962–964.
20. Whittemore AS, Harris R, Intyre J. The CollaborativeOvarian Cancer Group. Characteristics relating toovarian cancer risk: collaborative analysis of 12 U.S.case-control studies. II. Invasive epithelial ovariancancers in white women. American Journal ofEpidemiology, 1992, 136:1184–1203.
21. Rossing MA et al. Ovarian tumours in a cohort ofinfertile women. New England Journal of Medicine,1994, 331 :771–776.
22. Venn A et al. Risk of cancer after use of fertility drugswith in-vitro fertilization. Lancet, 1999, 354 :1586–1590.
23. Artini PG et al . Fertility drugs and ovarian cancer.Gynecology and Endocrinology, 1997, 11:59–68.
24. Glud E et al. Fertility drugs and ovarian cancer.Epidemiology Review, 1998, 20:237–257.
25. Hahn C, Di Pietro JA. In-vitro fertilization and thefamily: quality of parenting, family functioning and
child psychological adjustment. DevelopmentalPsychology, 2001, 37:37–48.
26. Creating common ground. Report of a meeting betweenwomen’s health advocates and scientists. Geneva, WorldHealth Organization, 1991 (WHO/HRP/ITT/91).
27. Sutters B. Be brave and angry. London, InternationalPlanned Parenthood Federation, 1973:5.
28. United Nations (1999) World Contraceptive Use 1998Data sheet. United Nations, Department of Economicand Social Affairs, Population Division, New York.United Nations Publication (ST/ESA/SER.A/175) SalesNo. E.99.XIII.4-ISBN 92-1-151330-8.
29. Farley TMM. The WHO standardized investigation ofthe infertile couple. In: Ratnam SS, Teoh E-S,Anandakumar C, eds. Infertility Male and Female. TheProceedings of the World Congress on Fertility andSterility, Singapore, October 1986, 4:123. Lancaster,Parthenon Publishing Group, 1986.
30. Smitz J et al. Incidence of severe ovarian hyper-stimulation syndrome after GnRH agonist/hMGsuperovulation for in vitro fertilization. HumanReproduction, 1990, 5:933–937.
31. Human Fertilization and Embryology Authority. HEFAAnnual Report 1999. London, HEFA, 1999.
32. Beauvoir S de. The second sex. London, Pan Books,1949.
33. Hord C et al. Reproductive health in Romania: reversingthe Ceausescu legacy. Studies in Family Planning, 1991,22:231–240.
Section 1
Infertility and assisted reproductive technologiesin the developing world
Infertility and social suffering: the case of ARTin developing countries
ABDALLAH S. DAAR, ZARA MERALI
Introduction
While the prevalence of infertility in developingcountries is difficult to assess given inconsistenciesin defining infertility, between 8% and 12% of couplesaround the world have difficulty conceiving a child atsome point in their lives, “thus affecting 50 to 80 millionpeople”(1) . In some areas, particularly in sub-SaharanAfrica, up to one-third of couples are infertile (2).Throughout the world, the core prevalence of infertilityis about 5%, attributable to anatomical, genetic,endocrinological and immunological problems (3).Between countries and regions, infertility rates varydramatically, corresponding to the incidence ofpreventable conditions that lead to infertility. Whilewomen’s infertility is the greater focus of research,health care attention, and social blame, male infertilityis the cause or contributing factor to infertility inapproximately half of infertile couples (2).
Infertility in developing countries raises distinctand complex problems beyond those well known todeveloped nations. The effects of infertility and theconcomitant need for its health care managementrelate to the cultural realities of specific regions.
While the relevance and need for assistedreproductive technologies (ART) may be readilyestablished, some challenge their use in developingnations. This criticism is levelled on two grounds.First, given the overpopulation problem in many
developing countries, it is argued that overfertility,rather than infertility, should be the focus of familyplanning programmes. Second, treating infertilitythrough expensive ART cannot be justified in lowresource settings where other more pressing needsmust be given priority.
From an analysis of the suffering that arises frominfertility, these criticisms of the use of ART indeveloping countries can be rebutted. Infertility indeveloping countries is pervasive and a seriousconcern. Further, there is evidence that the infertilityrates that are generally quoted are, in fact, under-estimates. The consequences of infertility indeveloping countries range from severe economicdeprivation, to social isolation, to murder and suicide.It is suggested that the overpopulation and limitedresource arguments falsely target ART and lack a morecomprehensive understanding of the public health,social, psychological, economic, political and moralissues that are involved.
Infertility is a major problem in developingcountries
In poor resource areas and in developing countries,the need for infertility treatment in general, and ARTin particular, is great. These rates vary dramaticallybetween and within most countries. In particular ,
16 ABDALLAH S. DAAR, ZARA MERALI
Africa records some of the highest infertility rates inthe world, mainly secondary infertility (Figure 1).
Secondary infertility is especially problematic inAfrica and Latin America. Noninfection-relatedinfertility is difficult to resolve without even somesimple form of ART. The impact of sexually transmitteddiseases (STDs) or reproductive tract infections thatare frequently the cause of secondary infertility maybe devastating. For example, Swinton et al. (5) arguethat a 20% incidence of untreated gonorrhoea insexually active adults may lead to a 50% reduction inpopulation growth due to the resulting infertility.
More so than in Africa, there is a lack of data onthe problem of infertility in Asia. Analysing infertilityin Asia is further complicated by first, the diversecultural, ethnic, and religious groups representedthroughout the region; and second, the widediscrepancies in public policy. In Asia, as with Africa,infertility is treated as an ancillary issue to over-population. India, in particular, has paid little attentionto infertility given that it is wrongly assumed to be acondition that does not threaten life. Rather, India’spolicy has focused on managing population size.
Notwithstanding the high rates of infertility indeveloping countries, there are substantial reasonsto think that these rates are underestimates. Manyanalyses of the prevalence of infertility in developingcountries are based on fertility data. The WHO 1991study (1) on infertility underscores the inherentlimitations in demographic studies that provide onlyan indirect indicator of primary infertility and animprecise indicator of secondary infertility. Moreover,divergent cultural understandings of motherhood orsevere social stigmatization associated with infertilitybias data, creating a subcategory of hidden infertility.
Figure 1. Comparison of primary and secondary infertlity according to regionsSource: Cates et al. (1985) (4)
The methods used in collecting, recording andanalysing data on infertility in contexts where severesocial harms persist around infertility should becritically examined.
Infertility has severe social consequences indeveloping countries
Infertility in developing countries extends beyond theloss of human potential and unrealized self. Theexperience of infertility causes harsh, poignant andunique difficulties: economic hardship, social stigmaand blame, social isolation and alienation, guilt, fear,loss of social status, helplessness and, in some cases,violence (6–13) . Many families in developingcountries depend on children for economic survival.Without children, men and women may starve to death,especially in old age. In some communities, infertilepeople are ostracized as they are perceived to beunlucky or the source of evil, or they become theobject of public humiliation and shame. Some, even,choose suicide over the torturous life and mentalanguish caused by infertility. In other communitiesinfertile men and women are often denied proper deathrites. For women in developing countries, infertilitymay occasion life-threatening physical as well aspsychological violence (11,12). Childless women aregenerally blamed for their infertility, despite the factthat male factor causes contribute to at least half ofthe cases of infertility around the world. In developingcountries, especially, motherhood is often the onlyway for women to enhance their status within thefamily and community.
In Asia, being childless has more negative social,
0%
20%
40%
60%
80%
100%
Africa Asia Latin America DevelopedNations
Primary infertility (%) Secondary infertility (%)
Infer tility and social suffer ing: the case of ART in developing countr ies 17
cultural and emotional repercussions for women than,perhaps, any other non life-threatening condition. Aninfertility study in Andhra Pradesh, India, reportedthat approximately 70% of women who experiencedinfertility would be punished for their “failure”through physical violence. Nearly 20% of the womenreported that their husbands used severe violence asa result of their childlessness (12).
Much less published research is available on theconsequences of infertility in Latin America. Fromwhat we do know, communal families are common-place. That is, children are integral to families’ prestige,honour, and happiness. Children are often cared forby multiple, extended family members, which makeshaving children central to family life. Thus couplessuffer extreme emotional and psychological stressover infertility. In certain parts of Latin America,including Mexico, children are an important part of thefamilies’ economic prosperity and survival. The roleof children for economic survival is a recurring themethroughout developing countries. There is a lack ofresearch on the consequences of infertility for womenin Latin America. However, anecdotal sources indicatethat violence in relation to infertility is not common inLatin America.
The World Health Organization defines health as“a state of complete physical, mental and social well-being, and not merely the absence of disease orinfirmity.” By this definition, infertility is a major causeof diminished health in developing countries. Indeed,few health conditions could more profoundly orpervasively affect a person’s well-being in manydeveloping countries than infertility. For whensomeone presents with infertility, he or she is oftendenied voice or advocacy, he or she does not haverecourse to therapy, and he or she is blamed for theinfertility. Couple infertility is used against the afflictedcouple, or exclusively against the woman, as ajustification for social isolation, abuse, violence,indignities, physical and mental torture, and some-times murder. Infertility not only infringes upon thehuman right to health, it often leads to a violation ofthe most basic moral protections that are intrinsic tohumanity itself.
We propose a continuum to categorize the harminflicted by infertility and to demonstrate the increas-ing severity of social suffering (Figure 2). Thiscontinuum illuminates the multiplicity of harms thatfollow infertility, and it underscores the severity ofsocial suffering characteristic of infertile people indeveloping countries.
In developed countries, the consequences ofinfertility rarely extend beyond level two; in deve-loping countries, at least in Asia and Africa, theconsequences of infertility are infrequently as mild aslevel three. Thus the very nature, severity and impactof infertility harms in developing countries differsignificantly from those found in developed nations.A significant difference between the two contexts isthe availability of and access to infertility treatments,especially ART.
Infertility must become a social priority
While accurate figures are difficult to obtain, there islittle doubt that access to ART is extremely limited inall developing nations. Accurate information on theper capita availability and regional accessibility ofinfertility treatments needs to be collected. Evenaccess to infertility information is severely limited indeveloping countries. While access to ART isextremely rare, the cost is even more prohibitive.However, there are differences between regions thatsuggest promising alternatives for improving theaccess and affordability of ART.
Assisted reproductive technologies are embeddedin a global background of high fertility, over-population, and population control. According to thetheory of economic modernization (14), many low-resource nations fail to achieve development basedon their population size. In a demographic discourse,the overly populous character of developing nationsequate with poor performance and retarded develop-ment. Hence, there is a failure to make infertility aresearch or treatment priority and acknowledge it as apublic health issue.
Moreover, the overpopulation discourse and lackof social focus on infertility exacerbates women’sinequitable treatment in developing countries. AsGinsburg and Rapp (15) have observed, women’sbodies are frequently the locus through which social,economic, and political power is exercised. Fertilityand reproduction represent mechanisms throughwhich what Foucault (16) calls biopower is exercised.The lack of medical discourse on infertility and ARTexacerbates the harms of infertility. It contains theexperience of infertility as a private harm for whichindividuals, usually women, are to blame. It contributesto the narrow health approach of family planningclinics that often falsely disconnect STD management,maternal and child health facilities, and the more
18 ABDALLAH S. DAAR, ZARA MERALI
comprehensive objectives of the WHO definition ofhealth.
The central difficulty associated with infertility indeveloping countries is that infertility transforms froman acute, private agony into a harsh, public stigma withcomplex and devastating consequences. Even ifinfertility were so narrow in its impact, a harm toindividuals rather than to society, it would be no lessa serious public health concern. Given the pervasive-ness of infertility and the seriousness of its harms,infertility is a substantive public health problem.According to the WHO definition of health, it couldbe argued that the emotional and psychological harms
associated with infertility are health harms. Denyingpsychological harm as a serious health problem is aclassic manoeuvre that has been the cause of perva-sive health care discrimination in most countries.Moreover, infertility does transform a potentiallyprivate, individualized health problem into socialsuffering. Infertility has the potential to disrupt peace,exacerbate poverty, and devastate communities. Theharms caused by infertility are pervasive, sociallyembedded and serious, precisely because infertilityinteracts with a complex network of social relation-ships, social expectations and social needs.
Infertility in developing countries translates into
Figure 2. Continuum of the consequences of infertility
(i) The distinction between mild, moderate, severe and verysevere physical violence is based on the frequency ofbeatings by the husband, cuts and bruises, abusiveemotional or verbal behaviour of the husband toward thewife, intimidation resulting in fear of the husband, familial orcommunity physical or emotional violence, and sexual abuse(including refusal of sexual relations or rape) by the husbandtoward the wife. The greater the number of indicators ofviolence, the greater the degree of violence recorded(adapted with revisions from Unisa 1999 (12); see alsoPapreen 2000 (11)).
(ii) The distinction between economic stress, seriouseconomic hardship and severe economic deprivation marksthe presence and extent of loss of income due to loss ofchild labour, loss of job availability due to social alienation,inability to operate familial business (for example, farms) ifapplicable, GDP per capita relative to others in the country,self-sufficiency, financial indebtedness to others (seeBergstrom 1992 (6) for some limited examples).
(iii) The distinction between social alienation and socialisolation culminating in loss of social status marks thepresence, frequency or extent of social avoidance (notspeaking to persons, avoiding persons, not being invited tosocial gatherings); disrespectful and humiliating socialtreatment even within oneÊs own social class (for example,being referred to by derogatory names); social assumptionthat the couple (or in some cases the woman only) afflictedwith infertility is evil or cursed, familial mocking or blame,social blame for social harms (for example, woman blamedfor health epidemic arising in the community because she isinfertile); overall denigration of social status (quality oflifestyle, respect and honours of society) (see Bergstrom1992 (6); Griel 1997 (9); Gerrits 1997 (8) for someexamples).
GuiltSelf-blameFear
Marital stressEconomic stress (ii)HelplessnessDepression
DeathViolence-inducedsu ic idestarvation/disease
Lost dignities in death
Mild marital or social violence and abuse (i)Serious economic hardship (ii)Social alienation (iii)
Moderate to very severe marital or socialviolence and abuse (i)
Severe economic deprivation (ii)Social isolation and abuse culminating in loss
of social status (iii)
Level 1
Level 2
Level 3
Level 4
Level 5
Level 6
Infer tility and social suffer ing: the case of ART in developing countr ies 19
an ailing body, an unfulfilled human identity, anddisturbed social relations that have direct social,political, and economic impact. Accordingly, deve-loping countries need to re-evaluate social and healthcare research and treatment priorities to reflect theimpact of infertility in their societies.
Reply to the overpopulation and limitedresources arguments
Two key arguments are frequently used to challengethe development of new reproductive technologies indeveloping countries. First, the argument fromoverpopulation suggests that an overpopulatedcountry should not prioritize infertility management,for the overpopulation poses a demographic problemfor the country and for the global community.
The primary response to this argument is thatindividuals should be able to reproduce “if, when andas often as they wish,” as it was stated in thedefinition of reproductive health adopted by theUnited Nation’s 1994 International Conference onPopulation and Development. References in both theUniversal Declaration of Human Rights and theConvention on the Elimination of All DiscriminationAgainst Women may also be interpreted to argue for aright to access to infertility treatment through ART.For, if infertile persons do not have access to ARTbecause this would “contribute” to overpopulation,why save lives in developing countries using medicaltechnologies, as this too would have an “over-population effect”? If it is thought that it is justifiedto employ medical technologies to prevent suffering,why is it not justified to use medical technologies toalleviate suffering from infertility? Distinguishing thecases requires the assumption that the harms ofdisease necessitate medical technology in a way thatthe harms of infertility do not.
Some think that infertile people should adoptchildren, given the number of children in developingcountries that are available for adoption. Manyregional studies indicate a lack of availability of suchchildren and the social customs that resist givingchildren up for adoption. In Cameroon, letting go of afamily’s children may be shameful and bring disreputeto an extended family. Children belong in the care ofextended families. Moreover, Asian families report anintense fear that adoptive children will not reciprocateparental love and security (12). The argument thatinfertile people should adopt instead of having their
own biological children, in the context of the over-population problem, is rather weak. For why shouldfertile people not have one less child and adopt oneinstead, for example? Proposing adoption as the onlyalternative for infertile couples, in the context of globaloverpopulation, denies the importance of reproductiveautonomy and it distributes social responsibility foroverpopulation unjustly upon the infertile.
Macklin (17) has observed that “a far moreeffective and ethically desirable way of curtailingpopulation growth lies in education of women indeveloping countries, along with other modes ofdevelopment shown to be determinants of loweringpopulation.” Denying infertility treatments includingART to infertile persons is simply ill-consideredpopulation control policy. A more effective means tomanage population size is to assure a right toeducation that virtually all developing countries havecommitted to when the UN General Assembly adoptedthe Universal Declaration of Human Rights.
The second argument, the limited resourcesargument, suggests that developing countries shouldnot allocate resources for expensive technology thatcan benefit only a few. Proponents maintain that acountry’s resources should be directed toward theprevention of infertility (18). While the affordabilityof ART is a problem that needs to be assessed in thespecific context of a country’s needs and economicconditions, it cannot be assumed that ART isunfeasible. Rather, given the social suffering andpublic health harms associated with infertility, researchshould be directed towards finding effective, low-costsolutions to infertility and this exploration shouldextend to ART. Macklin contends that it is not at allobvious that infertility treatments should not be a keyhealth care priority, especially when their pervasive andgrave consequences are considered (17). The ideathat infertility treatment is not a health care priority isbased on the fallacious assumption that it does nothave devastating, material and life-threatening conse-quences. Indeed, since the consequences of infertilityare so severe in developing countries, infertilitytreatment should assume an even higher priority indeveloping countries than it does in developedcountries.
Sen (19) has persuasively argued that rightscannot be justifiably denied on the basis of govern-ments’ generalized comments on the scarcity ofeconomic resources. The same kind of argument hasbeen used to deny women’s rights around the world,a right to education, and even development rights to
20 ABDALLAH S. DAAR, ZARA MERALI
developing nations. As Sen (19) observes, a carefulexamination of governmental budgets in bothdeveloping and developed nations frequently revealsmismanagement of funds, rather than an inability tofinance social and economic rights.
Many studies have established that in vitrofertilization (IVF) may be cost-effective and feasiblein developing nations (19–29). In some instancesART may be the only way to treat infertility, even ifprevention programmes are successful. Often, affluentpeople have the means to travel to developedcountries for treatments; however, the costs may setthem back financially while a developing nation’sscarce foreign currency reserves are expended (30).Others, who cannot afford the costs of a treatmentabroad, might be obliged to sell off their remainingproperty, often with severe personal consequences.Finally, if governments cite scarce resources as thejustification for not funding ART, this is a cause forgovernments to think creatively about infertilitysolutions, rather than a justification for rejecting allART advances and development. The ColombianProfamilia Programme is a good example of theimplementation of ART in developing countries. Itdemonstrates how govern-ment support for nonprofitorganizations may be vital in providing affordableaccess to infertility care (2). Cooperative public andprivate partnerships have the potential to makeinfertility care affordable and to make access more just.
The potential for public–privatepartnerships
Public–private partnerships (PPPs) are joint venturesthat may: (i) bring in technical resources (technology,people, knowledge) at lower costs; (ii) promote effi-ciencies in the public sector; (iii) attract foreigninvestors and capital; (iv) introduce and developeffective processes, practices and standards forinfertility treatment in developing countries; and (v)instil greater accountability and responsibility. Aframework that ensures knowledge transfer throughPPPs would enable domestic drug companies tomanufacture their own infertility drugs, especially forthose drugs whose patents have expired. Furthermore,public–private clinics may be a source of revenue thatmay be used to support other health care objectives.For example, Indian clinics have been successful inattracting business from people coming from wealthiercountries.
Developing nations often have a cost-competitiveadvantage due to inventiveness under adverseconditions, longer working hours, cheaper labour,involvement of volunteers, etc. The cost of ART maybe further reduced, if research confirms that similarART success rates are achievable with less expensivestimulation protocols.
Finally, as demand for ART increases and supplyexpands, costs will decrease due to economies of scaleand increased competition. Developing countries arewell positioned to advance their health caretechnologies relative to other technologies, becausethese are often less dependent on multinationalcorporations. Medical knowledge is readily availableand transferable across borders. Developing countrieshave substantial social capital in the field of healthcare through existing NGOs and skilled, nativepractitioners. This affords the public sector strongernegotiating power and greater autonomy in PPPs.
Protecting reproductive rights and meeting healthcare needs are not inimical objectives. Governmentpolicy on ART will necessarily reflect its societalvalues, religious commitments if any, traditionalways of life, and economic conditions. Having theprogrammes and infrastructure for existing repro-ductive technologies may facilitate the introductionof other reproductive and genetic advances that mayprove indispensable to better health care in the future.
Conclusion
Evidence supports the conclusion that there is acompelling need for infertility treatment beyondprevention. In many instances, ART are the last hopeor the only means to achieve a child for couples. Thereis a heightened need for ART in developing countries.While developing countries have generally notestablished adequate infertility programmes, mainlydue to arguments based on overpopulation and cost,some notable exceptions (2) raise hope of successfuland just implementation of ART, perhaps throughpublic–private partnerships. A failure to evenconsider examining low-cost models of ART will beto conceive of developing countries as perpetuallydeveloping, rather than developed, with respect topublic health.
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27. Serour GI et al. In vitro fertilization and embryo transferin Egypt. International Journal of Gynecology andObstetrics , 1991, 36:49–53.
28. Yang YS. The program for in vitro fertilization andembryo transfer at National Taiwan UniversityHospital. Journal of the Formosan Medical Association,1998, 8 :116–118.
29. Zegers-Hochschild F et al . Pregnancy rate in an oocytedonation program. Journal of Assisted Reproduction andGenetics, 1992, 9:350–352.
30. Edouard L, Olatunbosun OA. The case against newreproductive technologies [Letter to the Editor]. BritishJournal of Obstetrics and Gynaecology, 1997, 104:969.
22 OSAOSAOSAOSAOSATTTTTO FO FO FO FO F..... GIW GIW GIW GIW GIWA-OSAA-OSAA-OSAA-OSAA-OSAGIEGIEGIEGIEGIE
ART in developing countries with particular reference tosub-Saharan Africa
OSATO F. GIWA-OSAGIE
Introduction
It is a common saying that “prevention is better/cheaper than cure”. This saying is universallyapplicable in the field of infertility. The ability toconceive, conception itself, and successful preg-nancy, delivery, and infant survival, are of specialimportance in Africa where the cultures of the peoplesplace a premium on childbearing and -rearing. Thecauses of infertility in general, and tubal and maleinfertility, in particular, are mainly preventable. Thetreatment of tubal infertility and of most forms of maleinfertility increasingly involves the use of assistedreproductive technology (ART). ART is far moreexpensive than strategies and actions required toprevent infertility. Of adult couples in Africancountries it is estimated that 10%–25% are subfertileand of these subfertile couples female factors accountfor about 55%, male factors for 30%– 40% of causes,while 5%–15% of causes are unexplained. Tubo-peritoneal factors are the single most common causeof infertility in African couples followed by oligo-azoospermia from whatever cause (1–3).
The most common cause of infertility in Africa isinfection (2–5) of which the two sexually transmittedinfections (STIs), gonorrhoea and chlamydia are themain culprits in both males and females. Delayeddiagnosis of STIs, lack of diagnosis, incompletetherapy, no therapy, or inappropriate therapy
compound the problems of STIs in Africa. After STIs,infections during or after abortion and during and afterchildbirth represent the next major cause of femaleinfertility in Africa. The latter explains the preponder-ance of secondary infertility over primary infertility inAfrica (1,2).
In comparison, the developed countries of Europeand North America have more endocrine causes ofinfertility and have better facilities for the diagnosisand appropriate therapy of STIs and can therefore beexpected to have better prognosis in infertilitymanagement. In Africa, there are more tubal factors,more irreversible oligo- or azoospermia and lessresources for the management of infertility due toeconomic, political, capacity-building factors and theseverity of disease.
The focus of this paper is sub-Saharan Africa.However, the Republic of South Africa has beenexcluded as the level of scientific activity there is moreakin to the developed countries than the realities indeveloping countries. Information for this review wasobtained through personal enquiry from healthpersonnel in the countries of sub-Saharan Africa,from publications in scientific journals, and conferenceabstracts, and news media and from site visits.Requests for information were made to doctors andrelevant health personnel in the following countries:Cameroon, Ghana, Guinea, Kenya, Nigeria, Senegal,Sierra Leone, Togo, Uganda and Zimbabwe. In the
ART in developing countries with par ticular reference to sub-Saharan Africa 23
case of Cameroon, Ghana and Nigeria, information wassought from identified practitioners of ART. Responses,which varied in content and value, were received fromSierra Leone, Senegal, Ghana, Nigeria, Cameroon andZimbabwe. Some of those who have declared in themedia that they practice ART and have had ARTsuccesses did not make their statistics available. Inspite of these difficulties, it was still possible to gainan insight into what is being practised in the field ofART in sub-Saharan Africa through indirect sourcesand a few direct sources.
Objectives
The goal of this paper was to obtain the followinginformation relating to ART in the subregion:
• Is ART being practised?• Where and by whom?• What methods of ART are available?• Cost of ART per cycle;• Statistics and results of ART;• Sources of equipment and consumables;• Technical collaboration, if any;• Assessment of opinion on relevance, need,
affordability and accessibility of ART.
Types of ART practised
Virtually all forms of ART are now available in thesubregion namely: artificial insemination by husband(AIH); donor insemination (DI); in vitro fertilization(IVF); gamete intrafallopian transfer (GIFT); zygoteintrafallopian transfer (ZIFT); intracytoplasmic sperminjection (ICSI); embryo freezing and embryo donation;surrogate motherhood.
The most widely practised methods are AIH andDI, and IVF (6–8). Oocyte donation is also available(9). The least widely available methods are ICSI andembryo freezing. Adjunctive methods such as laserassisted hatching and implantation are not yetavailable.
Table 1 shows the methods of ART available percountry listed. From information available fromvarious sources, the countries that have centre(s)offering donor semen insemination, IVF and relatedART are Cameroon, Ghana, Nigeria, Togo andZimbabwe. Other countries, such as the BeninRepublic, Kenya and Sierra Leone have physicianswho offer AIH.
ART was available usually in a sustainable mannerin private clinics rather than in the public sector. Theusual pattern was for the practitioner(s) to have startedthe procedure in the public sector and then moved tothe private sector for want of funding in the publicsector. A classic example was the experience of theLagos University Teaching Hospital team of Giwa-Osagie, Ashiru and Abisogun who produced docu-mented pregnancies through IVF in 1984, 1986 (10)and a live birth in 1989. There was no public sectorfunding and the service transferred to the privatesector. The successes from IVF at the Lagos UniversityTeam were the first in West, East and Central Africathen. Now all the ART units doing IVF in West, Centraland East Africa are in the private sector or incorpora-ted as foundations. This has serious implications foraccessibility and equity. The sources of consumables,equipment and technical collaboration were influen-ced by the country in which the principal clinician orembryologist had his training in ART. Equipment andconsumables for AIH, DI and IVF were purchasedfrom the United Kingdom, Germany, Holland, France,Sweden, USA and Australia, in order of frequency. All
Table 1. Methods of ART available in various countr ies in sub-Saharan Africa (excluding South Africa)
Country AIH/DI IVF GIFT/ZIFT Oocyte donation Egg sharing Embryo freezing TESA ICSI
Nigeria Yes Yes Yes Yes Yes Yes Yes YesGhana Yes Yes N/A N/A N/A Yes Yes YesCameroon Yes Yes N/A N/A N/A N/A N/A N/ATogo Yes Yes No No N/A N/A N/A N/ASenegal Yes Yes N/A N/A N/A N/A N/A N/ABenin Republic Yes No No No No No No NoZimbabwe Yes Yes No Yes Yes Yes Yes YesKenya Yes No No No No No No NoSierra Leone Yes No No No No No No No
N/A: information not available
24 OSAOSAOSAOSAOSATTTTTO FO FO FO FO F..... GIW GIW GIW GIW GIWA-OSAA-OSAA-OSAA-OSAA-OSAGIEGIEGIEGIEGIE
ART practitioners used gonadotrophin-releasinghormone analogues mostly on a long-protocol, fordownregulation followed by gonadotrophin stimula-tion. The ultrasound scanners were from Austria,Germany, Japan and the USA. All centres recoveredoocytes transvaginally under ultrasound guidancewhile some still performed laparoscopic recovery fora few cases that were difficult to access transvaginally.The indications for IVF were tubal factor infertility,which accounted for over 60% of cases in most series,followed by male factor infertility and combined tubaland male factors. Unexplained infertility and endo-metriosis were not so common indications andaccounted for less than 20% of indications for IVF.
The countries with which there is/was technicalcollaboration are listed in Table 2. The main countriesare France, Germany, the UK and the USA. There wasvery little intra-African collaboration and most ART
practitioners in Africa were not aware of the activitiesof similar practitioners in the subregion although theART centre in Lome, Togo had some discussions withone centre in Tema, Ghana. This lack of communica-tion led to many claims at being the “first” to achievevarious milestones in the subregion.
Table 3 summarizes ART activities in establishedART units in Nigeria. There is close cooperationbetween some centres and ART centres in SouthAfrica, the UK, Australia and Denmark. In one centrein Lagos, the egg recovery, embryology and embryotransfers, and ICSI are done at intervals when a teamfrom the UK comes to work at the centre. The centrein Harare, Zimbabwe, has visits from ART specialistsfrom Australia, the UK and South Africa to carry outquality checks and updates at intervals. One centrein Lagos, another in Abuja and one in Tema, Ghanahave had varying degrees of collaboration during theirstart-up phase with centres in the UK, Denmark andGermany. The embryologists of two of the threecentres in Lagos, the centres in Abuja, Tema andHarare are all indigenes of the respective countries.The results of AIH and donor semen insemination aresummarized in Table 3. Tables 4 and 5 summarize ARTstatistics from three units in Nigeria and the unit inZimbabwe (9,11–13).
Similar information on ART procedures includingDI was requested from the ART centres in Ghana andCameroon. Most centres transferred embryos at the4–8-cell stage, although there is an increasing tendencyrecently to transfer blastocyts. Three centres
Table 2. ART in sub-Saharan Africa: technicalcollaboration
Location of ART units Location of technical collaborators
Lagos, Nigeria UKAbuja, Nigeria UK/DenmarkTema, Ghana GermanyTema, Ghana USA/UKLome, Togo FranceYaoundé, Cameroon FranceDouala, Cameroon FranceHarare, Zimbabwe Australia/South Africa/UK
Table 3. AIH and DI in some countries in sub-Saharan Africa
AIH DI
Total cycles Cycles per Pregnancy Total cycles Cycles per Pregnancyannum rate (%) annum rate(%)
Giwa-Osagie et al. (1985) 35 – 71*Lagos (6)
Giwa-Osagie et al. (1995–2000) 830 138 22.8 1543 257 58.2Lagos
Wada et al. (1999) 32 25 – –Abuja (12)
Robertson et al. (2000) 100 22† – 20 30†Harare
Fraser B (2000) 20 – 70ÚFreetown
* Cumulative pregnancy rate at 8 months† Pregnancy rate after 3 cyclesÚ Cumulative pregnancy rate
ART in developing countries with par ticular reference to sub-Saharan Africa 25
Table 4. ART activities in established units in Nigeria and Zimbabwe
AIH/DI IVF ZIFT/GIFT Embryo freezing Oocyte donation ICSI
Lagos1. Advanced Fertility Clinic Yes Yes Yes Yes Yes No2. Providence Hospital Yes Yes No No Yes No3. The Bridge Clinic Yes Yes No No Yes Yes
Abuja4. Nisa-Premier Hospital Yes Yes Yes Yes Yes Yes
Harare5. Alfacare Yes Yes No Yes Yes Yes
Table 5. Statistics of IVF in some centres in sub-Saharan Africa
Centres Cycle/annum Pregnancy rate/ Pregnancy rate/ Multiple Take-home baby/OR ET (%) pregnancy rate (%) ET (%)
Alfacare, Harare (2001) 50 28 (frozen 15.8embryos)
Nisa-Premier (13), Abuja (1999) 50 15 21 16.6 14
Advanced Fertility Clinic, 50 16 21 14.3 14.1Lagos (1999–2000)
Bridge Clinic, Lagos (1999–2000) 159 19 21.6 36
Providence Hospital, Lagos (1999) 10 (oocyte 40 10donation)
transferred no more than three embryos at a time. Allcentres provide progesterone support after eggrecovery. Embryo freezing is available in two centresin Nigeria while oocyte donation is available in fourcentres in Nigeria. One centre in Lagos has practisedsurrogate motherhood but the overall experience ofthis is little. The cost of IVF and related proceduresvaries from the equivalent of US$ 1200 to US$ 4000per IVF cycle including drugs, with two centres inNigeria and one centre in Tema, Ghana stating that acycle costs about US$ 2500 at their centre. Twocentres in Nigeria engaged in egg-sharing schemesand charged between US$ 1200 and US$ 1800 perperson for egg-sharing cycles. The IVF centre inZimbabwe charges US$ 2500 per cycle of IVF, orUS$ 3500 per cycle including drugs.
The regulation of ART
In all the countries surveyed, there is no state regula-tion of ART. ART practitioners in the subregion,however, stated that they have a voluntary adherence
to guidelines set by the American Society ofReproductive Medicine, the British Human Fertilisa-tion and Embryology Authority or the equivalentbody in France or Germany. Because of the interactionand collaboration of the African centres withscientists from Europe, South Africa, Australia andAmerica, the African centres voluntarily abide withaccepted guidelines from those countries. The centrein Harare states that it has regular visits from topscientists from the UK, Australia and the USA to guideit and update it on quality control, ethics and newadvances. Most of the countries do not have nationalethics committees.
The relevance of ART
WHO has enunciated and propagated a holisticdefinition of health, which includes physical, mentaland social well-being and not merely the absence ofdisease or infirmity. Reproduction is vital for speciessurvival. Infertility causes major marital, family andsocial disruption in Africa. Africa has more of the type
26 OSAOSAOSAOSAOSATTTTTO FO FO FO FO F..... GIW GIW GIW GIW GIWA-OSAA-OSAA-OSAA-OSAA-OSAGIEGIEGIEGIEGIE
of infertility that can be solved by ART proceduresthan any other part of the world. ART is thereforerelevant in Africa. Sub-Saharan Africa, however, hasdeficits of capacity, finances and communication,which need to be addressed in a relevant and cost-conscious manner. In one centre in Nigeria, it wasestimated that 30% to 40% of infertile patients withtubal disease need ART procedures (14) . Both interms of the numbers of people that could benefit fromART and the cultural place of childbearing in sub-Saharan Africa, ART is relevant.
The need for ART
The need for ART in sub-Saharan Africa is related toits relevance there. The need for ART far exceeds theavailability of facilities and expertise, thereby creatinga large gap between need and availability and uptake.In Nigeria alone there are at least 12 million infertilepersons, and tubal factors, severe oligospermia andazoospermia account for the majority of the causes ofinfertility. As of 2000, the total number of IVF cyclesperformed in Nigeria was less than 600 cycles perannum. One can only conclude from this that the needis not being met at the present.
Affordability of ART
One way to assess the affordability is to consider itin relation to minimum wage. In Nigeria, a cycle of IVFcosts about US$ 2000–US$ 2700 (250 000 to 350 000Naira). The minimum wage in Nigeria is US$ 52–US$ 60 per month. A National Health InsuranceScheme is just about to start. A few companies andlarge federal government parastatals are prepared topay for only part of ART costs such as drugs, oroocyte recovery and embryo culture, but not foreverything. This means that most people who needART fund it themselves. ART is therefore not currentlyaffordable for the average Nigerian. The same is truefor all of West Africa. Because of the premium placedon childbearing, it is common to find that members ofthe extended family and friends contribute to make upthe cost of an ART cycle.
Accessibility of ART
Access to health care in most countries of sub-
Saharan Africa is not ideal and is mostly inequitable.Access to ART is no different. ART centres areusually in the major or capital cities such as Abuja,Dakar, Douala, Harare, Lagos, Lome, Tema/Accra andYaoundé. These cities are the centres of economic andacademic activity where the medical specialistsconcentrate and where there are patients who canafford to pay for medical services. Access is limitedby economic as well as physical access factors. Thereis also an educational factor (6). Many persons in thesubregion confuse artificial insemination with IVF andrelated procedures. There are groups within thesubregion who object to artificial insemination andother ART procedures on religious, ethnic or culturalgrounds. Access to ART can be improved in a numberof ways. Continuing increase in the level of basiceducation and literacy in the subregion will enhancecommunication and population awareness of repro-ductive health, including ART. The introduction andcorrect implementation of social/health insurance willenable health services to be more readily available tothose who need them. In many countries in thesubregion, there is a tendency to look at the privatesector as an opponent or rival of the public sector.Collaboration between the public and private sectorin health care delivery will increase access to healthcare for the populace. The government, through itshealth institutions, can reduce the costs of health careincluding ART by bulk purchase of drugs, consuma-bles and equipment. Private hospitals can also do bulkpurchase to enable them to cut their costs and reducecosts to the patients. In a subregion that is short infacilities, expertise and capacity, all of which have beenworsened by “brain drain” to Arabian Gulf States,Europe and the United States of America, centres ofexcellence should be established in some states withinthe subregion. This will assist the provision ofaccessible, cost-effective health care and ART. Thecosts of setting up these centres can be sharedbetween the countries, private sectors, individualsand international agencies such as WHO, theRockefeller Foundation, the Ford Foundation, the BillGates Foundation. These centres could offer researchand service at region-realistic prices. Baseline studieswill establish the best location of these internationalcentres of medical excellence.
Conclusion
The communication gap in Africa was clearly demon-
ART in developing countries with par ticular reference to sub-Saharan Africa 27
strated in the preparation of this paper. It wasdifficult—even with the aid of facsimile and e-mailcommunication—to collate available evidence. Manymedical practitioners were not aware of the activitiesof their colleagues in neighbouring countries, but wereusually up-to-date about events in the developedcountries of the world. The fact that there are well-documented successes through ART in sub-SaharanAfrica confirms that it is possible to transfer technol-ogy from more developed countries (7,9–11,13). Thereluctance of some ART centres in sub-Saharan Africato share their ART statistics even when contacteddirectly in person or by mail may be because theirresults are not as good as those from the developedcountries. If this is so, it is unfortunate because suchdisparities in results should encourage collaborationwithin Africa as well as with countries outside Africa.My deduction from available evidence is that the IVFclinical pregnancy rates of most of the ART centresin sub-Saharan Africa are possibly between 10% and20% of oocyte retrievals, with probably 10%–20%spontaneous abortion rates, and take-home baby ratesof 5%–15%. These rates can be improved by takingaccount of uterine factors such as uterine synechiaeand fibroids and treating them before IVF attempts andby considering transferring up to four embryos ratherthan just two or three embryos. International agenciessuch as WHO and the various national governmentscan assist by encouraging and funding collaborativeintraregional as well as north–south research toimprove the results of infertility management and toadapt available technology to local conditions andfinances. The countries with ART centres should beencouraged and assisted to develop appropriateregulations and guidelines on ART. The subregionalART centres should be encouraged and empoweredto have collaborative meetings and to share theirstatistics and expertise. Such collaboration wouldensure that all the ART centres state their results inthe same manner and encourage the standardizationof procedures and equipment.
References
1. Giwa-Osagie OF et al. Aetiologic classification andsociomedical characteristics of infertility in 250
couples. International Journal of Fertility , 1984, 29 :104–108.
2. Cates W, Farley TMM, Rowe PJ. Worldwide patternsof infertility: is Africa different? Lancet , 1985, 2:596–598.
3. Osegbe DN, Amaku E.O. The causes of male infertilityin 504 consecutive Nigerian patients. InternationalUrology and Nephrology, 1985, 17:349.
4. Osegbe DN. Testicular function after unilateral bacterialepididymo-orchitis. European Urology, 1991, 19:204.
5. Oye-Adeniran BA, Giwa-Osagie OF. Bacteriospermia infertile and infertile men. Nigerian Medical Journal ,2000, 38:53–56.
6. Giwa-Osagie OF, Nwokoro C, Ogunyemi D. Donorinsemination in Lagos. Clinical Reproduction andFertility, 1985, 3 :305–310.
7. Ashiru AO, Abisogun AO, Giwa-Osagie OF. Fertilisationof pre-ovulatory human eggs and development in vitroin Lagos. The Endocrine Society, 6th Annual MeetingJune, 19–21, 1985, Baltimore, USA. Abstract 1434,p. 359.
8. Giwa-Osagie OF et al. Human oocyte recovery for invitro fertilisation. The use of cervical mucus and plasmaoestradiol as indices of follicular development. WestAfrican Journal of Medicine, 1988, 7:136–139.
9. Esangbedo J, Braimo O. Live births following transferof in vitro fertilised donated oocytes. Society of Gynae-cology and Obstetrics of Nigeria (SOGON), AnnualGeneral Scientific Conference, 1991, Abstract 12.
10. Giwa-Osagie OF et al. Clinical profile, assessment forIVF and the outcome of IVF in Lagos. 12th WorldCongress of Fertility and S terility, 1986, Abstracts p.737.
11. Giwa-Osagie OF et al. Successful outcome following invitro fertilisation and zygote intra-fallopian transfer ina private clinic. Society of Gynaecology and Obstetricsof Nigeria (SOGON), Annual General Scientific Confer-ence, 1999, Abstract 9.
12. Wada I, Odoma G. The success rates of intra-uterineinsemination (IUI) and timed intercourse (TI) aftersuperovulation with exogenous gonadothrophins. Societyof Gynaecology and Obstetrics of Nigeria (SOGON),Annual General Scientific Conference, 1999, Abstract10.
13. Wada I et al. Take home baby rate from a pilot in-vitrofertilization (IVF) project in Abuja, Nigeria. Society ofGynaecology and Obstetrics of Nigeria (SOGON),Annual Scientific and General Conference, 1999,Abstract 15.
14. Ogedengbe OK, Giwa-Osagie OF, Ogunyemi O.Implications of pattern of tubal disease for microsurgeryand in-vitro fertilisation in Lagos. Journal of theNational Medical Association , 1987, 79:510–512.
Section 2
Infertility and assisted reproductive technologiesfrom a regional perspective
Assisted reproductive technology in Latin America:some ethical and sociocultural issues
FLORENCIA LUNA
Introduction
Latin American countries differ in many waysincluding size, natural resources (for example, Braziland Uruguay), and the configuration of their popula-tions (indigenous population, of African origins, andmultiple ethnic backgrounds mainly of Europeanimmigrants). Such differences have influenced theformation of the many cultures in Latin America.Hence, all generalizations will have to be subject tosuch limits. Latin America is not a homogeneousregion; countries are diverse and have a cultural andsociological individuality. Despite their differences,however, Latin American countries share certainfeatures: wide gaps between poor and wealthy people,and the high prevalence of Catholicism. Even thoughthe Catholic Church may differ from country tocountry, religion does have a great impact on repro-ductive issues. And assisted reproductive technology(ART) is no exception.
In this paper, some ethical and social issues ofART in Latin America, particularly those influencedby the culture, religion or particularities of the regionare presented. However, it should be recognized thatit is very difficult to avoid concerns that are of auniversal nature or that are also present in otherregions of the world.
Availability of ART in the region
It is a fact that in the majority of Latin Americancountries, ART is not a high priority when comparedwith larger public health issues, particularly preven-tion of easily treated diseases.
ART lacks priority in public policies. In general inLatin America, ART is not provided in public hospitals.The few centres treating infertility problems offer verybasic treatments. For instance, in Argentina, onlydiagnosis of infertility is provided in public hospitalsbut no treatment is offered i. In Brazil, few publichospitals or centres offer ART, the Outpatient Clinicof UNICAMPii does not cryopreserve embryos orgametes and the cost of the drugs must be paid bythe patients. This is costly and ranges from US$ 750to US$ 2000 (personal communication with MariaYolanda Makuch). In Argentina, some of the privatefertility centres do have foundations that help peoplewith scarce resources. However, their impact is minimal.
The poor, then, cannot access these techniques.This situation should not be considered unique toLatin America; these services are not provided inmany other countries either. In the USA, for example,there are no publicly funded infertility treatments andmost private insurance companies do not cover them.
i The same point was made by Haroldo López from Guatemala. There is no IVF in hospitals.ii UNICAMP (Universidade Estadual de Campinas) is the State University of Campinas, in Saõ Paulo, Brazil.
32 FLORENCIA LUNA
However, in Latin America this situation is surroundedby a pervasive feeling of lack of justice and discrimina-tion.
In this vein, ART is perceived as a luxury forwealthy couples, and not as a service for anyonewanting a son or daughter. A frequently voicedprejudice is that poor women have a lot of children;they do not need these techniquesiii . Infertility isviewed as a problem of the wealthy, which furtherreflects the big socioeconomic gaps among thepopulations of this region; on the one hand, a wealthypopulation with access to highly sophisticatedmedical technology and, on the other hand, largenumbers of people who cannot even cover their basicneeds, let alone have access to expensive infertilitytreatment.
A first issue that explains this feeling of lack ofjustice is that even if these techniques are restrictedto the upper and middle classes with access to themthrough private centres, the deprived is the populationin need. It is this population that is most likely to havesexually transmitted diseases (STD) and reproductivetract infections (RTI) and therefore a higher incidenceof infertility (1,2). Makuch quotes a Brazilian studywhere 42% of women who consulted for infertility hadtubal obstruction because of reproductive tractinfection. Illegal abortions practised in deficientconditions may also leave this population withinfertility problems. In addition, some workingconditions or contact with pollutants may alter thequality and quantity of sperm. These are jobs oftendone by people with little education. It has beenreported that indigenous people from Guatemala, afterhaving been exposed to certain kinds of fertilizers,seemed to have problems of azoospermia (personal
communication with Haroldo López). Similar data onsecondary infertility have also been reported.
A second reason that may play a certain role inthe perception of injustice is related to the idea of aright to health care. This is especially strong inArgentina and Brazil. In the latter country, the notionof right to health care is present in many different fields(3). One example is Brazil’s position on the protectionof research subjects, or the use of generics for AIDStreatmentiv (4).
Many Latin American countries used to enjoy atradition of public health systems. In Argentina, evensome very costly treatments such as organ transplanta-tions, are carried out in public hospitalsv. This traditionof publicly supported health care is not the case in allcountries, for example, the USA, where the lack of ARTservices is not so strongly perceived as unfair as inother countries where this tradition has existed. Insome of the Latin American countries the ideal is inline with European countries and their strong supportfor public health systems. In addition, this traditionand ideal of a welfare system in health is accompaniedby at least a decade of deterioration in the public healthsystemvi. This gives rise to a feeling of resentment andof an increasing injustice in health care.
Regulations
Legal regulations
Another issue related to the above is that in many LatinAmerican countries, ART is not well regulated andmay vary widely. The 1998 Surveillance Study (5) onlyconsiders the situation in Mexico and Brazil as having
iii Discrimination is reinforced by the population control that has occurred recently in Latin America by which poor womenwere sterilized. These recent facts leave the impression that this group does not deserve help to achieve fertility. “Poorwomen are not allowed to have children.” This memory of past abuses is still present and shapes the perceptions ofdiscrimination.
iv When the Declaration of Helsinki was discussed and a double standard was proposed regarding the treatment to be providedto research subjects; the National Council of Health (Conselho Nacional de Saude) issued a declaration (Resolucao N 301, 3-16-00) asserting the maintenance of the “best proven criterion”. It argued against lowering standards to the detriment ofdeveloping countries. A similar attitude was taken by Brazil regarding the excessive HIV drug prices. Considering the importanceand growth of this pandemic in the country, Brazil is aggressively negotiating generic drugs with international pharmaceuticalcompanies in order to be able to give them freely to all the population in need. During the past seven years it has providedfree medication to 100 000 patients.
v Not only are costly life-saving treatments given, but also “non-vital” treatments such as plastic surgeries. This may raiseother concerns, such as what the criterion is for distributing scarce resources (a point I cannot undertake here). It also raisessuch questions as: Why is ART not provided while plastic surgery is?
vi This is another global process, and many resource-poor countries are feeling the impact of these kinds of internationalpolicies.
Assisted reproductive technology in Latin America: some ethical and sociocultural issues 33
legislationvii . In these countries ART is offered tomarried couples or to those in stable relationships.Embryo cryopreservation is allowed (5) but there isno provision for embryo donation, even if sperm oroocyte donation is allowed. Brazil accepts surrogacyonly if a relative is willing to undergo this procedure.
In startling contrast, Costa Rica forbids assistedreproduction through a Constitutional Amendment.It only allows homologous insemination. As a conse-quence, patients seek treatment in other countries inthe region (personal communication with CarlosValerio). Aside from the doubtful rationale for such aprohibition, an additional problem is that thisprohibition makes these techniques even moreexpensive and promotes “reproductive tourism”. I willnot go into each country’s legal situation or theconditions in which such laws are passed (whetherthey were the product of a public deliberation processor the imposition of some group).
Informal regulations
Countries with an “informal” kind of regulation (thatis, without legal regulations) suffer other kinds ofproblems. The first ethical or sociocultural problemsfaced—at the private practice level—are the difficul-ties in setting limits. Despite consensus documentsby the scientific community, this remains a pressingissueviii. What are the limits on medical interventions?Should physicians provide ART to single women?What about lesbian or homosexual couples? Shouldthere be an age limit for ART? Should these techniquesbe offered to postmenopausal women?
The lack of a law fixing the permissible or theimpermissible puts pressure on the providers. Theyhave to decide without an external rule that setslimits. In addition, in societies that are influenced bythe Catholic Church, whatever minimal interventionfalls outside the standard may easily be criticized(single women, postmenopausal women, etc.). Strictadherence to Catholicism goes against the gamut of
these techniques. However, Catholics who are notso strict may still have problems with some of thetechniques and for whom they may be provided (forexample, single, lesbian or postmenopausal women).Hence providers sometimes have to decide whatshould be done on a case-by-case basis and thesedecisions are ostensibly very difficult. This fostersan attitude of self-restraint in the physiciansthemselves. They want to be able to exercise theirprofession without troubling the status quo. In thissense, I will try to show later on that there is a subtleinfluence of religion on how ART is practised.
There is a widely felt need for regulation. However,legislation is not sought because of the fear of veryrestrictive laws, given the prevalence of the Catholiclobby. However, religion should not be a problem forthe practice of ART if it would be maintained withinthe religious boundaries. Religious people should,then, follow the teachings and dogma of their faith.The problem arises when there is pressure to imposea religious dogma in the legislation of a secularcountry; as all the Latin American countries are. Inthis sense, it is understandable that Costa Rica’s modelof total prohibition raises apprehension. In the caseof Argentina, some projected laws were so restrictivethat it would have been nearly impossible to implementthese techniques ix.
Even if there is no legal regulation, there is ascientific consensus in the region. An example is theconsensus on ethical and legal aspects agreed uponby a Latin American network, constituted in 1994 inChile (Reñaca) in order to provide guidance tolegislators, health authorities, women’s organizationsand the general public (7). Supposedly, individualclinicians agree to abide by it. Some of the consensuspoints are:
• ART are to be provided to infertile heterosexualcouples. They are unacceptable for single womenwho do not seek a heterosexual partner or who donot want to have recourse to intercourse (coitus)
vii This report considers three categories of countries. Countries with legislation (such as Brazil and Mexico), countries withguidelines (here Argentina is included), and countries without legislation or guidelines. Those mentioned are the only threeLatin American countries analysed in this report. Interestingly, there is not yet a law in Brazil. In a recent article about thesituation of ART in Brazil, the author mentions a CMF Resolution 1358/92 issued by the Federal Medical Council. This doesnot have the force of a law; it directs recommendations to the medical profession. It also mentions other three law projects—in 1997, Law Project N 3638, Law Project N 2855 and in 1999, Law Project N 90 (6).
viii These consensus documents are not always respected by all the infertility centres. They do not bind them. And there areknown cases of surrogacy, lesbian couples, postmenopausal women that use these technologies.
ix Argentina only has guidelines proposed by the Argentine Society of Fertility and Sterility.
34 FLORENCIA LUNA
as an expression of sexualityx (7).• Every cryopreservation programme must be linked
to a programme of donation or adoption ofembryos that makes it possible to find a mother forthose embryos that will not be transferred to theirprogenitorsxi (7).
Research on embryos is acceptable only when itis foreseen that the embryos will not be affected as aresult of the research. Even if the progenitors author-ize research that entails a mortal danger, the rightto life of the embryo should take priority and besafeguarded by the medical teamxii (7).
These issues are highly controversial and civilsociety may disagree. Some of these clauses implicitlygrant a status to embryos that may be problematic.For example, they exclude discarding unwantedembryos. Some women who seek these techniqueswould prefer to discard unwanted embryos rather thansubmit to a requirement that the embryos are donatedto another couple.
Religious impact
Religion is mostly perceived as a barrier to some ofthe uses of ART. Only the most conservative religiousviews endorse this position. Representatives of thisextreme view are practising Catholics who oppose anyof these techniques for the artificiality they imply(even the case of insemination).
One of the reasons proffered is the inseparableconnection between the unitive and procreativemeaning of marriage (8–10). Persons are not allowedto voluntarily dissociate these two. Some conse-quences of this position are:
—Assisted reproduction is unacceptable because itpromotes procreation in the absence of sex.
—The use of donor gametes constitutes the inter-ference of a third party in the holiness of marriage.
—The right to life from the moment of conception bansembryo cryopreservation, manipulation or theirvoluntary disposal. The biological identity of anew human being is already established in thezygote resulting from fertilizationxiii.
To this absolute and radical refusal of ART, it isinteresting to point out the practice of a “double moralstandard”. One thing is what religion says and anotheris what people do. The great majority of the populationcoming from a Catholic upbringing (84.4% claim to beCatholic) do not follow Catholic teachings. Thisphenomenon is not unique to ART; in contraceptionthe attitudes are identical. For example, abortion lawsare highly restrictive; however, illegal abortions arecarried out continuously. In Argentina, between350 000 to 500 000 illegal abortions are performedevery year. The same attitude seems to operate in ARTtoo. Zegers-Hochschild points out that:
Specific instructions directed to legislators,health providers and patients, containingthese and other directives [the teachings ofthe Catholic Church], have been vastly disse-minated. Hence, it is difficult to understandhow contraception, artificial inseminationwith donor sperm and assisted reproductioncan be so widely performed in the LatinAmerican region. During 1995, 7000 cycles ofassisted reproduction including 351 transfercycles with donated oocytes were performedin 59 centers throughout Latin America (8).
These facts speak of hypocrisy and a double moralstandard. They also speak of a lack of real deliberationand consultation with society in the legislative arena.They show a lack of tolerance and respect for beliefs
x My translation of: “… no se considera aceptable la aplicación de dichos procedimientos [técnicas de reproducción asistida]en mujeres solteras que no deseen tener una pareja heterosexual o que teniéndola no desean recurrir al coito como expresiónde sexualidad” (p. 10).
xi My translation and my emphasis of: “Todo programa de criopreservación debe ir ligado a un programa de donación oadopción de concepti que permita encontrar una madre para aquellos concepti que no serán transferidos a sus progenitoras”(p. 16).
xii My translation and my emphasis of: “La investigación en conceptus es aceptable sólo cuando la indemnidad de éste no seve afectada como consecuencia de la investigación. […] De esta manera, aunque los progenitores autorizaran una investigaciónque conlleve un peligro vital, debe primar el derecho a la vida y ser salvaguardado por el equipo médico” (p. 21).
xiii This third point prohibits only manipulation or destruction of embryos, not their creation and implantation. But takentogether with the first consequence which considers the artificiality, it gives a substantial opposition to all of these techniques.
Assisted reproductive technology in Latin America: some ethical and sociocultural issues 35
and practices other than the religious ones.Although many Constitutions uphold the separa-
tion of State and Church, in the majority of the LatinAmerican countries this is not respected. Strongpolitical pressure and lobbying from the religiousorganizations exist. And, as Zegers-Hochschild againrightly points out: “In Latin America, legislators(especially from the right wing of politics) havepreferred to legislate in literal conformity to principlesemanating from moral teachings of the CatholicChurch” (9).
Specific problems
Each technique presents a different challenge. I willonly focus on some specific issues that not only poseethical quandaries but that are also related to somesocial issues particular to Latin America. There is animplicit “priority” of embryos subtly seen in someattitudes and practices in the region by:
• reluctance to cryopreserve embryos when there isno law forbidding it;
• obligation to donate embryos;• use of certain “terminology”; and• the paradox of preimplantation genetic diagnosis
(PGD).
The consideration of the embryo in the “LatinAmerican culture” shapes and limits the options awoman or a couple may be offered. The first issue isthe limits or harms that may be involved in order toprotect embryos against the welfare of the women.
Religious background seems to play a role in theprovision of treatment, as well as in treatment-seekingbehaviour. Even though the above consensus docu-ment argues for the importance and beneficial aspectsof cryopreservation (7), Argentine ART centres limitthe quantity of embryos to be frozen (personalcommunication with directors of Argentine FertilityCenters). There is an ongoing trend by which centresare cryopreserving fewer embryos. Hence, womenmay have to be submitted more frequently to hormonesand medication with the inconvenience and harm thismay entail.
A second issue is that no option for discardingsupernumerary embryos is offered and the onlyalternative available—when a person does not wantto transfer the remaining embryos into herself—is todonate embryos to another couple. This, however, isa compulsive donation which can also have disturbingpsychological effects. It may prove to be especiallypainful when the donor cannot achieve pregnancy.
A third consideration arises with the practice ofembryo donation and its current denomination asprenatal adoption. Terminology carries weight, itimplies a particular way of understanding facts. Theterm prenatal adoption is deceptive and conveys theidea of an actual adoption. It is not a neutral term, muchless in a region where the embryo is sometimes moreprotected than women. I will not enter into thecontroversy regarding the ontological or ethical statusof embryos. However, with this denomination,embryos are considered as orphans, an analogy thatleads to paradoxes. If we were to accept that embryosare persons, the whole process of cryopreservationwould, at least, be odd—how could we freezepersons? Moreover, in vitro fertilization (IVF) couldbe seen as a massacre, due to the loss of embryoswhen transferring them to the woman’s uterus; andthe same practice of giving them up in adoption (withthe obvious intention of protecting them) may implytheir death and destruction.
Finally, the last issue is PGD. This is related to thehealth status of the embryo and the prohibition ofabortion. While the International Federation ofFertility Societies encourages screening for seriousdiseases which would be a potential threat to thepotential child’s health (5), the majority of LatinAmerican countries do not accept either discardingof embryos or abortion.
The nonacceptance of discarding embryos whilegenetic screening is permissible and available createsa paradox. In the case of Argentina, Chile and otherLatin American countries, embryos which arediagnosed with genetic abnormalities have to betransferred because they cannot be discarded. ARTcentres in Argentina report that they do not discardembryosxiv . This leads to a situation where a womanat risk must accept the embryo transfer and pregnancyknowing that the offspring may suffer from a serious
xiv In Brazil, the CMF resolution 1358/92 makes several recommendations although it does not have legal force. It states thatdiagnosis in the pre-embryos is allowed only for purposes of their viability or the investigation of hereditary diseases.However, the discarding of embryos is forbidden by CMF and two of the law projects (personal communication with DirceuGuilhem).
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or even fatal illness.Thus, either PGD should be banned, harming the
couple and the future offspring, especially if they areundergoing these procedures in order to avoidtransmitting a genetic disease; or else, PGD isundertaken and embryos with genetic problems arediscarded. In the latter case, the majority of fertilitycentres in Latin America deny that this is whathappens. This is another example of hypocrisy anddouble standards and can possibly harm the coupleor the offspring.
In such cases the responsibility of the physicianand the couple or woman are at stake. They areconsciously bringing into the world a baby with asevere disability or illness. A number of thornyquestions arise: Can we knowingly seek a pregnancyresulting in a handicapped or severely ill offspring?What are our responsibilities towards this futurehuman being? Should we avoid bringing what hasbeen called “evitable suffering” into the world (11)?Arguing that only healthy embryos and fetuses shouldbe allowed to survive is challenged by the disabilitygroups, who argue that abortion of defective fetusesor refusal to implant abnormal embryos discriminatesagainst those with disabilities. These radical proposalsseem too extreme. If they consider preventivemeasures as discriminatory then they could alsoobject to warnings on alcoholic beverages, about therisks of birth defects (12). The disability groupsimplicitly suggest that it is wrong to interfere with thenatural order of things, an extreme view that wouldobject to any medical treatment.
Taking into consideration the different perspec-tives (radical and controversial), one could argue thatevaluation of the moral responsibility of knowinglybringing into existence a severely handicapped childand the final decision about it should be made by thecouple. But this would imply offering the possibilityof discarding severely damaged embryos, a claimednonexisting option in Latin America.
Other issues
Although not only related to the situation of LatinAmerica, two more issues of critical importance are:(i) secrecy in gamete or embryo donation; and (ii) thewidespread use of intracytoplasmic sperm injection(ICSI), although follow-up of ICSI children intoadolescence and adulthood is not yet possible.
Secrecy and gamete donation
Secrecy is particularly important in ART. Despite thewidespread use of ART, it is often associated withfeelings of shame. Such feelings often lead the ARTparents to avoid open discussion about their infertilitytreatmentsxv. Secrecy regarding the origins of the childin cases of gamete donation is controversialxvi. Zegers-Hochschild illustrates this point:
In countries like Chile, less than 10% ofcouples with babies born as a result of ARTare willing to express publicly their views onthis form of technology which enabled themto become parents. Furthermore, none of thecouples that have become parents with theassistance of donor gametes have told theirchildren. It is evident from this sad realitythat, in a way, these couples live a certainform of isolation and feel the need for keepingsecrecy for the rest of their lives (8).
Even more, this can be problematic for the child,not only because of the secrecy in the family, orbecause later on the child might find out the informa-tion that was withheld, but also because of the geneticdifference between the child and the parentsxvii (14).This is particularly important in the cases of somegenetic diseases, where knowledge of family historyis important for preventive measures to be taken bythe offspring (14). Moreover, with the advancement
xv This kind of analysis is present from different backgrounds. Daniels, from New Zealand, points out that depriving the childof this information is considered as a protection. And he points out that “This desire to give protection is, I believe, basedon adults’ discomfort with infertility, the practice of semen, oocyte and embryo donation and their belief that there issomething ‘wrong’, ‘stigmatizing’ or ‘marginalizing’ about being conceived in this way”(13).
xvi There are different degrees of openness: the fact of a donor intervention shared with the child; the identity of the donormay be told to the child. The latter depends on the legislation or on the possibility of getting such information.
xvii Family therapy experience indicates that family relationships are damaged when they are based on deception, and thatsuch deceptions lead to stress and anxiety. Psychological problems are also mentioned. In addition, finding out the truthabout one’s genetic parents later in life may erode the trust in parents (those who kept this information). It may come outin psychologically disturbing situations, around a crisis period: in the middle of a fight, after a divorce or the death of the“supposed” parent. Unexpected disclosure to the child in such contexts may be very damaging (14).
Assisted reproductive technology in Latin America: some ethical and sociocultural issues 37
of genetics and the popularization of DNA tests,secrecy about genetic origins seems an “old-fashioned” attitude that will need to be reconsideredin the near future.
Whether the child should have access to informa-tion about his or her origins and if so, at what point isone of the controversies still present in the world’sethical and legal arenaxviii. There are still conflictingpositions between those who oppose the rights andinterests of the gamete donors to stay anonymousand the rights and interests of the offspring to knowtheir origins.
The ethical debate can be framed in relation to thenotion of “best interest of the child” (14). One of thedifficulties is the lack of agreement on how thisconcept should be interpreted and what it means.Those who argue in favour of secrecy of the informa-tion and anonymity of the provider defend the viewthat this information will be damaging to the identityof the child and to family relationships (15,16) . Thisis the position most endorsed by the medicalcommunities around the world, including the one inLatin Americaxix (17). Opponents of this practicecontend that there is growing evidence to thecontrary. They quote studies showing a number ofoffspring claiming that they have been psycho-socially damaged by the secrets that have been partof their families (14,18). Still other important issuessuch as the right to information about oneself is atstake. Findings from adoption studies are usuallyused to provide empirical support (14). However, itshould be recognized that this issue is not particularto Latin America. Here the consensus documentstrongly defends anonymity, which as mentionedearlier, is the main position of physicians (7).
ICSI
ICSI has been widely used in ART. However, there areserious problems voiced by feminists (19), ethicistsand the scientific society. These concerns are raisedby certain Latin American physicians too (20).
In the Surveillance Study the following commentwas made: “It has been suggested that ICSI shouldcompletely replace conventional IVF as even betterpregnancy rates might be expected if normal sperma-tozoa are injected” (5).
The same study reports: “ICSI is a more expensivetechnique, it is time-consuming, requires moreequipment and extra skills, and in addition to theinvasive nature of the procedure, it does not givebetter results” (5).
These are not conclusive reasons for avoiding thistechnique. It might be less convenient, but the trulydisquieting facts appear in the summary of the samereport: “Follow-up studies of children show noincrease over controls in congenital anomaliesdiagnosable at birth. There is a special concern aboutthe reproductive potential of male offspring conceivedusing ICSI. There are unknown risks (e.g. cysticfibrosis and microdeletions in the Y chromosomes) butthere may be others” (5) . And as Jacques Cohenpoints out: “Despite recent animal work, the ICSItechnique was essentially developed through itsclinical application in the human.” Until now there aresome studies with children up to 9 years of age andthere are still concerns not only regarding thosefuture adults but also multigenerational problems.
The Surveillance Study recommends that thisinformation be disclosed and that informed consentof participants be obtained. However, it seems highlyquestionable that this procedure continues to beimplemented without having clear results about thehealth and reproductive consequences of theprocedure on the offspring in the medium- and longterm. Its lack of certainty and its possibility of harmmerits more caution and the continuation of well-designed, controlled experimentation. Here again,questions arise about the ethical permissibility toknowingly harm or risk the future offspring.
xviii For example, Sweden (1984), Austria (1992) and the State of Victoria in Australia (1995) have adopted legislation allowingthe offspring access to this information; on the contrary, Norway (1987) and Spain (1996) have legislated for anonymity(14).
xix As Daniels points out “…the emphasis on not sharing information was established by doctors. There were understandablereasons for this—DI being regarded as akin to adultery, the social attitudes surrounding sexuality and the legal status of thedonors and offspring to mention the most obvious” (17). In the case of Latin America, Reñaca’s document explicitly saysthat donors’ identity should not be disclosed, but leaves it to parental responsibility to disclose gamete donation. In Brazil,the CMF Resolution protects medical secrecy for the donor’s identity.
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Other sociological aspects
Gender issues
In a report for public discussion in the Parliament,Silvina Ramos, an Argentine sociologist, pointed out:
In a social and cultural context where mother-hood is seen as necessary for the personalrealization of women, the finding of infertilityis a devastating experience: the infertilityexperience is seen as a vital crisis….Consider that infertility in our culture is asocial stigma… (21).
This quote perfectly depicts the importance ofmotherhood for women in Latin America.
A recent work of Luisa Barón reinforces theprevious point. Baron analyses the psychologicalaspects of the female partner in cases of male infertility.The study looked at 100 couples with male infertilityand under-35 women with no evident pathology whotook part in the ICSI (89/100) and donor insemination(11/100) programme. What was interesting was thepoint about sharing emotions with others: 84% of thepatients did not talk to their husbands because theyfeared they would hurt their feelings; 81% did not talkwith their families to protect their partner’s image.But, at the same time, the study also reports women’saggressive attitudes towards partners (22).
This study reveals how hard it is to express theseemotions, how women hide this problem and blamethemselves. It also shows how “macho” attitudes existnot only in males but are reinforced by the women’sattitudes. This also indirectly shows the socialpressure of being a mother and the difficulties ofundergoing these techniques.
The feminist voice
Criticism of these techniques is widely endorsed byfeminists working in this field. Particularly importantare these visions in Brazil and also, but with less force,in Argentina. Feminists are very suspect of thesemethods. Instead of focusing only on the impact theymay have on the individual’s private life, they providea bigger picture of the problem. They focus on thepolitical, social and economic consequences that thesetechnologies have. One of the points they make is thelack of long-term experimentation and the quickapplication to patients.
Changes in the technique are very quick andmodifications of new protocols withoutenough time for the clear evaluation of long-term risks can be observed, which show theexperimental nature of these methods (19).
They fear long-term consequences or side-effectsfrom these techniques in the woman or in the child.They have also criticized the use of women as a meansof achieving pregnancy when the male is the cause ofthe problem, mainly because the procedures are moreinvasive of the woman’s body. An example of thisappears in Barón’s study, previously presented. Thefemale partners had no demonstrable cause ofinfertility; however, 89% underwent ICSI, a moreinvasive procedure for the woman than donorinsemination.
Feminists have also expressed fear about whathappens in the laboratories, especially in countrieswhere there is no legal regulation, quality control or alicensing system for clinics (6,19,23).
What is extremely interesting is that for almost“opposite reasons” the very progressive views offeminists, who endorse respect for women, supportabortion, and fight for reproductive law enforcement,agree with the conservative views of the CatholicChurch, which as a religious authority objects to allART.
Possible accessibility
Upper- and middle-class infertile couples have accessto ART through private centres, yet such treatmentremains inaccessible to those who cannot afford thecosts, despite the fact that they are in need. Forexample, it is this population that is most likely to haveSTD and RTI (1,24). Daar also mentions that secondaryinfertility in Latin America is 40%.
While recognizing the complexities of a fairdistribution of resources in a public system, solutionsare always complex and controversial. There are twopossible approaches from an ethical perspectiveregarding ART. The first one is a full coveragecriterion, which represents a goal or ideal that shouldbe tried to be applied. It endorses the right to healthcare, and argues for a comprehensive health carepackage including ART. It justifies these practicesfrom the perspective of justice in health care. Societyhas an ethical obligation to ensure equitable accessto health care for all (25). This approach emphasizes
Assisted reproductive technology in Latin America: some ethical and sociocultural issues 39
the importance of having a child, the suffering andtragic situation that an infertile couple faces. ARTshould be included as part of the individual’s moralright to reproductive freedom. From this perspective,a negative right (i.e. the noninterference of the Statein the reproductive choice of the couple or woman) isnot enough. Such a right only allows the choice orfreedom of wealthy people. This position argues thata positive right is needed. This positive right givesthe possibility to all populations in need to haveaccess to these techniquesxx (26). Arguments from amoral stance are the right of self-determination, contri-bution to the well-being of the woman and the couple,and equality (25) . This position defends a widecoverage of these services, although it need not beunlimited. It may recognize certain limits on repro-ductive freedom, as well as on provision (for example,the number of attempts of a certain technique).
However, serious consideration should be givento a second answer which recognizes the scarcity ofresources in these countries. This approach does notemphasize so much the provision of these costlyprocedures, but rather the prevention of infertility toavoid further detriment to poor women who havealready been excluded from treatment. This secondapproach points to the costs of these procedures, thelack of resources in the region and the percentage ofsterility that arises from a lack of services in the areaof reproductive health. In this sense, it stresses theneed for fertility regulation including the use of contra-ceptives and prevention of unwanted pregnancies orunsafe, illegal abortions. It attacks some of the causesof infertility: poor prevention and lack of effective carein the area of STD; failure to provide support forbehaviours that reduce the incidence of infertility-causing diseases (not only by reinforcing theseservices, but also by increasing global education).
Although this second approach does not arguefor total coverage, and gives prevention priority overIVF or ICSI, it targets the needy. They are the oneswho are most likely to have infertility problems dueto lack of sex education, lack of contraceptive devices,and untreated STD. Within this framework, proposalsmay differ on how much ART should be covered,depending on need and available resources.
This second approach also means a commitmentto a more comprehensive answer to the problem:considering ART in Latin America separately from
basic reproductive health seems to be an irrationalapproach. If contraceptive services are denied, if STDare not adequately treated, if IVF embryos areworshipped, if abortions of genetically abnormalfetuses are forbidden, and the focus is only on provid-ing ART, at least one important point is missed. ARTcannot be maintained as a purely scientific objectivetechnique that circumvents and tries to prevent thepressure certain ideologies pose without any connec-tion to the major suffering of women, or as anendeavour that uses euphemisms to avoid pseudo-moral or religious criticisms. It is not healthy tomaintain such a hypocritical stance. It is, rather ,advisable to implement an integral and comprehensiveapproach to ART, including reproductive health ofwomen and men as a priority. Such an approach couldbe achieved through a broader range of clinicscovering not only ART but other reproductive healthservices, through capacity building, emphasis ongender issues, and also with the involvement ofconsumers.
Conclusions
Even if ART is widely practised throughout LatinAmerica, it still presents many challenges. Some of themain difficulties are related to the particularly sensitiveissue of the moral and ontological status of theembryo.
Although sociocultural and religious valuesshape the ways of providing ART in Latin America, itremains remarkable that all those involved do notengage in a dialogue: religious views are based ondogma or authority; physicians maintain their ownscientific stance; feminist concerns are marginalized;patients and human rights advocates are unheeded.Our common history of authoritarianism and dictator-ships may still be shaping this process. This lack ofdialogue, thus, may need more years of democracy,tolerance and the real exercise of open deliberationbefore the incredibly difficult dilemmas ART poses inLatin America can be worked out.
Acknowledgments
I wish to thank several colleagues from the region for theirhelp and collaboration, among them, S. Ramos, L. Barón,
xx As I suggested at the beginning of the section, it should be acknowledged that positive rights in the reproductive area arecontroversial while reproductive freedom as a negative right is usually the accepted approach.
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M. Makuch, R. Llanos, E. Hardy, A. Rotania, L. Bahamondes,M. Correa, F. Zegers-Hochschild, I. Pacheco, H. López, C.Valerio, F. Carneiro. And a special recognition to R. Macklin,S. Lancuba and S. Sommer who read an earlier version ofthis paper.
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1. Makuch M, Botega N, Bahamondes L. Physician–patient communication in the prevention of femalereproductive tract infections: some limitations. CadernosSaude Publica, Rio de Janeiro, 2000, 16:249–253.
2. Fernandez MS, Bahamondes L. Incidência dos fatôresetiológicos de esterilidade conjugal nos hospitaisuniversitários de Campinas. Revista Brasileira deGinecologia e Obstetricia, 1996,18:29–36.
3. Luna F. Is ‘best proven’ a useless criterion? Bioethics,2001, 15:273–288.
4. Baylac JP. El derecho a la salud es social. Clarín,2001:24.
5. Jones H, Cohen J. Surveillance 1998. Fertility andSterility, 1999, 71:6–34.
6. Guilhem D. New reproductive technologies, ethics andlegislation in Brazil: a delayed debate. Bioethics, 2001,15:218–230.
7. Red Latino americana de Reproducción Asistida.Consenso Latinoamericano en aspectos ético-legalesrelativos a las técnicas de reproducción asistida.Reñaca, Chile, 1996.
8. Zegers-Hochschild F. Cultural diversity in attitudestowards intervention in reproduction. In: Geoffrey MHWaites et al., eds. Current Advances in Andrology.Proceedings of the VI International Congress ofAndrology . Italy, Monduzzi Editors, 1997:411–417.
9. Zegers-Hochschild F. Cultural expectations from IVFand reproductive genetics in Latin America. HumanReproduction Update, 1999, 5 :21–25.
10. Zegers-Hochschild F. Reflexiones sobre los inicios delindividuo humano. Revista Médica de Chile, 1997,125:1500–1507.
11. Harris J. Wonderwoman and superman. Oxford, OxfordUniversity Press, 1992.
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13. Daniels K. An examination of the best interests of thechildren in the field of asssisted human reproduction.Eubios Journal of Asian and International Bioethics,
1998, 8:146–148.14. Daniels K, Taylor K. Secrecy and openness in donor
insemination. Politics and the Life Sciences , 1993,20:155–170.
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Attitudes and cultural perspectives on infertility andits alleviation in the Middle East area
GAMAL I. SEROUR
Introduction
Medical ethics are based on the moral, religious andphilosophical ideals, and principles of the society inwhich they are practised. It is therefore not surprisingto find that what is ethical in one society might not beethical in another. It is mandatory for practisingphysicians and critics of conduct to be aware of suchbackgrounds before they make their judgement ondifferent medical practice decisions (1). The ethicalattitude of the individual, whether a patient or a treat-ing physician, is often coloured by the attitude of thesociety, which reflects the interest of theologians,demographers, family planning administrators,physicians, policy-makers, sociologists, economistsand legislators. Responsible policy-makers in themedical profession in each country have to decide onwhat is ethically acceptable in their own country,guided by international guidelines which should betailored to suit their own society. Truly ethicalconduct consists of personal searching for relevantvalues that lead to an ethically inspired decision.
In a part of the world such as the Middle East,where three major religions, namely Judaism,Christianity and Islam emerged, religion still means alot and greatly influences behaviours, attitudes,practices and policy-making (2). This explains why,though many other parts of the world witnessed thesecularization of medical ethics and its loss of religious
influence during the past two decades, the MiddleEast area did not experience these changes to a similarscale.
As infertility and its treatment are related toprocreation and the preservation of humankind, theattitudes and cultural perspectives regarding it andits alleviation are extremely sensitive issues for theMiddle Eastern people. Prevention of infertility andits relief are of particular significance in the MiddleEast area because a woman’s social status, her dignityand self-esteem are closely related to her procreationpotential in the family and in the society as a whole.Childbirth and rearing are regarded as family commit-ments and not just biological and social functions (3).
There are different modalities available for thetreatment of infertility in both the female and malepartners, depending upon the cause of infertility. Someof these modalities have been practised for hundredsof years and were never of ethical concern; medicaltherapy, hormonal therapy, corrective and recons-tructive surgery for female or male infertility are someof these modalities. The general ethical principles,which govern the medical practices in general, are alsoapplicable to all these lines of treatment. All thesemodalities of treatment were not of a major ethicalconcern because they did not separate the bondingof the sexual act from the process of conception.Reproduction was only possible when both partnershad sexual intercourse mostly within the frame of
42 GAMAL I. SEROUR
marriage for months or years after undergoing thesemodalities of treatment (4).
With the advent of assisted reproductive technol-ogies (ART) since the birth of the first test-tube babyLouise Brown in the UK in 1978 (5), it became possibleto separate the bonding from the reproductive aspectsof sex. ART, whether in vivo or in vitro, enabled womento conceive without having sex. This challenged theage-old ideas and provoked discussion. Furthermore,ART made it possible for the involvement of a thirdparty in the process of reproduction, whether byproviding an egg, a sperm, an embryo or a uterus. Theuse of ART also made it possible for scientists, forthe first time, to be able to handle human gametes andhuman embryos in the laboratory.
There are several factors which affect the attitudesand cultural perspectives of members of the societytowards ART. Some of the important factors will bedealt with in this text with special reference to theethical issues and principles involved in providingand utilizing such technology for the treatment ofinfertility.
Religious and cultural factors
It was not surprising that all these new modalities ofART created and provoked debate, disagreement andcontroversy among all societies and religious sectorsall over the world, including the Middle East area.
Infertility and its remedy is allowed and encour-aged for all sectors in the Middle East. For Muslimsand Christians it is essential, as it involves preserva-tion of procreation and humankind (6,7) .
The Jewish attitude to infertility treatment is basedon the fact that the first commandment from God toAdam was “Be fruitful and multiply”. This is expressedin a Talmudic saying from the second century, whichsays “Any man who has no children is considered adead man.” This attitude arises from the Bible itselfand refers to the words of Rachel, who was barren,“Give me children or else I die” (8).
Though ART as an additional line of treatment ofinfertility would have been expected to be welcomedin the Middle East area, the instalment of ART centresin many countries in the area was delayed until themid-1980s due to several factors, the most importantof which were religious and cultural factors.
The handling of human gametes in the laboratoryand the involvement of a third party in the process ofconception created the most bizarre and inconsistent
attitudes in many countries all over the world andparticularly in the Middle East area (6,7,9,10). It wasnot until the Fatwas from Al-Azhar in 1980 (6), theIslamic Fikh Council in Mecca in 1984 (10), and theChurch of Alexandria in 1989 (7) that the proceduregained popularity and became widely acceptable tothe medical profession, patients, religious leaders andpolicy-makers in most countries of the area. Thesebodies and organizations issued guidelines whichwere adopted by the National Medical Councils andMinistries of Health in the various countries andcontrolled the practices of ART centres.
The guidelines encouraged couples to seekinfertility treatment including ART, as long as therewas medical indication for its use. However, it made itclear that gametes of a third person should not beused and the fertilized eggs should be transferred tothe uterus of the wife whose eggs they were within avalid marriage contract. No egg donation, spermdonation, embryo donation or surrogacy was allowed.There were little differences among these guidelines,mostly on the issue of surrogacy. While the IslamicFikh Council of Mecca and the Church of Alexandriapreviously allowed surrogacy to be performed on thesecond wife of the same husband or a friend of thefamily, respectively, both councils soon after deniedsurrogacy and their guidelines became identical withthose of Al-Azhar. The promulgation of theseguidelines was just a response to the needs of thecommunity, and the discussions and debates whicharose in the area, as well as the problems anticipatedwith the practice of surrogacy with special referenceto the cultural and religious background of the peoplein the area.
These guidelines and legislation played a majorrole in comforting patients and physicians. In theeighties, seeking infertility treatment was associatedwith secrecy, feelings of shame, doubt and evensometimes guilt, but in the nineties such feelings werereplaced by openness about seeking infertilitytreatment and ART in particular. This was confirmedin several studies conducted at the infertility and invitro fertilization (IVF) centres in Egypt (11). Theintroduction of intracytoplasmic sperm injection (ICSI)for male infertility played a role in the change ofattitudes of many couples to ART. This happenedbecause men or husbands in the structure of the familyin the area are usually the more influential members indecision-making. When the female factor was thecause of infertility, not uncommonly, husbands wouldbe reluctant to seek medical advice early in marriage,
Attitudes and cultural perspectives on infertility and its alleviation in the Middle East area 43
especially when the treatment was not conventional.Husbands were very reluctant to participate in or toagree to their wives undergoing ART for the treatmentof female factor infertility. Also, the fact thatpolygamy is a possible solution for husbands to fatherchildren if the wife was the cause of infertility mademany husbands reluctant to agree to undergo ART,especially in the rural areas. However, when ICSI wasintroduced it offered great hope to many infertile men,especially those with severe oligoasthenospermia orazoospermia. Husbands became very enthusiasticabout ART and they took the initiative and encour-aged their wives to undergo this new modality oftreatment once it became available. The objections andresistance of male partners to undergo ART almostdisappeared. This encouraged many couples in thearea to make use of ART for the treatment of theirinfertility.
More recent debates and conferences addressednew practices of ART, such as selective fetalreduction, preimplantation genetic diagnosis (PGD),cryopreservation of human gametes and embryos,surrogacy and sex selection. Guidelines on thesepractices were published and made known to thepublic and helped patients and physicians to formulatetheir attitude towards these new practices (12–17).These guidelines were basically consistent with theprevious guidelines. They also discussed andformulated guidelines on new practices in the field ofART in the light of new knowledge which becameavailable. They were published by different authoritiesin the area, including the organization of IslamicMedicine in Kuwait, the International Islamic Centerfor Population Studies and Research, Al-AzharUniversity, Egypt and by other scholars and scientistsin international journals and textbooks.
Cost
Another factor which hindered early establishment ofART centres in many countries of the area was thehigh cost of such centres, as many of these countrieshave limited health resources. In the eighties, theestablishment of an ART centre with acceptedinternational standards would cost about US$400 000–US$ 500 000 (18). This relatively high costlimited the instalment of such centres in governmentalinstitutions. Most of the centres in the majority of thecountries in the area are in the private sector. The costto the patient is still quite high in relation to the
average family income. Indeed, this is a particularlydistressing factor for both the patient and thephysician, as ART is not supported by the healthauthorities in many countries in the area. Manyorganizations, companies and government authoritiescover medical expenses of their employees but notthose expenses related to infertility treatment. Policy-makers do not consider infertility to be a disease.Consequently, infertile patients have had to cover allexpenses for their infertility treatment in mostcountries in the area. In one study in Egypt, it wasshown that only 63% of those patients who neededART seen at a private infertility centre could afford tohave the procedure done. Only 40% of those who didnot get pregnant after the first attempt at ART couldafford to have the procedure repeated (19).
The ethical principle of justice implies that allpeople should have equitable access to health careservices. However, because of the rapidly increasingcost of medical technology and advanced health careservices in different fields of medicine, the questionof resource allocation becomes a pressing andsometimes a decisive one. If the country has adequateresources and can provide basic health services aswell as advanced health care services, there is noproblem. In countries where resources are limited andbasic health services are lacking, implementation ofadvanced health care services, though it could benefita certain sector of the population, could be unjust,because it deprives a major sector of the populationof basic health services. In this context, there is acollision between the principles of justice and equity(20 ).
The principle of liberty guarantees a right tofreedom of action, including the right to have accessto health care services such as ART. However, inmany countries, resources are scarce and many needypatients cannot exercise such a right of freedom ofaction. By contrast, rich members of the society notuncommonly have access either to private centres inthe country or to the desired services in one of thedeveloped countries. This certainly violates theprinciple of justice, which requires that everyone hasequitable access to necessary goods and services.
A mechanism should be found in these countriesto allow the needy to have access to such expensivecentres. A suggested solution for such situations maybe donations to provide support for the treatment ofthe poor and needy at these centres. The donationsmay be provided by those rich members of societywho have had successful treatment in these centres,
44 GAMAL I. SEROUR
by pharmaceutical companies which profit from thesecentres, and possibly by funding from researchprojects conducted in these centres (20). Provisionof services at governmental and university institu-tions, establishment of charitable projects andappropriate collaboration with drug companies andother commercial enterprises committed to causes ofsocial justice are some alternative mechanisms.Arrangements might also be considered by whichprivate ART centres, perhaps as a condition of statelicensure, would be required to offer a proportion oftheir services at no cost or very low cost to needyrecipients. For instance, governmental or othersubsidies might be paid to private ART centres wherepublic facilities are few, or the fees charged by privatecentres to those with adequate means to pay mightinclude a surcharge to fund services for patientsunable to pay the full, or any, fees.
Accessibility of ART
Concerns of equitable access to ART go beyondeconomic equity. The professional skills and sophis-ticated equipment required to establish an ART centrehas resulted in only a small number of such facilitiesin most countries and these are largely concentratedin major private centres in major cities. Residents ofrural areas often find services they can affordgeographically inaccessible. The challenge of takingART services to rural areas appears almostinsuperable. This is particularly the case becauseundergoing ART treatment entails several visits bythe patient to the ART centre, which may extend overa four- to six-week period for each treatment cycle.More should be done to prevent infertility in ruralareas. In countries where more than 70% of all birthsare attended by traditional birth attendants (Dayas),aseptic precautions are not always observed, resultingin a high incidence of pelvic infections and secondaryinfertility. Furthermore, harmful practices, whether bythe patients or the doctors, have been shown to resultin a high incidence of iatrogenic infertility (21) .Improvement in the standard of health care servicesand health education, especially in the rural areas,would prevent a substantial number of cases ofinfertility. Clinical care of treatable infertility shouldbe promoted, but equitable provision of ART toovercome irreversible fertility among rural and remotepopulations present a continuing challenge (17). Untilthe early nineties, only a few ART centres existed in a
few countries of the area. Patients had to travel fromone country to another or, if they could afford theexpense, they had to travel to one of the Europeancountries or to the USA. Even in the same country,couples sometimes had to travel long distances to thecapital of the country to undergo the procedure andhad to stay away from home for some time. Thiscreated unacceptability of the procedure for manycouples, even though they could afford to have theprocedure done. However, today ART centres areavailable in almost all countries of the region and inmany countries there is more than one centre, depend-ing upon the size of the country and its population.Such accessibility played a role in changing theattitude of many couples in these countries regardingthe procedure.
Techniques and complications
When the successful outcome of ART was firstpublished in 1978, the procedure involved laparo-scopic retrieval of the oocyte in a natural cycle (5).Most of the patients at that time had had severallaparotomies which made oocyte retrieval a difficultprocedure, needed a lot of experience and was aprocedure associated with risks to the patients. Also,both the patients and the treating teams had to sufferfrom long, tedious monitoring and working hours.These problems, coupled with the relatively low live-birth rate following the procedure, had a negative effecton the attitude of patients towards the procedure andseveral medical associations and obstetrics andgynaecology societies in many countries in the areaquestioned the whole procedure and its cost-effectiveness. WHO called an expert scientific groupmeeting on ART for evaluation of the whole issue(22). However, improvements in ovarian stimulationprotocols, simplification of the technique andmonitoring of the procedure, and the introduction ofcryopreservation significantly improved the results(23). ART is today considered to be an effectivemanagement of infertility and has an acceptableincidence of complications. Complications rarelyendanger the life of the patient (24,25) . This had apositive effect on the attitudes of the patients towardsART. However, when such treatment is offered, theindications should be definitive. Patients should bemonitored properly and measures should be taken tominimize the incidence of complications (24,25).
Attitudes and cultural perspectives on infertility and its alleviation in the Middle East area 45
Acceptable guidelines and legislations onART in the Middle East area
Today ART guidelines for Christians and Muslims inthe area of the Middle East are almost the same. A fewdifferences existed in the eighties but with the finalmodifications of these guidelines by various religiousauthorities they became almost identical (2). However,Jewish guidelines and legislations are different.
There is near unanimity in that the use of semenfrom the husband for artitificial insemination byhusband (AIH) is permissible if no other method ispossible for the wife to become pregnant. Masturba-tion should be avoided if at all possible, and coitusinterruptus or the use of a condom seem to be thepreferred methods for semen collection.
Artificial donor insemination (AID) is notaccepted by most rabbinical authorities. All Jewishlegal experts agree that AID using the semen of aJewish donor is forbidden. Some rabbinical authoritiespermit AID when the donor is a non-Jew. The attitudefavoured by Jewish religious authorities with regardto IVF and embryo transfer (ET) is based on thecommandment of procreation in the Bible. Manyrabbinical authorities permit the collection of semeneither by coitus interruptus or in a perforated condom.In the case of ovum donation or embryo donation,there is a divisible partnership–ownership of the eggand the environment in which the embryo is con-ceived. Jewish law states that the child is related tothe one who finished its formation; the one who gavebirth. The religious law decrees that only the offspringof a Jewish mother may be regarded as a Jew. Freezingof sperm and pre-embryo is permitted in Judaism onlywhen all other measures have been taken to ensurethat the father’s identity will not be lost. The Jewishreligion does not forbid the practice of surrogacy (8).
In the field of embryo research, the Biblical andTalmudic law holds that the full status of a humanbeing is not present at the moment of fertilization, butis acquired after a period of postimplantationdevelopment. An important feature of Jewish thinkingin this area is that embryos outside the womb, analo-gous to gametes, have no legal status unless parentalintent gives them life potential by implantation andpregnancy. An embryo made for IVF treatment andmaintained in vitro without the potential forimplantation could therefore be donated and used fortherapeutic research. This would be in line with life-saving duty, which is strong in Judaism (26).
For Muslims and Christians, since marriage is acontract between the wife and husband during thespan of their marriage, no third party intrudes into themarital functions of sex and procreation. A third partyis not acceptable, whether he or she is providing asperm, an egg, an embryo or a uterus (6,7,12,13,19) .
If the marriage contract has come to an endbecause of divorce, or death of the husband, artificialreproduction cannot be performed on the femalepartner even using sperm cells from the formerhusband.
At an International Workshop on “Ethical Implica-tions of the Use of ART for Treatment of InfertilityUpdate”, organized by the International Islamic Centerfor Population Studies and Research, Al-AzharUniversity in November 2000, there was a vigorous,principled debate on whether a couple’s preservedembryo could properly be implanted in a wife after herhusband’s death. The strict view was that marriageends at death, and procuring pregnancy in anunmarried woman is forbidden by religious laws; forinstance, on children’s rights to be reared by twoparents, and on inheritance. After due time, the widowmight remarry, but could not then bear a child that wasnot her new husband’s. An opposing view, advancedas reflecting both Islamic compassion and women’sinterests as widows, was that a woman left alonethrough early widowhood would be well and tolerablyserved by bearing her deceased husband’s child,through her enjoying companionship, discharge ofreligious duties of childbearing, and later support.Unable itself to resolve the conflicting views, theworkshop recommended that the question beforwarded to the Islamic Research Council regardingwhether an ART centre could agree to a widow’srequest for thawing and implantation of an embryocreated while her husband was alive (17).
The Grand Mufti of Egypt stated that permissionhad been given once for embryo implantation after thehusband’s death, based on the circumstances of theparticular case (personal communication). The GrandMufti made it very clear that permission was given inthat particular case for several reasons combinedtogether. The husband had agreed to the procedureof ART including ET when he voluntarily came to theIVF and ET centre and delivered his semen sample.He was informed by the IVF centre that his spermshad successfully fertilized the oocytes from his wife.He informed the centre that he would bring his wifeon the day of ET to have the procedure done. Thehusband’s parents witnessed all these arrangements
46 GAMAL I. SEROUR
and reported to the Grand Mufti that the man died inan accident on his way to the centre with his wife tohave the procedure completed. All members of thefamily strongly supported the transfer of the cryo-preserved embryos and all guaranteed that therewould be no heritage problems in the family. Althoughpermission for implantation was granted in thisparticular case, it should not be generalized, and eachcase should be considered on its own merits (27).
Surrogate motherhood
Although it was allowed in the past (7,10), the presentstatus in the region is that surrogacy is forbidden.Very recently an intensive debate started in Egypt onthe issue of surrogacy. Many scholars, lawyers andphysicians from Egypt and the other Arab countriesparticipated in this debate. For the first time,supporters of surrogacy declared their views on thisissue and strongly defended it. They defended it onthe basis of response to a patient’s demand and tosatisfy the urge for motherhood in a patient who hashad her uterus previously removed because ofmultiple fibroids. The Islamic Research Council helda special meeting in April 2001 to discuss this issue.The Council published its statement whichcondemned surrogacy on the basis of third partyintrusion into procreation. However, there was nounanimous agreement from its members on thestatement (28).
Multifetal pregnancy reduction
Multifetal pregnancy reduction is only allowed if theprospect of carrying the pregnancy to viability is verysmall. It is also allowed if the life or health of the motheris in jeopardy (3,13,29). The couple should becarefully counselled on this issue and the finaldecision should be left to the couple. The physicianshould obtain the voluntary informed consent of thecouple before performing multifetal pregnancyreduction for high-order multiple pregnancy. The high-order multiple pregnancy is reduced to two. Theprocedure is a must for quadruplets and higher-ordermultiples. In the case of triplets, the issue is not veryclear and the choice of the couple is the determiningfactor in such situations (30).
Sex selection
Preimplantation genetic diagnosis for sex selection forthe prevention of sex-linked diseases is allowed.However, sex selection for the mere choice of sex isgenerally not acceptable (20). Some had recentlyadvocated the use of PGD for social reasons andrestoration of sex balance in the family (31). However,this policy is not supported by either Muslim orChristian scholars in the region.
The Cairo Workshop of 2000 recognized theimportance of PGD, but was guarded about its use onnonmedical grounds, such as sex selection or familybalancing, considering that each case should betreated on its own merits. The medical application ofPGD was seen as marking progress in the field of ART,and as a welcome alternative to prenatal diagnosisthat results in abortion. Muslims have not acceptedthe opinion of the Roman Catholic Church adopted in1969 that human life be considered to begin atconception, but adhere to the view that human liferequiring protection commences some weeks, perhapstwo weeks or so, from conception and uterineimplantation. Accordingly, decisions not to attemptimplantation of embryos produced in vitro ongrounds that they show serious chromosomal orgenetic anomalies, such as aneuploidy, cystic fibrosis,muscular dystrophy or haemophilia, are acceptable.PGD is encouraged, where feasible, as an option toavoid clinical pregnancy terminations of couples atexceptionally high risk (32).
More contentious is nonmedical PGD, particularlyfor purposes of sex selection. Sex selection technol-ogies have been condemned on the ground that theirapplication is to discriminate against female embryosand fetuses, thereby perpetuating prejudice againstthe girl child (33) and social devaluation of women.For instance, the Convention on Human Rights andBiomedicine of the Council of Europe provides that“The use of techniques of medically assistedprocreation shall not be allowed for the purpose ofchoosing a future child’s sex, except where serioushereditary sex-related disease is to be avoided” (34).The Workshop endorsed the condemnation of suchdiscrimination and devaluation, but considered thatuniversal prohibition would itself risk prejudice towomen in many present societies, especially whilebirths of sons remain central to women’s well-being.Family balancing was considered acceptable, forinstance, where a wife had borne three or fourdaughters and it was in her and her family’s best
Attitudes and cultural perspectives on infertility and its alleviation in the Middle East area 47
interests that another pregnancy should be her last.Employing PGD to ensure the birth of a son mightthen be approved, to satisfy a sense of religious orfamily obligation and to save the woman fromincreasingly risk-laden pregnancies. The Workshopconsidered that an application for PGD for sexselection should be disfavoured in principle, butresolved on its particular merits (32).
Pregnancy in the postmenopausal period appealsto egalitarians as it is just for old women to havechildren since older men have always been able tofather children. However, the issue is not that simple.Men are not directly involved in the process ofpregnancy, childbirth and, to a great extent, in theprocess of mothering the newly born child, at least inthe first few months of life. These reproductiveprocesses may carry an increased maternal risk tomothers, especially if pregnancy occurs in the latefifties or sixties (3). Also, postmenopausal pregnancymay increase the chances of the children becomingorphans at a young age. Postmenopausal pregnancy,at least at present, involves egg donation, and apossible increased maternal risk. Pregnancy in thepostmenopause using the wife’s frozen–thawedoocytes or embryos overcome the problems of mixinggenes (3).
The Cairo Workshop of 2000 was able to agree onthe recommendation of postmenopausal pregnancywhen it is necessary. Its agreement marked a point ofdevelopment, since earlier the possibility of post-menopausal pregnancy was considered dependent onovum donation, which was disapproved of in principleat the 1991 Conference (13). The 1997 Workshopsimilarly found that “pregnancy […] after menopauseis extremely dangerous for both mother and child, alsoinvolving a third party and, accordingly, isunacceptable in the Muslim world” (15). Neither the1991 nor the 1997 meetings took account of theprospect of cryopreservation and in vitro growth, ifnecessary, of a woman’s own ovum for IVF andpostmenopausal implantation. The Cairo Workshopin 2000 considered this as a still remote but feasibleprospect, and shaped its recommendation accordingly(17).
The Workshop considered the special carenecessary for the safe induction and completion ofpregnancy in a woman who was of advanced, orbeyond normal, childbearing years, and of the easiercase where premature menopause affects a woman whowould otherwise be of suitable maternal age. TheWorkshop took account of children’s needs of parents
likely to survive at least into their mid-adolescence. Itaccordingly recommended that research efforts beconcentrated on the prevention of prematuremenopause and that attempts at postmenopausalpregnancy be permissible in exceptional casesjustified by the maintenance of integrity of a child’sgenetic parentage, the pressing nature of thecircumstances, the relative safety to mother and child,and parental capacity to discharge childbearingresponsibilities (17).
Gene therapy
Gene therapy includes somatic cell gene therapy,germ-line gene therapy, enhancement geneticengineering (whether somatic cell enhancement orgerm-line enhancement), and eugenic geneticengineering. Genetic manipulation is desirable toremedy genetic defects (3,16). Serious ethicalquestions begin to arise in borderline cases, when theaim of genetic manipulation shifts from therapy to thecreation of new human types. Though there was ageneral approval of somatic cell gene therapy, ethicshas not been able to solve the dilemmas of germ-linegene therapy (3,16,20).
Allied with stem cell research is the prospect ofgene therapy (35) . Progress in somatic cell genetherapy, which alters the genes only of a treatedpatient, has suffered recent setbacks. Germ-line genetherapy, which would affect all future generations ofa patient’s offspring, remains little short of beinguniversally condemned and prohibited. The CairoWorkshop in 2000 recognized that genetic alterationof embryos before their cells have reached differentia-tion—that is while they are still totipotent—wouldconstitute germline manipulation. The Workshopfound that little would be added to reiterate prevailingcondemnation, and offered less of a recommendationthan an observation. The Workshop stated that genetherapy is a developing area that may be used withART in the future. It is critical that its use be clearlybeneficial, focused on alleviating human suffering(17) .
The focus on therapeutic applications wouldexclude purely cosmetic uses and goals of enhance-ment of nonpathological conditions. Alleviation ofgenetic diseases and pathological conditions alonewould exclude such applications as to make peoplewho would be within the normal range of physique,capacity, and aptitude, taller, stronger, more likely to
48 GAMAL I. SEROUR
achieve athletic success or to be more intelligent orartistically sensitive or gifted. The backgroundconcept was that gene therapy might be legitimate,not to promote advantage or privilege, but to redeemgenetically or otherwise physiologically inheriteddisadvantage (17). Though gene therapy andhandling human embryos at the early phase ofembryonic development would be acceptable forMuslims and Jews until two weeks or more afterfertilization, the issue is rather complicated for theChristian sector of the area.
Some branches of Christian thought (in theProtestant tradition) regard full human status assomething which is acquired gradually, and whichmight therefore not be present in the early embryo.Protestant theology, however, is very diverse, and itis more difficult to find a single source of authorityon this issue to which reference might be made. It is,in fact, part of the Protestant ethos that moralquestions are determined by the individual conscience,and there is, therefore, room for a variety of stanceson this point. Protestant thought, therefore, mayaccept that this is an issue on which Christians mayhave very differing views, with these differing viewsbeing compatible with Christian beliefs. However, onemust not forget that there are many fundamentalistProtestants, whose views are as strict as those of theCatholic Church on issues in human reproduction.
The most strongly argued opposition to the useof embryos for therapeutic or research purposes is tobe found within the Roman Catholic tradition. In theCatholic view, a human being comes into existence atthe time of fertilization, and the embryo is thereforeconsidered as a human individual having the right toits own life. An individual embryo should thereforebe given the opportunity to develop into a maturehuman being. It is an implication of this position thatit is necessary to strictly control the fertilization of ovain vitro, and it is impermissible to use supernumeraryembryos for therapeutic purposes. This is because thelife of that embryo is sacred and it cannot be endedby any human agency.
This brief statement of some of the major religiouspositions on the use of embryos reveals a starkcontrast between religious notions of the status of theembryo. If the question is defined as the embryo’smoral status, the various religious traditions are proneto take opposite positions. If it is defined in a broaderperspective, then there may be room for someagreement (26).
Uterine transplant
The Cairo Workshop in 2000 recommended thatresearch in uterine transplantation in animals couldgo forward. However, if and when it should prove tobe safe and effective for possible use in humans,within approved transplantation guidelines, furtherconsideration of the use of this procedure should bereferred to the Islamic Research Council fordiscussion. Other organizations and authorities, suchas the Church of Alexandria, may have to do the same.An issue would be whether such transplantationwould violate the prohibition against third-partyinvolvement in a married couple’s reproduction.Involvement might not be as personal as gametedonation or surrogate motherhood, but may not simplybe analogous to, for instance, anonymous kidneydonation that enables a person to survive and becomea parent, due to the influence the uterine environmentmay have on the child’s biological development andpersonality (17).
Less novel but worthy of serious attention areconditioning issues of donors’ competence, free andinformed consent to total hysterectomy, their tissuecompatibility with potential recipients, and theirchildbearing or postmenopausal status. A menopausaluterus can function normally under hormonalstimulation and, once transplanted into a recipientwithout rejection, could receive an ovum released bythe recipient and fertilized by her husband in thenormal way. A mother might thereby donate a uterusto her daughter to allow birth of her grandchild. TheWorkshop was aware of an apparently abusive anddisastrous pioneering attempt at uterine transplanta-tion in Saudi Arabia (36), illustrating the potential forexploitation of donors, and also consideredrecipients’ indications for the procedure. These wouldinclude congenital absence of the uterus, extremeuterine hypoplasia, previous medically compelledhysterectomy, destruction of the endometrium byinfection such as tuberculosis, and excessivecurettage following dilatation and curettage.
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34. Council of Europe, Directorate of Legal Affairs.Convention for the Projection of Human Rights andDignity of the Human Being with regard to the Appli-cation of Biology and Medicine. Convention on HumanRights and Biomedicine, Strasbourg, 1996, Art. 14.
35. El-Bayoumi AA, Al Ali K. Gene therapy: the state ofthe ART. Rabat, Morocco, Islamic Educational,Scientific and Cultural Organization (ISESCO), 2000.
36. Kandela P. Uterine transplantation failure causes SaudiArabian government clampdown. Lancet , 2000,356 :838.
50 OSATO F. GIWA-OSAGIE
Social and ethical aspects of assisted conceptionin anglophone sub-Saharan Africa
OSATO F. GIWA-OSAGIE
Scope
This paper focuses on the anglophone countries ofsub-Saharan Africa. The sources of information arethe Gambia, Ghana, Kenya, Nigeria, Sierra Leone andZimbabwe. Information has been gathered from visitsto these countries, correspondence with colleaguesin these countries, from the media, publications, anddiscussions with informed persons.
Sociocultural context
In this subregion there are multiple ethnic groups andlanguages. In Nigeria alone, there are over 50 ethnicgroups and languages. However, in the subregion,English is the main language of official communicationand the countries share a colonial past. There aredistinct cultures and practices that affect the percep-tion of fertility and inheritance. In matrilineal societiessuch as among the Akan of Ghana, the intensepressure to have male children is not as obvious as inpatrilineal societies, since inheritance and child-ownership is on the mother’s or sister’s side. Inpatrilineal societies, the vast majority of West Africaincluding the Ga and the Ewe of Ghana and virtuallyall of Nigeria (1), it is particularly important to havemale children. In these patrilineal cultures the maleoffspring inherits the estate and maintains the family
name. In sub-Saharan Africa, polygamy is still widelypractised. Several countries in the subregion in West,Central, East and Southern Africa have significantMuslim populations in which a man is allowed by hisreligion to have up to four wives. The traditionalAfrican societies also allow polygamy, and the peoplehave practised polygamy (1). This combination ofantecedents has produced an environment in whichpolygamy is common and is tolerated, if not encour-aged, in modern times. Polygamy produces competi-tion between wives for mating rights, pregnancy,childbearing and great pressure to produce male heirsin patrilineal societies. Polygamy also results in anincrease in the average number of children per manand therefore the average size of the family unit,compared with a nuclear family. Concerns about childsurvival serve as a push factor for the desire for morepregnancies and children. In this sociocultural context,therefore, it is not surprising that the accepted interna-tional definition of infertility may not be satisfactory.A multiparous woman in a poly-gamous family mayconsider herself a prime candidate for fertilityenhancing therapy because she has no male childrenor may seek treatment after less than 12 months ofunprotected sexual intercourse.
Social and ethical aspects of assisted conception in anglophone sub-Saharan Africa 51
Causes of infertility
Several of the social and cultural practices in thesubregion contribute to infertility. Genital scarificationor mutilation, and vaginal incisions offer portals ofentry for genital infections, which can, and do, damagethe fallopian tubes. Child marriages and pregnancies,which often lead to complications of labour and thepuerperium, as well as labour and delivery inunhygienic circumstances, cause secondary infertility.Unsafe abortions in adolescents and young adults area major cause of secondary infertility in Africa. Therotation of mating dates between wives in a poly-gamous marriage easily leads to intercourse atnonfertile times as well as infrequent individual femaleexposure to sexual intercourse, which may be a causeof infertility (2). In sub-Saharan Africa, the maleusually controls the finances and so determineswhere his spouse(s) go for medical treatment.
It is also quite common for the male partner toconfuse sexual potency with normal male fertility,which can result in him refusing further investigationof himself or his wife if the practitioner insists on himbeing properly investigated. A man who contracts asexually transmitted infection (STI) can easily infectall his wives and partners. In some cases he mayensure that he and his favourite partners get properlytreated but abandon his less favoured partners whomhe then refuses to have sexual intercourse with. Suchneglected female partners may have inappropriatetreatment just because they do not know any betteror they cannot afford appropriate therapy.
The mother-in-law and peers play an important rolein shaping health-seeking behaviour. They may directthe infertile couple to a practitioner they know or toone of the many fringe churches (3) or traditionalmedicine practitioners. In traditional African society,a presumptive diagnosis of male or female infertilitycan be made by giving the man a second wife who isyounger than his first wife. If she fails to be pregnant,the man is presumed to be the cause of infertility. Thesame thought process allows a diagnosis to be madeif the woman in an infertile marriage marries anotherman who already has children and becomes pregnantor fails to become pregnant. A distinction is madebetween potency and fertility and, in many ethnicgroups, the words for impotence and failure to make apartner pregnant are distinct and different. There is,however, no attempt to relate failure to achievepregnancy to the content of the semen. In mostcultures of the subregion, amenorrhoea which is not
due to pregnancy or lactation, is seen as beingunnatural and is viewed with seriousness as ispregnancy that is prolonged beyond 10 months.
Treatment of infertility
The older relatives or peers are usually the first portsof call for the couple with infertility. It is thereforeobvious that the level of reproductive healthinformation available to peers and relatives affects thehealth-seeking behaviour of couples. TraditionalAfrican society recognizes the role of native doctors,herbalists and spiritualists in everyday mattersincluding the diagnosis of the causes and manage-ment of infertility. These cultures also accept a rolefor traditional gods and goddesses. In most parts ofSouth Western Nigeria and among some ethnicgroups along the West Coast of Africa, the seagoddess, Olokun, is believed to be the giver of fertility,wealth and the good things of life. The role of nativedoctors, herbalists, spiritualists and the new churchesmay be said to be that of fertility counsellors andpsychotherapists in Western medical interpretation(3) .
In the traditional society of many ethnic groupsin the subregion, male infertility was treated throughsurrogate fatherhood and, within the family, by naturalinsemination. When the family is convinced that theirson is infertile, his brother or another very closerelation is allowed to have intercourse with the wifeto bear children for the infertile brother/relation. Beforesuch a relationship starts, the wife would have beencounselled by her husband and/or a close relationsuch as an elderly uncle/father or mother-in-law. Thematter is never openly discussed outside the familyand the biological father of the children will not claimthe children. In modern scientific medicine this is akinto donor semen insemination using a known relateddonor. The rationale for the choice is to ensure thatthe offspring is from the man’s family gene pool. Intraditional society it was easy to ensure thatinformation did not flow beyond the village boundary.In some cultures in this subregion also, an infertilewoman would “marry” a younger wife to bear childrenfor her husband. This practice still occurs amongsome Ibos of Eastern Nigeria and among some Edosof South Western Nigeria (4). Quite often thisyounger wife is a relation—sometimes a cousin orsister—of the older infertile wife. The older wife andthe younger wife, their husband and their children all
52 OSATO F. GIWA-OSAGIE
live together. In some cases the younger wife lives inthe village while her older children live with their fatherand the older wife and are brought up as the childrenof the older wife.
In virtually all cultures in this region it is accepted,and it is a common saying, that it is only a woman thatknows the father of her child(ren). However, if she hashad multiple sexual partners, she would not know whothe father is. The traditional Edos of Nigeria attemptto solve this riddle of paternity by deciding that if awoman has multiple partners in a pregnancy cycle, theman who had intercourse first with the woman in thecycle in which she became pregnant is the father ofthat child (4). Yet, the concept of any pregnancy duringa marriage belonging to a woman’s husband is strongin many cultures. Among some Ibos of EasternNigeria, any child conceived by a woman while stillmarried to a man, even if separated, is recognized asthe child of the man. This is even extended to anychildren borne by the woman after the man’s death ifthe woman’s new partner has not returned the dowrypaid by the dead man. It is therefore clear that theapproaches to fertility, infertility and paternity withinthe cultures of sub-Saharan Africa are fairly versatile.Traditional therapies for female infertility include:manual transabdominal massage of the uterinefundus—this technique is common among the Ijawsof the Niger Delta area of Nigeria; transvaginalrepositioning of the uterus for presumed retroversion;and application of herbs to the vagina. All thesetherapies are supposed to aid the outflow of impuritiesfrom the uterus. Sacrifices of poultry, goats or ramsmay also be performed to the gods/goddesses thatmay be annoyed or to invite their favour so thatpregnancy may occur. Gifts or sacrifices may also bemade to ancestral spirits while followers of variousreligions, including Christians (3), often fast, applyanointed oil to their bodies or drink what they describeas “holy water” to hasten pregnancy. This is thebackground in which modern assisted conception hasbeen brought to sub-Saharan Africa.
Modern assisted conception
Natural, within-the-family insemination is a familiarprocess in some cultures. Therefore, artificialinsemination is not that strange, but the idea of a thirdparty, unknown donor of sperms is not welcomebecause of fears of heredity, disease and mental illnessin the donor. On the other hand, educated couples
prefer unknown donors to family or related donors.Among women, the concept of donor eggs andembryos is very new, but indications in those requiringit is that they accept it when there is no choice andmany such women prefer a related donor. Is the womanmore tolerant of the whole process of donor gametesbecause she carries the embryo while the man is anoutsider even when he has donated the semen? Thevast majority of couples keep insemination tothemselves and do not tell people about it. The mainconcerns are about the appearance of the baby, themental health of the baby and the absence ofantisocial behaviour such as stealing and drunken-ness. In vitro fertilization (IVF) is accepted when thereis no other choice of method and is looked upon asbeing more acceptable than donor insemination oroocyte donation. Surrogate motherhood is not spokenabout—the main fear is the risk of the carrier not givingup the baby or developing a relationship with thesperm donor.
The past two decades of the 20th century haveseen the interplay of traditional and modern conceptsregarding infertility in Africa. Evidence supports theconclusion that traditional African society recognizedthat infertility could be due to female or male factorsand that the society had its own remedies, howeverscientifically imperfect, for infertility. The advent ofwestern education, urbanization and the rural to urbanmigration has had an impact on the perception andmanagement of infertility in Africa.
Ethical aspects of assisted reproductivetechnologies (ART)
The ethics of ART in Africa is influenced by thecultures of the peoples and the status of men, womenand children in the societies.
Traditional family relationships
The child is valued as the embodiment of the familygenes into the future. He is trained accordingly andpart of this process involves the child helping withfamily activities and work at home, or in the farm inrural societies. As the child grows into adulthood itis expected to carry the adult responsibilities of hisgender and family. The child is therefore a valuedmember of the family. The woman’s role relates to thevital role of ensuring continuation of the family, tribe,and race through procreation (1). The woman brings
Social and ethical aspects of assisted conception in anglophone sub-Saharan Africa 53
up the children, manages family domestic matters aswell as farming in the rural areas, and trading in thecity. She is expected to be faithful and obedient. Asshe gets older, bears children, and enters the meno-pause, she is accorded increased societal value. Nowfree from menstruation, the menopausal woman inmany African societies can participate in family andethnic activities with almost the same status as maleelders. In matrilineal societies, the older female isusually given more status and respect than her malerelations in family matters, although the civil societyis still male dominated. These family relationships areimportant in understanding how some ethical issuesare considered and how decisions on them may bereached.
Consent
Consent is a crucial part of deciding the ethical statusof any procedure such as assisted conception.Consent, or lack of it, also has vital legal implications.The prevailing body of universal ethics requires thatinformed consent be obtained before procedures arecarried out. Where an underage person requires ART,informed consent would have to be obtained from thejunior’s parent(s) or guardian(s). This was theundisputed ethical and legal position until about 20years ago. In the last decade of the 20th century, somesocieties—particularly in Western Europe and NorthAmerica—placed substantial premium on the abilityof mature juniors, who are under the legal age ofconsent, to consent to procedures such as familyplanning and related procedures. In sub-SaharanAfrica, the under-age person is deemed to be firmlyunder the care of her parents, guardians, adult siblingsor close relations who have to give consent to anyprocedure. If ART were to be necessary in juniors,therefore, these adults named above would be theones to give consent!
The legal right of the adult female to give consentfor procedures, including ART, is recognized. If sheis married, the adult female would be encouraged, andbe expected to obtain her partner’s consent, whichwould be mandatory if his gametes are required forinsemination or other ART procedures. In the Africancontext, it would be disastrous for a man to find outthat his partner had undergone ART procedureswithout his knowledge and consent. A few womenwould like to undergo procedures without telling theirhusbands. These cases are usually due to stressesexisting in the marital relationships, or between the
woman and her in-laws. We have been studying someof these matters in our fertility practice and somepreliminary results of our surveys in Lagos may beinstructive. Of 150 couples (male/female partners)100% chose not to tell anybody about their treatmentif it was donor insemination, 70% would tell nobodyof it, irrespective of whether the semen used washusband or donor semen; 30% of the women wouldhave preferred their male spouses not to be told theywere receiving donor semen; while 80% of men whosewives required donor insemination would havepreferred this not to be revealed to their female partner.In only three of 267 consecutive pregnancies by donorinsemination did the patients reveal this fact toanybody. Among the first 15 IVF babies in Lagos, onlysix parents were happy to reveal this fact to otherpersons once the babies were born. Of 30 couples whorejected donor insemination as therapy, 17 acceptedinsemination with mixed (donor/husband) semen.These preliminary urban-based experiences indicatean evolution in the attitude of urban Africans to ART.With a growing population of educated females andmales, there should be more openness in the discus-sion and acceptance of ART (5).
The status of babies born from ART
Since most couples who conceive with ART do notannounce this fact, there is no reason to expect suchbabies to be viewed differently from those conceivednaturally. The fact that the mothers are seen to bepregnant before delivery further consolidates theposition of the offspring. African parents of childrenconceived with the use of donor semen do not declarethis and do not adopt the offspring. The offspring isregistered and brought up as a biological, normaloffspring in every way. Were this not so, there wouldbe a problem if a male heir in a patrilineal family wereto be from donated sperms, as his adversaries couldargue that he was not a genetic and rightful heir.Because of this potential legal and socioculturalproblem, most practitioners of ART in Nigeria arereluctant to keep long-term records of their donors.Without records it would be impossible, therefore, toestablish the aforementioned case, although DNAanalysis would provide enough evidence to ascertainor disprove paternity. This matter should also beviewed in the context of the traditional society inwhich some ethnic groups accept that a son shouldinherit and procreate with the young widow of hisfather, and that a fertile brother can save the face of
54 OSATO F. GIWA-OSAGIE
the family by impregnating the wife of his infertilebrother. It would be interesting to observe how theshrinking world with information technology andmore education will affect the social, cultural, andethical aspects of infertility and family life in sub-Saharan Africa.
ART regulation
In all the states reviewed there is no state regulationof ART. This must be because the governments of thesubregion think that ART is not being practised to anysignificant extent yet. This status of benign neglectsuits those who prefer the field of ART to be kept outof the public arena. However, with frequent mediareports of successes in the field of ART in the sub-region, that position is likely to change in the not-distant future.
Conclusion
Assisted conception is new to Africa. Certain formsof it, such as artificial insemination , were already beingpractised in traditional societies. The first IVF babyin West Africa was delivered at the Lagos UniversityTeaching Hospital in 1989. By the year 2001, there arenow assisted conception centres in Abuja, Dakar,Douala, Harare, Lagos, Lome, Tema and Yaoundé,which carry out human IVF, while the technique of
artificial insemination is even more widespread inAfrica. In spite of this, the techniques are still notavailable widely enough, considering the populationthat requires the procedures. Virtually all the countriesthat now have ART centres have no legislation regulat-ing the procedure. There is a need for encouragementof South-to-South collaboration for the evolution ofregion-specific adaptations which may take intoconsideration the diverse circumstances, including thecultures of sub-Saharan Africa. International agenciessuch as WHO need to enable these processes to takeplace.
References
1. Wall LI. Hausa medicine: illness and well-being in aWest African culture. Durham and London, DukeUniversity Press, 1998.
2. Giwa-Osagie OF et al. Aetiologic classification and socio-medical characteristics of infertility in 250 couples.International Journal of Fertility, 1984, 29:104–108.
3. Bolaji Idowu E. African traditional religion—a defini-tion. London, Fountain Publications/SCM Press, 1973:205–206.
4. HRH Erediauwa Ukuakpolokpolo, the Oba of Benin:personal communication, 2001.
5. Giwa-Osagie OF, Nwokoro C, Ogunyemi D. Donorinsemination in Lagos. Clinical Reproduction andFertility, 1985, 3 :305–310.
ART and African sociocultural practices: worldview,belief and value systems with particularreference to francophone Africa
GODFREY B. TANGWA
Introduction
Although it is often controversial or misleading tomake generalizations about Africa, one of the safestand less controversial of such generalizations is thathuman procreation is highly valued in Africancultures. This should not, of course, be interpretedto mean that there are parts of the world or cultureswhere procreation is not valued. Procreation is a valuefor human beings in general and within all humancultures. But the ways and manner in which this valueis manifested and expressed differs from place toplace, from culture to culture, and these differencescan be used as a rough gauge of the extent ormagnitude to which the value is affirmed or upheldagainst competing values. There is no part of Africawhere children are not greatly valued and where, as aconsequence, large families do not exist or polygamyis not practised.
Children are so highly valued in Africa thatprocreation is everywhere considered the mainpurpose of marriage and the main cause of, if notjustification for, polygamy and other forms of marriagewhich may be considered more or less strange fromthe perspective of other cultures. Conversely,childlessness remains the main cause of divorce, as achildless marriage is considered to be equivalent tono marriage at all. The idea of “illegitimate child” or“bastard” is one that could make no sense and had
no application in traditional Africa because of the veryhigh value placed on children. In Cameroon, it is verycommon for the parents of a girl who is approachingher thirties as a childless spinster to urge her to tryand get a child by all means “before it becomes toolate”. If afterwards she finds a husband, her parentsare usually only too happy to keep her premaritalchild, who often, in any case, bears the father’s name.
Some consequences of the great love forthe offspring
All population control policies, family planningstrategies, birth control plans and all recommendableprocedures that obstruct the direct link between sexualintercourse and possible conception have had toreckon with very resilient attitudes in Africa, arisingultimately from a worldview and value system in whichchildren and, consequently, conception are greatlyvalued. The failure of the condom, for example, toserve as a method of prevention against the deadlyHIV/AIDS infection in some parts of Africa to thesame extent as elsewhere in the world could be linkeddirectly to this fact, that the high value placed onchildren and procreation has been transferred to thesexual act as basically an act of fecundation. It is verysignificant to note that, in cases of certain cancers,many Africans prefer death to having any of their
56 GODFREY B. TANGWA
body parts directly connected with reproductionsurgically removed.
In traditional as well as modern Africa, there is,perhaps, no category of patient that the healercounsels more frequently than the infertile woman andthe impotent man. These are medical conditions thatvery few Africans are willing to accept with resignationas long as the last possible healer has not beenconsulted and the last possible method or producttried. Also, everywhere in Africa there is some formor other of the maternal cult, which considersmotherhood the plenitude and crown of womanhood,while a childless man may often be bracketed with thechildren, a very degrading thing in a culture in whichgreat respect is accorded to age and status. Again,on the approach of death, a childless person is parti-cularly terrified because, while death is considered atransition into the realm of the ancestors, the living-dead, life, well-being and prosperity in that realm isbelieved to depend on the reciprocal interactionbetween the progeny and the ancestors, between theliving kin and the living-dead (1).
Therefore, assisted reproduction of almost anyputative type would, prima facie, be of great interestin Africa and assisted reproductive technologies(ART) could not fail to generate great interest andeven excitement in Africa. Nevertheless, ART in Africais fraught with a number of problems and contradic-tions. But, before considering these, the situation inCameroon and francophone Africa will be brieflypresented.
ART in Cameroon, the Central African sub-Region and francophone Africa
In the francophone countries of central Africa as wellas the rest of francophone Africa, as indeed in sub-Saharan Africa in general, the sociocultural system,attitudes and practices make infertility and childless-ness in general a highly undesirable condition and,more or less, a metaphysical curse. The socialimportance attached to fertility cults (1), to birth,naming and initiation rituals, to marriage, death andburial ceremonies, flow from a logic of, and accord wellonly with, generalized fecundity and procreativity.Any assistance towards fertility is therefore highlyvalued and sought.
In francophone Africa, Cameroon has a leadingposition in the domain of medically assisted reproduc-tion and two centres for in vitro fertilization and
embryo transfer (IVF-ET) exist in Yaoundé and Douala,although they each present very different attitudes,results and outlook. Other francophone Africancountries, notably Algeria, Benin, Burkina Faso,Central African Republic, Chad, Congo, EquatorialGuinea, Gabon, Mali, etc. have all had some of theirpatients coming to Cameroon or are currently tryingto learn from Cameroon and are in the process ofsetting up their own facilities for medically assistedreproduction.
The Centre de Chirurgie Endoscopique etReproduction Humaine Chantal Biya (CCERH) wasinaugurated in Yaoundé on 6 March 1998. Conceivedas a part of the Fondation Chantal Biya , the CCERHis presently hosted by the Department of Obstetrics,Gynaecology and Human Reproduction of theYaoundé General Hospital.
In 1999 (1–3 December), about 750 delegates fromall parts of the world gathered in Yaoundé for the“First Pan-African Congress on Endoscopic Surgeryin Gynaecology”. According to press reports (2), allthe Congress participants were unanimous thatgynaecology in Africa in the year 2000 would bemarked by great technological progress, particularlyin endoscopic surgery. During this conference, whichwas held at the Yaoundé Conference Centre (Palaisdes Congres), an exhibition on endoscopic surgicaloperations was performed at the CCERH and transmit-ted live by the Cameroon Radio and Television (CRTV)to Congress participants.
The Centre de Techniques de Pointe enGynecologie-Obstetrique (CTPGO), Douala, wentoperational in the middle of 1996. The Centre, whichworks in collaboration with Dr Guy Cassuto’sLaboratoire DROUOT (Paris), is run by a team of fourgynaecologists and two biologists.
Since 1997, the CTPGO has attempted IVF-ET ona total of about 200 women, of which 45 have beensuccessful, giving a percentage success rate of about19% as against 25% reported in the industrializedworld. The average age of the couples seeking toundergo the procedure in Douala is about 45 years, afactor on which the Centre partly blames the high rateof failure. The main indication for treatment has beenproblems related to the fallopian tubes of the woman(91%). A number of potential patients have presentedseeking IVF-ET with sperm other than that of ahusband but have, so far, been turned away on thegrounds that the Centre is still too young, has nofacilities for gamete storage, and that the ethicalproblems involved here are more complex and require
ART and African sociocultural practices 57
more careful consideration. Since 1997, the per patientcost of the treatment in Douala has progressively beenreduced from 1.5 million CFA francs (about US$ 2500)through 1.2 million CFA francs (US$ 2000) to 1 millionCFA francs (about US$ 1700) today. The Centre claimsthat all its babies are doing fine and that it is followingup on several of them systematically.
Evaluation
Although medically assisted reproduction generally,and IVF-ET particularly, generates a lot of interest inthis part of the world, for reasons some of which havealready been evoked, it also raises many questionsand problems. It can be said that, for good or ill, ARThas a place and a future in Africa. But one of theproblems connected with it has to do with its cost. Ata cost of 1 million CFA francs (about US$ 1700) inCameroon, for instance (said to be only about 25% ofthe cost elsewhere), this health care procedure isaffordable for only a very small minority of the small,though by no means negligible, number of coupleswho stand in need of it anywhere in Africa. Infertilityis commonly understood to be indicated if, after 12months of regular normal sexual practice withoutcontraception, a couple has not succeeded inachieving pregnancy (3). Between 75% and 80% ofall couples are said to achieve pregnancy within thesecircumstances and, if the waiting period is extendedto 24 months, around 90% of all couples succeed inachieving pregnancy. In the absence of any reliablestatistics, there is no reason to suppose that theincidence of infertility in Africa is much more or muchless than the global average which has been estimatedat 10% (4). It is not, therefore, a health care servicethat public health authorities could justifiably try topromote in the face of other urgent health andreproductive health problems facing a greaterproportion of the population. It is thus most suitable
for only the private sector, where pure economicconsiderations, the profit motive and promotionaladvertisement will be the main determinants ofdevelopments.
ART, whose medium- and long-term impact is stillto be assessed, is liable to subvert and damagetraditional African sociocultural ideas, attitudes,customs and practices that have hitherto adequatelyhandled and cushioned the problem of infertility. Inmost parts of Africa, biological parenthood is de-emphasized to the advantage of social parenthood.Because of this, infertile couples, frequently under aveil of ignorance, can solve their problem not with thehelp of technology but through a social network. Thepossibilities are many and varied: a brother or otherrelative discretely fathering a child for another, a sistermore or less openly begetting a child for another withthe latter’s husband, a wife “marrying” another wifei tobeget children for her with her husband, begging,giving and receiving a child as a special gift, adoptingchildren, assimilating children into families withoutprior intention or further calculations, etc.
Although some sort of counselling would usuallybe given to couples seeking ART, the psychologicaleffects of undergoing the procedures, especially onthe unsuccessful cases, need to be very carefullyassessed. And, although ART children are said to benot any different from naturally conceived childrenand to be generally doing fine, only careful and long-term study and follow-up can determine theirpsychological if not physiological status vis-à-vischildren conceived and born more normally. For now,the fact that these children are “test-tube babies” isconcealed from them and neighbours, but, sooner orlater, it will become known.
Furthermore, infertility might have a genetic originand the resort to ART to solve this problem meansthat the genetic defect involved is sustained andperpetuated in the population in such a way thatresort to technology will be the only option for an ever-
i The practice is quite common among several African communities, whereby a married woman who is unable to beget childrenof her own arranges to marry another woman, on whom she may personally pay the dowry, so that the latter could begetchildren with the former’s husband, and such children are considered as her (the “woman-husband’s”) children. This approachis practiced among the Igbo of Nigeria (7). Marriage in Africa is a very complex institution with a diverse variety of interestingvariations from community to community. While the variation described above was not practiced among the Nso’ of theBamenda highlands of Cameroon, some “Queen Mothers” such as the famous Yaa wo Faa (8) could marry other women whobegot children (with any men of their own choice) and such children were considered as the Yaa’s children. That is how someNso’ people today pass for second-degree princes and princesses (won-wonntoh) when, in fact, they have no drop of royalblood in them. The bottom line is that, in many parts of Africa, biological parenthood is downplayed in favour of socialparenthood and that marriage is considered as being more of a family, lineage and community affair than a contract betweenindividuals (9).
58 GODFREY B. TANGWA
increasing number of persons within that population.This prospect needs to be carefully weighed againstthe present benefits of providing satisfaction toinfertile couples or unconventional couples seekingto become parents.
The providers of ART in Africa presently operatewithin a legal and ethical vacuum, as the legal systemsof most African countries have not yet caught up withthe rapid developments in the field of reproductivehealth, as indeed in many other domains, while preciseethical guidance is not yet available. There are,therefore, real dangers of abuse and the possibilityof unregulated experimentation without any fear ofconsequences or repercussions. Providers are thusleft with only their own personal moral sensibilitiesand sensitivity or their consciences as the guidinglights for their actions and acts within the field. ButART is certainly an area where personal morality andgood intentions alone, while necessary, are far fromsufficient. The domain belongs to public morality andneeds both clear ethical guidelines and appropriatelegislation.
Above all, the wider implications of ART—itsmechanization of reproductive processes, its sever-ance of the link between “love-making” and “baby-making”, its dispelling of the mystery of procreationthrough human mastery, its de-mystification ofmotherhood, so central to the status of women inAfrican cultures, its reduction of reproduction toproduction and the human control and obsession withquality implied, etc.—would be hard to harmonize withthe most general of African metaphysical and religiousconceptions and beliefs, value systems, ideational andideological thrusts, customs and consolidatedpractices.
Conclusion
There seems to be some contradiction about theworldwide concern with, interest in and promotion ofART that needs recognizing. How can this concernand interest be reconciled with the global emphasison, and campaigns for, population reduction, whosesuccess can be seen in the downward trend ofpopulation growth, especially in the industrializedworld? In describing the advantages of endoscopicsurgery (see above), Professor Maurice AntoineBruhat ironically remarked that the greatest challengeof medicine in the third millennium would be thecontrol of reproduction because it is no longer
desirable to continue breeding at random and fillingthe earth with great numbers of people. Concern withpopulation reduction would seem more consistentwith encouraging the infertile to courageously accepttheir condition rather than trying to do everything tohelp them overcome it. Before asking the fertile tovoluntarily refrain from procreating in the interest ofpopulation control, would it not be logical first to askthe infertile to voluntarily spare themselves thetrouble, cost and pain of medically assistedreproduction? As a fertile person, to become awareof the trouble and pain infertile persons take just toget a child, is to realize just how lucky one is to befertile. Such a realization is not likely to be a helptowards the prospect of voluntarily refraining fromprocreating, which alone can eventually help to reducethe population growth rate of poor or impoverishedAfrican countries or communities to manageableproportions.
Although at the individual personal level Africanpeople’s attitudes towards ART may be determinedby their technophobia or technophilia, it is clear that,at the level of society or culture in general, technologyas such is not what counts but rather the uses to whichit is put, its general implications and the surroundingpackaging with which it comes. In my natal language,Lamnso’, there is the saying: “wan dze wan a dze limnyuy” (a child is a child, the handiwork of God), whichconnotes the unconditional acceptance and love of aneonate, irrespective of its individual and particularcharacteristics (5) . This, incidentally, has theimplication, among others, that the ART child wouldbe as welcome and as loved as any other childconceived and born in any other manner. The moralimplications of this saying are very important in viewof the innumerable differences and enormous varietywith which individual babies/human beings come fromthe hand of God or Nature.
In view of this, one of the deeper and moreimportant implications of ART is that it is inevitablyconcerned with quality control (6) and that thisconcern has the direct implication that we can nolonger say that a child is a child, the handiwork of God,but rather, in this case, a deliberate work of humanhands or, more precisely, of human technologists.Fletcher’s work just cited, which attempts to discussthe ethics of increasing human control of thereproductive domain, is a paradigm of optimism andbig thinking about reproduction technology. Thework is full of such expressions as: “quality control”,“controlled human baby-making”, “increasing the
ART and African sociocultural practices 59
quality of the babies we make”, “human reconstructionof humans”, “biological manufacture of human beingsto exact specifications”, “discarding the surplus”, etc.In the African perspective, within the context that Ihave tried to describe, suggesting that one putativebaby is of “better quality” than another would beconsidered outrageous, if not completely meaningless.
Part of the “packaging” of ART, as it comes toother peoples and cultures from the industrializedwestern world, that would not sit well with Africanideas and attitudes, is its almost overt connectionwith business and commercialization, patenting andmarketing, talk about quality control, shopping andadvertising, and all the media publicity that goes withthese. This packaging can and needs to be modifiedor changed if ART is to be firmly planted in thebackground soil of traditional African culture, customsand practices. Within that background, the categoryof mystery, the God-metaphor and the constantaffirmation of human limitations and fallibility arevery important and cannot be easily discarded orignored.
References
1. Tangwa GB. Bioethics: an African perspective.Bioethics , 1996, 10:183–200.
2. Cameroon Tribune, 6 December 1999, centrespread,pp. 8–9.
3. Pepperell RJ, Hudson B, Wood C. The infertile couple.Edinburgh, London, Melbourne and New York, ChurchillLivingstone, 1987.
4. Harrison RG, de Boer CH. Sex and infertility. London,New York, San Francisco, Academic Press, 1977.
5. Tangwa GB. The traditional African perception of aperson: some implications for bioethics. HastingsCenter Report 30 , 2000, 5:39–43.
6. Fletcher J. The ethics of genetic control: ending repro-ductive roulette. Buffalo, New York, Prometheus Books,1998.
7. Uchendu VC. The Igbo of Southeast Nigeria. New York,Chicago, San Francisco, Toronto, London, Holt,Rinehart and Winston, 1965.
8. Tangwa GB. Road companion to democracy and merito-cracy: further essays from an African perspective.Bellingham, USA, Kola Tree Press, 1998.
9. Lantum DN. Nuptiality in the Jakiri District ofCameroon , ABBIA, 1982.
60 ANJALI WIDGE
Sociocultural attitudes towards infertility andassisted reproduction in India
ANJALI WIDGE
Introduction
It is estimated that about 8%–10% of couplesexperience some sort of infertility in their reproductivelives (1). In India, primary and secondary infertilityfigures, as given in WHO studies, are 3% and 8%,respectively (2,3). Evidence from a village-level studyin the state of Maharashtra in India puts the level ofinfertility at 6%–7% (4) . According to the recentNational Family Health Survey in India, 3.8% of womenbetween the ages of 40 and 44 years have not had anychildren and 3.5% of currently married women aredeclared infecund (5).
As in many developing countries, in India tooinfertility treatment is not part of the reproductivehealth services offered. There is no public healthprogramme that focuses on infertility in the Indiancontext, though the International Conference onPopulation and Development (ICPD) programme ofaction states that reproductive health services shouldinclude prevention and appropriate treatment ofinfertility (6). The Ninth Five-Year Plan (1997–2002)document of the Government of India has includedinfertility in the comprehensive reproductive and childhealth package.
The recent AIDS epidemic has raised an interestin understanding sexually transmitted diseases (STD);however, the interventions focused on reproductivetract infections (RTI) and STD are not adequate to deal
with the whole gamut of infertility problems. Theknowledge that contraceptives are being rejected forfear of infertility has also contributed to the recentinterest in the topic (7).
According to Jejeebhoy, there is a paucity ofstudies in India exploring the perceptions andexperience of infertility, even though there has beenan adequate exploration of priorities for social scienceresearch on infertility (8–10). Rigorous social scienceresearch in the context of infertility, its causes andconsequences and a focus on programme needs havebeen suggested. According to her, the little evidenceon the levels and patterns of infertility in South Asiacomes mostly from censuses and surveys. Theparticular factors that may be associated causally withinfertility require a qualitative focus, such as the studyin Egypt on culturally specific determinants ofinfertility (10) . There is also very sparse researchavailable on the sociocultural and behaviouralcorrelates of infertility in South Asia. Sexuallytransmitted diseases, maternal health factors, poorhealth and nutritional status of women which couldlead to fetal wastage, age (adolescent sterility andinfertility among premenopausal women), lifestyle-related infertility, previous contraceptive use,marriage patterns, occupational patterns, availabilityand accessibility of reproductive health services,levels of education, economic status and women’sautonomy are recognizable correlates of infertility (8).
Sociocultural attitudes towards infertility and assisted reproduction in India 61
The new reproductive health package of theGovernment of India envisages, besides otherservices, the provision of infertility services throughthe health care delivery system. Besides being asequelum of sexually transmitted infections, infertilitycould also be an outcome of poor obstetric andgynaecological practice (11). Inadequate research isavailable on these causes of infertility. For example,RTI can be acquired through lack of access to cleanwater, unsterile procedures during childbirth orabortion and other bad medical practices. Services forinfertility and RTI are available only at district andsubdistrict hospitals and some community healthcentres. The social factors that may cause infertilitysuch as poor health care, nutritional status, contracep-tive methods or environmental factors were notconsidered important earlier (11).
Objectives
There are only a few studies in India that have focusedon the sociocultural context of fertility-seekingpractices in relation to infertility and childlessness.Even fewer studies have focused on the socialimplications of infertility and assisted reproduction.This paper summarizes some of the key findings ofmost of these studies. It also provides an overview ofsome of the literature on how people’s beliefs, values,and sociocultural norms shape the way in which theydeal with infertility and how they determine treatment-seeking behaviour, including the use of assistedreproductive technologies (ART), in the Indiancontext. As it is critical to understand the way in whichmotherhood and female identity is constructed in asociety, literature on the social construction ofmotherhood and female identity in India is alsoreviewed.
Background
The sociopolitical context
In India, infertility appears to be an unimportantquestion for policy-makers and women’s groups alike.As an example, none of the programmes of the nationalreproductive health policy has focused on imple-menting preventive and curative services for infertilitytreatment. Infertility seems to be a relatively un-important issue, as it affects only a few couples in an
“overpopulated” country. Among them, even fewercouples, those of a certain class group, are able toaccess ART. These are the primary reasons that thevoice of the childless woman is absent in the feministand policy debates surrounding reproductivetechnology in India. Hence, neither the issue ofinfertility nor the implications of ART are given anyvalue. However, irrespective of the number, or theclass of women who are affected by infertility, or haveaccess to infertility treatment, the infertile or thechildless woman is a focus for patriarchal power andthis has major social repercussions for the woman.Structural inequalities too cannot be ignored, as evenchildless women who are not at the lower end of thesocial strata are situated in the patriarchal Indian family.
The issues surrounding pregnancy, childbirth andmotherhood are very complex in all societies. There isa huge stigma attached to being infertile/childless andchildlessness has negative implications in Indiansociety, especially for the woman. Fertility defineswomanhood and womanhood is defined by a woman’scapacity to “mother”. Since it is the woman whobecomes pregnant and gives birth, society putspressure on her to “mother” even though the male maybe the one who is infertile. There is no space for infertilecouples as part of the governing definition of thefamily, which burdens the woman even more. In mostsocieties, including India, men need children to haveheirs and to prove their masculinity. The system ofpatriarchal descent, patrilocal residence (residencewith or near the patrileneal relatives of the husband),property inheritance, lineage and caste are respon-sible for the extreme importance given to fertility inIndian society (12). Due to social pressures exertedby such systems, women go through all kinds oftreatments to have a child. Women want to havechildren (sons, in the Indian context), because it bringsthem power in real terms, and also because, for many,it is the only power-base they have from which theynegotiate the terms of their existence.
Social/cultural construction of motherhoodin India
The identity of a woman in India is formed in relationto the values, meanings and symbols of Indiansociety. Her self is affected by the cultural worldoutside. The meanings and values of the culturalidentity are internalized. The ideology of motherhooddiffers according to the sociocultural context,ethnicity, and class. In India, which is mostly a
62 ANJALI WIDGE
patriarchal society, motherhood has connotations ofrespect and power. Here, the “mother goddess” asmother is highly revered, but real-life mothers arerespected to a very limited extent, and that respect isusually for mothers of sons. This can vary dependingon factors such as gender relations, class and caste.A woman is considered “complete” or “real” onlywhen she becomes a mother. She proves her woman-hood in this way and feels secure in her marriagebecause it is believed to bond the marital relationship.As a mother she feels she has accomplished what shewas supposed to do as an adult woman.
The ideology of motherhood is related to the wayfamilies are structured on kinship practices anddepends on the variations in them. Ideas aboutwomanhood and motherhood are linked to family andmarriage. Family organization and marriage areimportant to understand reproduction and mother-hood. Kinship is also important in understandinginheritance, rights over children, authority andresponsibility of members of the family or kin-group.The way the patriarchal family is structured is one ofthe major causes of inequality between men andwomen and of the understanding that motherhood isone of the major roles of a woman in society.
The mothering role of women is reproduced insociety irrespective of whether women becomemothers or not and the ideology of motherhood isdependent on the way a society constructs it.Motherhood is seen to be positively significant inmany traditional societies, since women’s reproduc-tive capacity is something which women consider theirsource of power, and as defining their identity andstatus. It is also considered a resource for women whoare denied the experience. This is true of childlesswomen who centre their whole life on the fact thatthey cannot become mothers or bear children andhave to pay a social cost for it. The ideology ofmotherhood in Indian society explains why fertility isso important. Feminine identity is defined by theideology of motherhood, being fertile is important andinfertility is a huge problem. Though the control offertility might be a problem for the state, yet infertilityis very important in the cultural context as kinship andfamily ties depend on the progeny.
Throughout India, marriages take place early andare arranged by parents, with partners chosen withina caste, subcaste or a superior caste, but not withinvery close kin. The man is usually a stranger to thebride, which puts her in a very vulnerable position.The bride is expected to bring enough dowry, be
efficient in housework, be respect-ful and serve eldersand the husband, besides also bear sons. In a jointfamily, living with the in-laws, the bride has furtherlack of control over her life, and despite beingproductive, usually has no control over resources.
The bride’s major role is mothering and taking careof the house. Only when she becomes a mother of ason does she feel completely at home in her husband’shouse. The notion of purity is very strong and controlover her sexuality begins at puberty in her parent’shome, and continues after marriage. After marriage thebride is controlled by the patri-kin and because of itspatri-local nature, feels isolated among strangers.Even when the family becomes a (semi) nuclear unitwith only the husband, wife and children, it continuesto have economic and ritual ties with the patri-family.Therefore, for the bride/wife, the situation remainsalmost unchanged. She attains some freedom onlywhen she becomes a mother or when her mother-in-lawbecomes old.
The patriarchal, patri-local and the patrilinealnature of the family exists even today. Marriage is arelationship between two families rather than betweentwo individuals but certain aspects of patriarchy arecommon to most patri-kin groups, irrespective ofwhether they are from the north or the south,especially when it comes to women’s overall status inthe family. Joint families, whatever type they might be,define property relations and regulate marriage andinheritance. Nuclear families seem to be moreadvantageous to women as they might give themrelative freedom. Though it had been said thatmodernization would bring about nuclear families andsubsequently various other changes such as freedomof marital choice, increase in divorce, disappearanceof dowry, etc. this change has been minimal. Somerules of patrilineality are relaxed, but to a limitedextent, as marital choice is rarely free and dowry exists.There are inequalities within the family in terms ofdivision of labour and distribution of resources.
Adoption is encouraged only within the family sothat property stays within the same group. As relationby blood is so important, illegitimate and adoptedchildren are not accepted easily. Earlier, the mostimportant reason for males to have more than one wifewas the desire for a male child. Even now, in spite ofthe law against polygamy, there are some men whohave two wives, because they could not have a childwith their first wife.
Sociocultural attitudes towards infertility and assisted reproduction in India 63
Sociocultural context and consequences ofinfertility/childlessness in Indian society
Since a woman is defined by her fertility, sheinternalizes the motherhood role to the extent that ifshe is infertile, she feels worthless. Then she proceedsto do all she can to reverse the situation. The experi-ence of infertility/childlessness is usually marked byanxiety and fear, societal pressures to conceive andsocial stigmatization, and various trials of varioustreatments. Infertility is a major problem in the contextof important domains of social life such as kinship,inheritance, marriage and divorce patterns. It ispolitical in the sense that it is in the overpopulatedstate’s interest to control fertility and not beconcerned about infertility. It is a threat to a woman’sidentity, status and economic insecurity, to a man’sprocreativity and to lineage, familial and communitycontinuity. Infertility has very often been comparedto bereavement and can be a wrecking experience forboth the woman and the man. It may lead to identitydilemmas, lowered self-esteem, frustration and a senseof powerlessness (13).
There are many reasons for the importance givento biological children in society. It is assumed that thedesire to have children is normal and parenthood ispart of the natural order of things. Some childlesswomen might not be that enthusiastic about mother-hood but want a child to satisfy their in-laws orhusband, or experience pregnancy, childbirth orparenthood. Some are under external pressures tohave children (as in India). For some, it makes themfeel part of daily life and for some couples a child islike an achievement. For some men, having a child isproving their sexual potency. It is important forwomen, because for them there is a link betweenfemininity and fertility. Motherhood also gives womena female adult identity and a reputation of a respon-sible human being. Children provide emotionalsatisfaction, make life interesting and provide areason for living. People also want children becauseit is almost like a biological need, as they want to seea part of themselves in their child. Some want to beable to spend the wealth they have acquired orachieved on someone, and a biological offspring isthe best person to spend it on. Having a child for somecouples affirms their love for each other as a child isseen as a binding factor. A child is also looked uponas someone who helps an urban middle-classhousewife spend her time, since the child occupiesher and gives her status in society, she also has
something to talk about with other women. A poorwoman has children for economic reasons too. Themore children she has, the more earnings there are forthe family as a whole. So children are preciousresources for her, as she usually cannot send them toschool.
Among the studies/research that have focused onthe sociocultural context and social isolation issuesresulting from childlessness are those conducted byJindal and Gupta (14), Singh and Dhaliwal (15), Neff(16), Patel (17), Iyengar and Iyengar (18), Prakasamma(20), Unisa (19), Widge (21) and Mulgaonkar (22).
According to Das Gupta, Chen and Krishnan,children in Indian society are looked at as a source oflabour, income, happiness and security in old age. Theperceptions of women’s roles and attitudes may beshifting, especially in the upper and middle classes,but procreation still remains an important factor in thesocioeconomic well-being of most Indian women (23).The Indian tradition demands that all marriages mustresult in children, preferably male ones. In thepatrilineal Indian society there is a strong desire for ason to continue the family line and perform religiousrituals for the salvation of departed souls.
Jindal and Gupta, through their study, reiteratedthat in India the social pressure to become parents iseven more because of the joint family system and theinfluence of elders. If the couple is infertile, there isloss of status and prestige. Among the women thatthey studied, social problems increased with theduration of marriage or duration of infertility, whilethese decreased with increase in age, education andincome of the husband. The problems were inverselyrelated to education and economic independence.Insistence on a male child was responsible for suchproblems in both primary and secondary infertilitycases when the first offspring was female. Poverty andilliteracy emerged as important socioeconomicdeterminants of these problems (14).
Patel’s anthropological study of fertility beha-viour in a Rajasthan village illustrates that thegraduation in status through motherhood is so markedthat barrenness is a dreaded condition. Parenthoodconfers honour on a couple and a person’s image andrespectability gets enhanced with every additionalchild’s birth and survival. Childbirth lends stability andsecurity to the bride’s relationship with members ofthe household. As far as she can prove her fertility inabout three years, even the birth of a daughter iswelcome although a son is always better. Childrensymbolize prosperity and happiness. A household
64 ANJALI WIDGE
without children is unfortunate and unbearablydesolate, “one that pounces on one like a glutton”(khali ghar khavane daude). The importance of sonsis very obvious in all caste groups as they have anumber of functions to perform towards the dischargeof kinship and ritual obligations. It is a matter ofserious concern if a woman does not bear a child for4–5 years. Barrenness is held as a curse. Besidesbeing inauspicious for auspicious occasions, she isinsulted and is under constant pressure and facesinnuendoes during quarrels and disputes. Rarely ismale fertility questioned whereas her fecundity isdoubted. Even though men are not oppressed due totheir childlessness, they do face some humiliation.Childless widows do not have the status and emotionalmoorings of widows with children but among somecastes, childless widows are more likely to getremarried (17).
Neff explored the social construction of infertilityamong the matrilineal Nayars of South India. Theresearch shows that it is the duty of matrilineal kin toattend to the family god of fertility and to the needsof females of the matrilineage to see that they fosterprogeny in the kin group’s best interests. When thisresponsibility is violated, powerful forms of negativeconsequences may transpire for all lineage members,in the idiom of curses of family fertility godsi (16).
According to Prakasamma, procreation, continuity,perpetuation through the progeny and the need forself-preservation form the social construction ofinfertility in India. The study revealed that infertilitythreatens the social acceptability of a woman, herlegitimate role of a wife, her marital stability, security,bonding and her role in the family and community. Thechildless woman is not considered feminine andsuffers from low self-worth and blame. The cycle ofdenial–treatment–frustration–resignation leads toemotional strain. If there is a case of a second marriage,there is loss of entitlement (20).
Mukhopadhyay and Garimella conducted a studyon reproductive choice that revealed a high rate ofmorbidity among the women, apart from inadequateservices and supplies and a near-total absence of male
support or sensitivity towards female health problems.Women carried the burden of infertility alone and theyhad a nagging fear of desertion by their husbands(24). The blame for sterility lies entirely with the femalepartner, conclude Devi et. al., who studied the socialfactors contributing to sterility in the state of Manipur(25).
Recent research by Gerrits, Unisa, Widge andMulgaonkar has also highlighted the consequencesof childlessness (19,21,22,26). The women who wereinterviewed for the study conducted by Widge feltthat motherhood is still the most important goal for awoman. The blood-bond between mother and childovertakes the one with the husband. Maternal instinctin most cases in the study was perceived to be anindividual urge. The woman is usually blamed forchildlessness while men hesitate to even get tested.Childlessness also brings exclusion from the socialnexus of mothers and couples with children. Peopleare usually insensitive to this problem and sometimesmake pointed references to it. Moreover, children seemto be the central point of discussion for mothers, so achildless mother feels excluded and her childlessnessbecomes more obvious. Most couples that arechildless centre their lives on trying to conceive orcoping with not being able to. Friends are not verysupportive but are less interfering than relatives/extended family, as the latter can make the couple feelexcluded. The couples who were interviewed felt thatit is very important to have a son, as lineage, kinship,dowry and old age concerns are prime. The mother-hood role is internalized by women. The studyconducted by Widge reiterates the connectionbetween fertility–womanhood–motherhood in Indiansociety (21) .
According to Iyengar and Iyengar, one of thesocial consequences of infertility in the study theyconducted in Southern Rajasthan is the practice ofnata (by which a person can take on a new spouse)that is prevalent in this area. About 20% of childlesswomen were affected by this practice but, interest-ingly, about 15% of the women had taken anotherspouseii (18,27) .
i In the ritual of pampin tullal performed to propitiate these gods, concepts of fertility are extended to include other “auspicious”forms of prosperity. In the ritual, unattached Nayar women serve as proxy for the well-being of the matrilineage. Theseunattached women—infertile, unmarried, “separated”, and widowed—are, for the natal kin group, symbolic virgins (kanya),the life force (sakti) of which lineage members seek to harness for their well-being.
ii In Ladakh (a high-altitude region of the Himalayas in North India), there is evidence for low rates of marriage among womenthat may be attributable to the practice of polyandry (one woman with more than one husband). Wiley presents an analysisof 1981 Indian Census data that documents low natural fertility in Ladakh. Age-specific fertility rates derived from thenumber of current births are also unexpectedly low. The most likely explanations for low marital fertility include sterility
Sociocultural attitudes towards infertility and assisted reproduction in India 65
Unisa suggests that early marriage, early initiationof cohabitation and early spontaneous abortions maybe the reasons for some of the higher rates of infertilityin the state of Andhra Pradesh where she carried outher study. According to her, the rate of childlessnesswas 5% among currently married women aged 20 yearsor more. Cross-cousin marriages and close bloodrelative marriages are common in South India, whichcould be a determinant of infertility. In this study, alarge number of women had married a close relative.Although the extended family system is the norm inIndia, a majority of women in this study lived innuclear families. Unisa feels that childless women arekept purposely from celebrations of newborn childrenand celebrations of first pregnancies, as their presenceis considered inauspicious. Many people expressedthe opinion that a childless couple should also notbless a newly married couple as that might result inthe newly married couple’s childlessness. After a fewyears of marriage, a childless woman avoids cere-monies. Some of them were called godralu (a Teluguterm with a negative connotation meaning a womanwithout eggs). Actual and anticipated rude commentsat social functions forced many women in this studyinto becoming social recluses. About 20% of thesewomen considered themselves to be a source of badluck. Unisa pointed out that the women themselveshad low self-esteem as a result of these negative socialattitudes (19) .
Mulgaonkar reiterates through her study inMumbai that women are usually blamed more thanmen are for their childlessness (22). This has beensubstantiated by Dhaliwal et al. (28), Jejeebhoy (8),Jindal et al. (14) and Unisa (19). Most women feltthat they were blamed and stigmatized for theirchildlessness. Men in the study attributed theirinfertility to fate and God’s will. They felt that therewas a right time for motherhood and fatherhood andthat it was too late for women to become mothers afterthey were 25 years old. These concerns related to lackof adult identity (male and female), also proving theircapability of motherhood, status in the family, thestigma of late motherhood and lack of security in oldage. Children are valued by women because theycontinue the patrilineal family line and helped themestablish a relationship with the elders in the family.Many women felt that it was important to have the
blessings of elders to have a child. Some women whowere interviewed felt they had to do more domesticwork as a result of their childlessness and some feltthat they had more time, as they did not have childrento take care of. Some complained that their health wasaffected due to the stress they went through becauseof their childlessness (22).
Many studies have pointed out the negative imagechildless women have of themselves, implying a rolefailure (14,21,23,25,26,29,30,31). The motherhoodrole brings fulfilment. The importance of parenthoodin Indian society reinforces the feeling of inadequacyof the childless couple. During religious and socialfunctions, couples interviewed by Mulgaonkarreported that they were the butt of rude comments,were made to feel inadequate, suffered from lack ofattention, and were questioned about their childless-ness. Some were excluded from such functions. Somealso felt that they were given unnecessary andsometimes wrong advice during these occasions. Butmany of the men did not have such experiencesthough a few of them did and they expressed theirdesire by interacting with other’s children (22).
Psychosocial consequences
Feelings of losing control over their body and theirlife are expressed by some women who are childless.For many women, conception becomes a pre-occupation resulting in anxiety, despair, depressionand various other psychological problems. This addsto the problems that already exist. They feel sad,disappointed and exhausted by the intensity of theiremotions because this problem has taken over theirlives (21,32). Some women who are infertile feelconstantly preoccupied with their body, waiting for asign of something going wrong or right. There isanxiety with the onset of menstruation and it is viewednot as a sign of femininity, but as a failure. There isconcern whether the pregnancy will continue or not,or preoccupation with the cause of infertility, or withunexplained infertility. In-depth interviews conductedwith infertile couples undergoing treatment haverevealed that women express disappointment at failingexpectations and that treatments allow hope but alsodefer final acceptance of infertility. Since thisexperience damages self-esteem it might have
from STD, high rates of fetal loss, and possibly nutritional constraints on ovarian hormone status. There are also high ratesof primary and secondary sterility within marriage, resulting in low completed parities for postreproductive age marriedwomen.
66 ANJALI WIDGE
repercussions on other relationships of the woman.In India, women often complain of being ridiculed bytheir in-laws for not being able to conceive. They feelrejected by their partners because they are made tofeel incomplete and the threat of someone else comingon the scene looms large (21).
One of the few psychosocial studies of infertilecouples in India revealed that infertility is a life crisisand a stressful experience with invisible losses,especially for women (33). They experience marital andpsychological instability, and stress and strain,including deterioration in the quality of life. The crisisis long lasting and not much is known about thestrategies adopted by infertile couples to cope withtheir childlessness. In the study, 77% of couples hadalterations in sexual response (reduction of sexualhappiness), which also has implications for the maritalrelationship. About 40% of the males blamed theirspouse whereas 36% of the wives tended to blamethemselves for childlessness, irrespective of whoseproblem it was.
The study revealed that relatives were moresympathetic towards men than women, as was alsosuggested by another study (34) that stated that morewives than husbands reported insensitive behaviourfrom their neighbours and friends towards theirchildlessness. Twenty per cent of the wives receivedthreats of divorce and women were consideredinauspicious for religious and ceremonial rites; and40% of women were socially ostracized. Womensuffered this indignity more than men; however, in-laws were more sympathetic as compared withrelatives. Women felt hopelessness and despair,resulting in suicidal tendencies five times more thanmen. Many felt a tremendous sense of guilt, blameand loss of self-esteem.
Mulgaonkar also focused on the psychosocialconsequences for couples and her study revealed thatcouples felt depressed and grieved, had lack of hope,loss of relationships with friends and relatives, doubtsabout their bodily functions and sexual competence,loss of health due to the specific treatment, feelingsof jealousy, anger, guilt, lack of social security andsupport, fear of extinction of family lineage, addictionto bad habits of chewing tobacco, smoking andconsumption of alcohol by some women and men asan effect of childlessness (22). Another study alsorevealed that infertile couples had sexual problems asa result of their childlessness and were unhappy abouttheir sexual lives (35).
The couples coped with infertility by involving
themselves in religious practices such as praying andvisiting religious places, by caring for others in thefamily, fostering relatives’ children and some by beinginvolved in social organizations. Some couples alsoexpressed the positive freeing aspects of childless-ness.
Women feel responsible for being childless and ifsomething goes wrong during a pregnancy they tendto blame themselves and feel guilty. This guilt, thoughself-imposed, has an obvious relation to the societalbelief that women are completely responsible forreproduction and are to blame if something goeswrong. Women are blamed if they are childless for 4–5 years, and they are considered inauspicious(bhanjhri). They are often considered to be possessedby a witch (daakan) (18).
The study by Dhaliwal and Dhall emphasized thatthere is a great social stigma attached to childlesswomen in Indian society, regardless of the medicalcause (28). Even identifying infertility is sometimesdifficult (15). Women face the blame for it and alsopersonal and social consequences, such as personalgrief, frustration, economic deprivation, ostracism,violence and marital disruption, including divorce.This has also been substantiated by some otherstudies (17–22,32) .
Son preference
In India, there is not only societal pressure to bear achild but to bear a male child who will continue thename and legacy of the family and provide physicaland financial security to the parents in old age. In apatrilineal society like India’s, where property isinherited by male heirs and passed on in the male line(even though legally women have a share), malechildren are desired. It is common to have another wifeif the first one cannot conceive, therefore maleinfertility is not considered as problematic as femaleinfertility. For the woman, there is always theinsecurity that the husband will remarry. Therefore,bearing a child (a son in this case) gives a womangreater negotiating space in the household. But if thecouple is childless, the woman is held responsible, asshe is the one who gives birth. She is not left guilt-freeeven when it is proved that conception is not takingplace because of a fertility problem in the male. Thein-laws usually support their son and blame thedaughter-in-law. Nevertheless, it is a blow to the maleego if he discovers that he is impotent or infertile. Itdoes not fit into his concept of malehood and virility.
Sociocultural attitudes towards infertility and assisted reproduction in India 67
Due to preference for sons, India has an unfortunatehistory of female infanticide and sex-selectiveabortionsiii. With access to sex-selective abortion afterultrasound and sex pre-selection methods, thesituation has become worse. The focus for the Indianwoman in a patriarchal context is not so much theexperience of pregnancy or childbirth but theenormous social pressure and the feeling of securityshe gets as a result of having a child, especially a malechild. Jindal and Gupta’s study revealed that when acouple’s previous offspring was female, socialpressure was the same as in cases of primary infertility(14).
Marital/family disharmony and domesticviolence as a consequence ofchildlessness in India
A childless woman not only faces problems with herin-laws because of her childlessness but also in hermarriage. The relationship between husband and wifeis sometimes strained, there are very few men whowould be supportive of their wife if she had aninfertility problem; but if the husband has the problem,the wife is mostly supportive and even tries to coverup and take the blame. Infertility also results in theconsequence of low self-esteem, as in some casesthere are threats to the woman of another marriage ordivorce.
When a bride gets married she is not seen just asa reproducer of sons but is also expected to contributeto productive labour. If the woman happens to haveany flaws (such as infertility) she may be ill-treated,as were some women in the study conducted byWidge. Besides the threat of the spouse marryingagain, there are threats regarding the woman’s claimto property. Widge reiterated through her study thatwhen women get married they have a sense of a lackof identity in the house they marry into. They are oftenvictims of violence and abuse and have nobody totalk to or share their pain with. The childless womanis considered inauspicious and feels unworthy andunwanted. The woman also wants to become a motherto feel complete and, as a mother, besides other things,she has greater access to resources. If the coupleremains childless, it mostly has a negative impact ontheir marriage, though some husbands are supportive
and defend their wives against family pressure orcriticism. There is a feeling that the extended familytakes advantage of the situation of childlessness (21).
Feelings of inferiority and self-defect in childlesswomen are exacerbated by the in-laws and husband.Disharmony with the in-laws and husband has beenreported by 34% and 16% of infertile women in thestudy conducted by Jindal and Gupta in North India(14). The pressure varies from taunting, to abusing,to violence and threats of abandonment and remarriage.Ignorance regarding male infertility was the maincause for this but husbands were more sympatheticwhen they were aware of a male factor in their infertilityor had one or more living children.
In the study conducted by Desai, Shrinivasan andHazra, none of the males were threatened with divorcefrom their wives but about 20% of women receivedsuch threats. About 15% of both men and womenconsidered remarriage. About 10% of the women alsofaced physical assault. Extramarital liaisons were alsoreported (33).
According to Patel, in the community that shestudied, if a woman cannot produce a child herhusband can divorce her or remarry, but not allchildless women have to face divorce or a secondmarriage as bride price here makes a second marriagevery expensive (17). Singh, Dhaliwal and Kaur alsofound instances of threats of second marriage,maltreatment of the childless woman within the family,taunting and physical assault by husband. The studyconcluded that grave social stigma continues to beattached to infertility and is largely borne by women(34) .
In Unisa’s study sample, only 4% of the womensaid that their husbands wanted a divorce in order tohave children, but in 12% of the sample, the husbandalready had more than one wife and 16% of the womenreported that they felt that their husbands wanted asecond wife. A few husbands were also havingrelationships with other women. Two-thirds of thewomen reported a harmonious marital relationshipwith no threats to their marriage. Unisa pointed outthat the harmonious relationship among these couplesmay be due to the awareness that infertility wastreatable in many cases and that women alone werenot responsible for this condition. But two-thirds ofthe women experienced violence from their husbands
iii The recent Census of India 2001 has revealed a marginal increase in the national sex ratios but very low sex ratios in somestates, even in relatively developed states such as Gujarat and Maharashtra. This low sex ratio is also being attributed topractices such as sex selection and female infanticide/feticide.
68 ANJALI WIDGE
and out of these, 13% felt that the reasons were partlydue to childlessness. Infertility did spur some men tophysical abuse or to take another wife. The level ofviolence decreased as the level of education increased(19). The incidence of physical violence as a resultof childlessness had also been reported in a study inNorth India (34).
Some women in the study conducted byMulgaonkar felt that the sole purpose of their marriagewas to have children but others, who felt that this wasonly one of the reasons to get married, felt that theycould do without children (22).
Treatment-seeking behaviour of infertile/childless couples in India
Though there are many consequences of infertility,the obvious commonly expressed consequencesinclude fertility-seeking behaviour which includestreatment mostly from traditional healers (36,37).More recent studies have also identified allopathy asone of the more popular treatments that are soughtbesides traditional treatments (19,22). Althoughinfertility treatment is available in governmenthospitals, there is often poor coordination betweengynaecologists, infertility specialists, surgeons andlaboratory technicians. Couples who can afford thecost of ART such as in vitro fertilization (IVF) areusing them increasingly (21).
A WHO multicentre study revealed that, inChandigarh (India), couples with primary infertilityhad more interest in treatment as compared to thosewith secondary infertility (37). Seventy-five per centof couples had a duration of infertility of more thantwo years prior to embarking on investigations, whilemore than a third came with a duration of more thanfour years. Women usually initiated the first contactwith a physician. The reasons for couples delayingseeking medical advice were because of the fear of afinal definitive diagnosis and partly because of thedread of the emotional stress and physical discomfortof the tests they would have to undergo. Some alsofelt that in seeking medical attention they wereadmitting failure in their efforts to conceive.
Many follow-up studies of infertile couples haveshown that 12%–16% of couples conceived over aperiod of 2–3 years. In one such study, 38% reportedpregnancy before treatment was even started, 27%
while investigations were being carried out and only35% completed treatment before onset of pregnancy(28).
The treatment-seeking behaviour of couples in thestudy conducted by Mulgaonkar depended on thesocioeconomic status of the couple, and the decisionfor seeking treatment involved other people besidesthe couple. Most couples sought treatment within thefirst year of their marriage. A few couples tookayurvedic and homeopathic treatment, though almostall followed religious practices. Most couples believedthat childlessness was a disease and that they wouldhave to spend a lot of time to undergo treatment atthe cost of participation in other activities (22).
In the study conducted by Unisa, one-quarter ofinfertile women never sought help, for the most partbecause of the high cost (43%) or because they felt itwas unnecessary (41%). Some women reported a lackof information regarding treatment and nonavailabilityof treatment nearby. Some were not able to getpermission from elders for treatment. In the patriarchalcontext, the problem of infertility was initiallyconsidered to be the woman’s problem and thehusbands were generally uncooperative. But in thissample, in many of the cases, the husbands went withthe wife and accepted treatment when required. Thesewomen, on an average, began allopathic treatmentiv
and visits to holy places after three years of marriage.Some even began seeking treatment after a year ofmarriage as a result of pressure, or their own impatience.Many women sought allopathic treatment first (73%)and then tried other options which includes othersorts of treatment (ayurvedic, homeopathic andunani), prayer, rituals and traditional treatments whenallopathy did not work and many cut their treatmentshort because they could not afford its high costs.Although 63% visited at least one holy place orspiritual healer (these are based on religious belief butare also readily available alternatives), surprisingly,most did so only after modern medical treatment failed.Strong beliefs and varied religious practices werereflected from the in-depth case studies, includingmany visits to specific temples of some Hindugoddesses. Some women continued to seek allopathictreatment for 25 years and some who took religioushelp did not give up for up to 32 years. A strong desireto have their own biological child is evident from thisbehaviour (19).
iv These include treatment from state health services and private doctors and hospitals; the use of ART is not mentionedspecifically by Unisa.
Sociocultural attitudes towards infertility and assisted reproduction in India 69
Seventy-six per cent of couples in the studyconducted by Singh, Dhaliwal and Kaur consultedprivate and government modern medicine practi-tioners, TBAs (traditional birth attendants) and faithhealers. But only 25% of the men underwent a sementest. More couples with primary infertility than withsecondary fertility expressed the desire for a child. Thecouples also incurred considerable expense fortreatment (34).
The study conducted by Iyengar and Iyengarrevealed that most couples wait for many years beforeseeking treatment, even though many women feel thatthey have a problem. Newly married women seemedkeener to seek treatment perhaps out of the anxiety ofa new relationship. Those women who had soughttreatment visited either a bhopa (faith healer), vaid(ayurvedic doctor) or an allopathic doctor. The oneswho went to a doctor were not investigated com-pletely. Male participation in infertility managementwas limited as it was difficult to convince men toundergo an examination. As revealed from one casein this study, one of the husbands resented that hehad been asked to be examined and that his fertilityhad been doubted and refused to cooperate. Beliefsabout women being possessed by evil spirits,combined with traditional practices in a patriarchalsociety and migration by men also affects the extentof utilization of services even if they are available (18).
The study conducted to understand the emotionalaspects of infertility by Desai, Shrinivasan and Hazraconcluded that most couples performed religio-magical practices to cure their infertility. Abstainingfrom visiting a place where a delivery has taken place,tantric rites, wearing charms and visiting astrologerswere some of the practices adopted by couples (33).Even in the community studied by Patel, women areusually expected to undergo indigenous treatmentsand various rituals are observed and vows made tolocal deities (17).
Assisted reproductive technologies: social,physical and psychological costs
There are social, cultural and family pressures thatimpinge on couples (who can afford it) to useadvanced technology such as IVF, gamete intra-fallopian transfer (GIFT) and intracytoplasmic sperminjection (ICSI). It has been suggested that somechildless women go through procedures such as IVFrepeatedly, although they believe that it is not
beneficial, is invasive and has risks of physical andpsychological damage. They do, however, repeat thetreatments due to a sense of being responsible forreproductive failure and because of the constantvalorization of motherhood as a woman’s mostimportant role. The repeated use of this technologyis also encouraged by physicians as it is commercialand profit-making (38–42).
The ambiguity towards the experience with IVFcycles has been revealed by many studies. However,it is believed that IVF focuses exclusively on bio-logical reproduction and curtails any potential for theredefinition of parenthood or infertility. In so doing,it reinforces the notion of the “natural” bond betweena mother and her biological children as well asreinforces the idea that the only desirable structureof social relations between adults and young childrenis the nuclear family or indeed one’s own biologicalchildren (43).
Seeking ART in the Indian context
In Indian society, where fertility is valued to the extentthat womanhood is defined as motherhood, ART givehope to the infertile even though only a few can affordit. Couples that come from the higher socioeconomicgroup, in the search to have their own biological child,can now have a child through high technologyoptions like IVF. In India where there is a stigmaagainst infertility and childlessness, this is perceivedas a great scientific achievement. Most couples whoopt for treatment are very apprehensive about thesocietal reaction to their childlessness. As in the West,the need for a child in India is not so much of abiological need but is a social one. Having a child isthe next immediate step after marriage for a woman.She is valued most for her fertility, if she is not fertile,she is not a “complete” woman (21).
According to Srinivasan, overestimates ofinfertility help justify the industry’s and the medicalpractitioners’ existence, but in a large country with alarge population it is a substantial number andrequires attention. IVF and other ART are promotedtoday for all forms of infertility. The Institute forResearch in Reproduction (IRR) began work on an IVFprogramme in 1982 to provide subsidised IVF. TheIndian Council for Medical Research (ICMR)suggested that this promotion would also help incouples accepting sterilization if they knew that theycould have a child through IVF and would indirectlyhelp the family planning programme (44). Besides, the
70 ANJALI WIDGE
services in the private sector are mostly market driven.According to an infertility specialist in Delhi, asprivate specialists invest a lot in acquiring hi-techequipment, the costs of service are therefore high(personal communication). According to anotherinfertility specialist, IVF clinics are mushrooming inIndia. There were 107 IVF centres in India in February1999, out of which 60 are active. Sperm banks also existin metropolitan cities (45). According to the Ministryof Health and Family Welfare in India, there are about60 centres in India offering ART (46). A few centresalso exist in the public sector. An evaluation of thepublic sector ART centres is proposed, followingwhich the existing ones may be strengthened withtrained and interested staff (47). The mushroomingof private centres combined with the lack of publicsector centres has created a situation of exploitationof helpless, childless couples. The first case ofsurrogate motherhood in the country, which receivedconsiderable media coverage in October 1997, has alsobrought the need for ART guidelines to the forefront.Recently the ICMR finalized ethical guidelines forART, but how they will be implemented remains to beseenv (48) .
In a study of 24 couples who underwent artificialinsemination (AI) in 1976, more than half the coupleswanted to undergo the procedure to have a child, somewanted to conceal their infertility and some wanted itbecause they preferred it to adoption, as they wanteda child of their own (49). In another study conductedabout 25 years later, only very few women and menagreed (among those whose childlessness was dueto the husband) to undergo artificial insemination bydonor (AID) (22). In another earlier study, there wasa very marginal acceptance of AID by couples inaddition to poor facilities for it (14), but according tointerviews conducted about four years ago by Gupta,there is a tremendous demand for AID in India, whichis offered by private medical practitioners. Accordingto her, one reason for seeking AI is to increase thechances of having a male child. Despite the demand,there are only a handful of sperm banks in India. Someof these do not follow WHO guidelines and supplyfresh semen to gynaecologists. The interviews alsorevealed that some doctors also conduct microscopictuboplasty, an operation to surgically reversetubectomy, but the services that are increasingly
offered are IVF, GIFT, etc. IVF is encouraged by suchdoctors as treatment for infertility. Research on IVFalso offers opportunities to identify and study factorscontributing to infertility. Some doctors offeredguarded criticism of these ART but some were clearlyin favour of low-cost, low-tech methods (32).
As far as the success rate of IVF is concerned, theICMR reports an average take-home baby rate of 20%–30% per cycle, but that has not been substantiatedby any studies (50). The best clinics in India claim a30%–40% success rate but it seems to be much lowerin reality (21,32). Moreover, this is the pregnancy rateand not the birth rate. Most clinics claim a highersuccess rate than 5%–10%, which is usually the ratereported by clinics in the West.
Some interviews with infertility specialistsconducted by Srinivasan (44) revealed that thoughdoctors quote a success rate of 30%–40%, it is usuallythe rate of biochemical pregnancies. However, thetake-home baby rate is not more than 15%. During thecourse of another study conducted at ART clinics inNew Delhi, none of the couples had a baby during thecourse of the study and only one couple had a babythrough intrauterine insemination (IUI). Most womenin the study underwent many unsuccessful IVF cyclesand had been through various unfortunate expe-riences with this technology. In spite of theseexperiences, some did not give up. Among the couplesinterviewed only one couple had adopted a baby girlfrom an agency after three unsuccessful attempts atIVF (21) .
The experience of childless women using IVF
Couples undergoing IVF, especially women, gothrough a very discomforting process of examinationand treatment. They do not have easy access toinformation and usually select doctors through trialand error. Most believe that the doctors have a verydefinite profit motive and sometimes mislead patients.It is difficult for most couples to understand proceduresand what the doctors tell them is usually not enough.Most women understand the complexity of theprocedure only after experiencing it. For most couples,the physical and psychological effects of thetreatment are hard to deal with and it is more difficultif complications arise. Some of the women interviewed
v Medical professionals, pharmaceutical giants, private insurance companies, sperm donors/banks, egg donors have a commercialinterest in ART. The fact that this technology has commercial potential and is unregulated could lead to a plethora ofunethical practices.
Sociocultural attitudes towards infertility and assisted reproduction in India 71
during the study at ART clinics in New Delhi hadexperienced complications during some procedures.
These women felt that their lives were centred onreproduction and the IVF cycles and that they couldnot take their thoughts away from pregnancy. Mostcouples perceived this treatment as a blessing forinfertile couples and those who could afford it, saidthey would like to try all kinds of treatment availablebefore they gave up on having a biological child. Thewomen felt that IVF increased their financial depen-dence on their husbands, which already exists, if thewoman is a housewife. Adoption is usually not analternative or is the last one for most couples.
Some couples had reservations about using donorsperms or eggs to have a child. In such cases, donoreggs were preferred from within the family. Donorsperms of unknown origin were usually acceptable butit depended on the couple. The lineage principle wasstill very important and some women did not want touse donor sperm or did not want their husbands toknow that donor sperm was being used for fear thatthey would not allow it (21).
ART are very expensive and only a few can affordthem. They are not offered in government hospitals,though some public sector companies reimburse somepercentage of the costs. Recently, the ICMR suggestedthat besides preventive measures, it is essential toreduce the costs of ART so that all couples haveaccess to them (50). It has also been suggested thatas ART are expensive, the option of adoption shouldbe offered and there should be a shift to preventiveservices (51).
Specialists of IVF interviewed for the study byWidge presented the technology as fairly successfuland unproblematic. They believe that infertility iseither on the rise or is being reported more than before.They felt that social issues need to be addressed, asthey are the cause of a lot of stress associated withinfertility and that, in Indian society, infertility is amedical, social and psychological problem. One of thespecialists pointed out that the only way there couldbe a change in social attitudes towards the infertile isthrough technology. She finds that women tend to bemore depressed than men because of infertility as theyhave to deal with many other pressures. Accordingto another specialist, some couples are stressed,others are able to cope better, some have plenty ofsupport, and others face family pressure. But they felt
that lineage is a major concern for most couples whoundergo IVF and that most women feel the pressureof motherhood. They mentioned marital breakdownsand some cases of bigamy due to stress associatedwith infertility. They also felt that there is not muchresistance among couples to using donated materialbecause of their desperation to have a child (21).
According to another infertility specialist,infertility treatment could be stressful for the patientand counselling is important. Most clinics do nothave a counselling facility for couples before andduring IVF procedures. There are no laws regardingthe (mis)use of ART or use of donor eggs and spermin India and these doctors feel that just a signedcontract or a waiver form is enough. They believe thatregulation should suit the needs of everyone. Imple-menting ethical guidelines would mean that thedoctors would have to look critically at issues ofinformed consentvi, screening donors, legal issues andthe quality of provided services.
Son preference and ART
There are also dangers of IVF perpetuating the alreadyprevalent unethical practice of sex-selective abortionsof female fetuses through methods such as pre-implantation diagnosis. IVF specialists offer this as achoice to the couple and do not believe that it amountsto perpetuating male domination and discriminationagainst the girl child. One of the specialistsinterviewed for the study admitted to offering sexselection, which is legal, and a choice for couples. Thisamounts to blatant perpetuation of male dominationand discrimination against the girl child, as most ofthe children selected would be males. One of theimportant and disturbing implications of IVF in theIndian context is the fact that a related technology canbe, and is being, misused for sex-preselection and theexisting law does not deal with it.
Attitudes towards adoption
Adoption was traditionally seen as a last resort forthe infertile couple. Though now perceived as anacceptable option very few couples actually adopt achild (8,19,21,22). Adoption within the family isencouraged more than adoption of any child,
vi Interviews with these specialists revealed that the concept of informed consent does not exist and there are not too manylimits these specialists would set for themselves in terms of how far they would go with the use or misuse of ART.
72 ANJALI WIDGE
especially of unknown origin. But it is resisted for along time and used as a last resort for most as it doesnot get societal legitimacy. Some women do not wantto adopt because they have feelings of inadequacyand want to prove their fertility. Some women felt thatindependent decisions regarding adoption are difficultto take in a joint family. As lineage is so important,some couples prefer to adopt from within the familyor a child is especially conceived for them from withinthe family. Surrogacy is uncommon in India, though itis quite common within families where a brother or asister gives up a child for adoption or has a childspecifically for the childless couple. There are varia-tions in what is seen as natural and what is tolerablein different cultures (21).
Earlier, most of the childless couples studied hada negative attitude towards adoption (14) and only amale child offered by a blood relative was acceptablefor adoption by the majority of couples. Possibilitiesof adoption are few because of the strongly rooteddesire of biological progeny (18). Couples usually saythat they would like to consider it as an option butfew actually adopt a child (15,19) . In Mulgaonkar’sstudy most couples (80%) did not accept the idea ofadopting a child for various reasons (22).
Conclusion
Motherhood in Indian society defines a woman’sidentity even before marriage because the prepara-tions for a self-sacrificing life begin long before sheis married. It is still the most important goal for awoman. The blood-bond between mother and childovertakes the one with the husband. If she cannotreproduce, due to whatever reasons, she is the subjectof ridicule and abuse. Children, especially males, givethe woman status within the patriarchal family (be itjoint or nuclear), define her identity, give herpsychological and emotional security and strengthenkinship bonds. But this responsibility of women tomother in India excludes them from public life and mostimportantly from power and authority. Infertile womenoften complain of being ridiculed by their in-laws fornot being able to conceive. If the couple remainschildless, it sometimes results in violence and at timeshas a negative impact on their marriage. Even if thewoman’s husband is infertile, she has to bear thesocial and psychological consequences. There is alsothe threat of divorce or debarment from property.
Women/couples seek treatment from traditional
healers but also from the modern systems of medicine.Some couples use AI and ART. Since IVF has beenintroduced in India it has given desperate couplesgreat hope and a chance to have their own babyinstead of going through endless treatments withoutany hope. In the search to have one’s own biologicalchild, couples that belong to the higher socioeconomicgroups can now have a child. In the present contextof consumerism and market-oriented technologies, theprivate health care sector and the pharmaceutical andgenetic engineering companies use the slogan of “helpfor the infertile”, but it is the companies that stand togain. There are hardly any subsidised clinics in Indiaand the government hospitals do not offer theseadvanced technologies. Preventive and curativeservices for infertility are not a priority.
Furthermore, the moral, ethical and social issuesraised by ART are unresolved. The problems posedfor parenthood, when the legal parent of a child bornto a woman who is neither its genetic nor social motherhave not been confronted in India. The issue ofcommercial surrogacy has not been debated in Indiaand emerged only recently when a case was reported.
These technologies are offered as a choice.However, in a country such as India, where modernand/or hi-tech infertility treatment depends on thecouple’s/woman’s ability to pay, there is not muchchoice. Moreover, due to the lack of regulation andlaws there are concerns about the lack of professional-ism and the safety of the treatments offered.
The total absence of monitoring and self-regula-tion can lead to the misuse of ART and relatedtechnologies. India, unfortunately, has a history offemale infanticide and sex-selective abortions offemale fetuses. The new law against sex-selectivetechnologies now includes technologies like pre-implantation diagnosis, but it remains to be seen if itis a deterrent. Legal battles regarding ART and/orsurrogate motherhood have been going on in theWest, but it will not be long before similar problemsare faced by the Indian society.
A set of rational and consistent policies to manageART is required. There should be a focus on non-technological solutions such as preventive measuresfor infertility, adoption of children of all sexes, raisingconsciousness to reduce the social pressures forbiological parenthood and on protesting againstperverse uses of ART.
The reality of the childless woman is complex.Experiences of infertile women with reproductivemedicine are not very pleasant but they still want to
Sociocultural attitudes towards infertility and assisted reproduction in India 73
use the technology, sometimes because it helps themnegotiate their position in the patriarchal family. Also,an overemphasis on the negative impact of thesetechnologies distracts attention from the politics andorganization of health care in general, from the legalsystem, from political struggles over the nature ofsexuality, parenthood and the family, and from theimpact of the varied material and culturalcircumstances in which people create their materiallives.
The problem of women’s health in India has to belooked at within a general context of poverty, classand gender inequalities and unequal access toresources. The health and well-being of women areimportant as a value. The politics and organization ofhealth care in general, the legal system, the nature ofsexuality, parenthood and the family and the presenteconomic structures all are important related issuesthat impinge on a childless woman.
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49. Rajan R. Artificial insemination. Journal of Obstetricsand Gynaecology of India, 1976, 26:733–738.
50. Indian Council for Medical Research. Need andfeasibility of providing assisted technologies forinfertility management in resource-poor settings. ICMRBulletin, 2000, 3:6–7.
51. Soonawala RP. Infertility management: issues and state-of-the-art. National Consultation on Infertility Preven-tion and Management. New Delhi, UNFPA, 1999.
Sociocultural dimensions of infertility and assistedreproduction in the Far East
REN-ZONG QIU
Introduction
The way in which people deal with infertility and theuse of assisted reproductive technologies (ART) areat least partly affected by the values and socioculturalnorms of the community in which they live. It is impor-tant to know how sociocultural traditions, beliefs andvalues define infertility and shape treatment-seekingbehaviour as well as views about ART. This paperaddresses the sociocultural and ethical dimensions ofinfertility and ART in the Far East and how they areembedded in the influential traditions of Confucian-ism, Taoism, and Buddhism.
Perceptions of sex and reproduction in theChinese culture
During the five millennia of her history, China hasdeveloped her own unique culture influenced primarilyby the teachings of Confucianism, Taoism andBuddhism. Although these philosophies appear tohave similarities in their cosmologies, how they viewsex and reproduction varies. For example, Taoistsbelieve in a spiritual sphere in which people willtranscend all mundane dichotomies between truth andfalsity, virtue and vice, beauty and ugliness, poor andrich, noble and mean, happiness and misery, etc. Inthis context they view sex only as a means to promote
health and longevity. Chinese Buddhists seek todiscard karma and reach the nirvana and view anydesire in sex or reproduction as unacceptable, if notsinful.
In the cosmology of the Chinese culture theuniverse consists of qi, a vital energy or a physico-psychological entity, and all things or beings in theuniverse are nothing but the different patterns of qi.Qi exists in two forms: yin and yang. The yin–yangdualistic theory emerged from the worship of sex andreproduction. An analogy was made between humanbirth (micro world) and creation of the universe (macroworld). Intercourse or interaction between yin (female)and yang (male) in the universe created all entities thateventually come from the “mysterious gate”. It isreflected in the sentences of Dao De Jing, such as“the mystery of mysteries is the gate of all wonders”,and “the gate of mysterious female is the root of theworld” (1). In the Chinese culture, the universe is anorganism which is capable of continuous repro-duction, transformation and creation. Chinesephilosophers had argued that sex is one of the integralelements of the human nature. “Eating and sex arehuman natures” (2), or “Eating, drinking and sex arethe greatest desires of human life” (3).
Yin–yang dualism was developed in the Book ofchanges , although these two concepts were putforward in about 600 BC. The yang represents theheaven (and the male), and the yin the earth (and the
76 REN-ZONG QIU
female). This dualism was accepted by both Confuciansand Taoists. According to the Book of changes,interaction between these two kinds of vital energyin the universe is the basis of life. “All things arecreated by the intercourse between male and female”,“If there had been no intercourse between heaven andearth, there would not have been all things in theworld”(4).
Sex
Sperm is called jing zi in the Chinese language, andcontains jing or yuan qi (vital energy) which meansthe essence of life and health. Male sperm is limited,but women’s vaginal secretion contains qi and bloodwhich are inexhaustible. Sex has dual goals, one is forreproduction or extending ancestors’ life, the other isfor health.
Taoists believe that there are some elements in thefemale body which are indispensable for immortalityand vice versa, so sex is indispensable for human lifeand health. Confucians believe that the function ofsex is reproduction. They maintain that reproductionis the only purpose of sexual intercourse. They alsobelieve that the primary role of the woman in societyis to bear children. But Taoists and Confucians sharedthe idea that men’s yang can be nurtured by women’syin, while women become healthy by absorbing yang.However, it is not clear how or why yang and its jingcan be enhanced by yin and yin nourished by yang.
Ancient Chinese thought that it is the fifth dayafter menstruation when women can conceivebecause on that day women’s yin abounds most. Somen should ejaculate on that day. Before and after thisdate, men should restrain themselves from ejaculationin order to keep their jing and absorb women’s yin asmuch as possible. Thus they can use women’s yin toenhance their yang which will rise up to the brain alongthe spine (bu jing huan nao). So if a man can keepstrong jing or yang when he has intercourse with awoman on the fifth day after her menstruation whenying in her abounds most, then she will becomepregnant and give birth to a healthy son. Due tostrong sexist views at the time, ancient Chinese writersnever mentioned giving birth to a girl. If a manejaculates at each time of intercourse with any woman,his jing or yang will be exhausted, he will not be ableto have a child, and he will even fall ill or may dieprematurely (5,6).
Few philosophers discussed sex for the purposes
of pleasure. One of them was Bai Xingjian (?–826), thebrother of a famous poet Bai Juyi in the Tang Dynasty,who wrote that sex is the greatest joy in human life(5,6) . Sex for pleasure and sex for health arecompatible. In Chinese traditional medicine, a healthylife entails a life with pleasure. However, forConfucians a healthy life entails a life with virtue ormorality based on Confucian ethical principles.Therefore, the order of priorities in the purposes ofsex should be: reproduction, health and pleasure.
In Confucian texts and tradition, infertility isalways blamed on women. However, in traditionalChinese medical texts it is recognized that there arethree elements that control reproduction: a man’s shen(kidney), woman’s tiankui and the chong-renchannels. It should be noted that in such texts thewords kidney, heart, lung, liver and spleen not onlyrefer to organs, but are also used symbolically andrefer to certain functions. The kidney keeps jing qiand controls growth, development and reproduction.Jing is the root of the human body (7). Jing is partlyinherited from the parents, and partly generated fromwater and food. Jing qi has the ability to promote thegrowth and development of the human body and alsocontrols the ability to reproduce. During adolescence,jing qi in the kidney or kidney qi increasinglyflourishes, and in ageing kidney qi is in decline. If aninfant is short of jing qi , it will suffer from hypoplasiaor dysplasia. If a young man is short of jing qi, he willsuffer from impotence, infertility or premature ageing.
Tiankui is called “shapeless water” whichcontrols menstruation (8). Ancient physiciansbelieved that a good order of menstruation isindispensable for reproduction, and if tiankui, as avariant of yin is abnormal, it will lead to disorders ofmenstruation.
Chong-ren channels are branches of the jingluosystem which come from the head to the kidney viathe liver; their function is to enhance shen . If they areobstructed, the shen will be weakened and reproduc-tion will be affected.
Explanations of infertility
In traditional Chinese medical texts, two differentwords are used to describe infertility. Man’s infertilityis called buyu which means the “inability of insemina-tion”, and woman’s infertility is called buyun whichmeans “inability to be pregnant”.
Writings from all periods of Chinese history
Sociocultural dimensions of infertility and assisted reproduction in the Far East 77
referred to the problem of infertility and tried to givesome explanations for its causes. Wan Quan describedthe abnormal structure of the female reproductiveorgans (the vagina in particular) as a cause of infertility(9). Sun Simiao, the author of The sincerity of greatphysicians (the equivalent of the Chinese HippocraticOath), pointed out that a closed uterus makes a womanunable to conceive, and that a man who suffers fromany serious diseases that can make the jing and qicold will become infertile (10). Other causes ofinfertility included: eating some poisonous herbs,inbreeding, excessive sex, suffering from seriousdiseases, etc. (3,11–13).
Moreover, infertility was believed to have moralcauses. People with Confucian or Buddhist beliefsconsidered infertility as a retribution for wrongdoingeither by the man, the woman or even their ancestorswho might have led an immoral life. According toBuddhist beliefs, if a man does something wrong inhis current life, as a retribution he will have nooffspring in his next life.
Confucian morality
In Chinese culture, Confucianism is dominant and ithas profound and wide influence in the Far East,especially in the Republic of Korea, Japan, Singapore,but less so in Malaysia, the Philippines, Thailand andViet Nam. Confucianism is mainly the philosophy andethics of morality, which teaches one how to be ahuman. According to Confucianism, humans are bornbiologically, but not morally. Therefore, one has tolearn how to be a human in the moral sense. Confucianethics are embodied in social conventions andinstitutions.
The central concept of Confucianism is ren(humaneness), which means love and care. There area number of ethical principles in Confucian ethicswhich embody ren and regulate interpersonalrelationships, such as filial piety (xiao) for children–parents, relationship, fraternity (ti) for brotherhoodand sisterhood, trustworthiness (xin) for friendship,kindheartedness, and benevolence (ci) for doctor–patient relationships, etc. However, among theseprinciples, filial piety serves as the basis for the others.According to Confucius the best way to learn ren isfrom near to far: “If you learn how to care about yourown parents and sisters/brothers, then you can learnhow to care about others” (The analects of Confucius).This idea is still very strong in China.
Filial piety requires that people extend the life oftheir ancestors, and make their family unlimitedlycontinuous from generation to generation. However,only a son, not a daughter, can do that. Some traditionsin Japan seem to share this idea (14). According toMencius:
There are three vices that violate the prin-ciple of filial piety, and the biggest is beingwithout an offspring (2).
In Confucianism there are some strong sexistviews. For example, Confucians emphasize the conceptof san cong (three types of obedience) for women,that is obedience to one’s father before marriage,obedience to the husband after marriage, andobedience to the son after the husband’s death. In thiscontext, a husband can divorce his wife using infertilityor a serious disease as a reason (5).
For Confucians, a person is not an independententity. On the contrary, a person exists only in aninterdependent relationship with other persons,especially with other members of her/his family orcommunity. So a person is a relational person, orperson-in-relation. This concept implies that whenmaking a moral judgement and behaving accordingly,the context in which the moral agent exists has to betaken into account. While the context is taken intoaccount, values which may be in conflict should bebalanced as well as all possible consequencesresulting from the various options.
Attitudes towards infertility
The Chinese attitudes towards intervention inreproduction have been influenced by cultural valuesand morality as well as by the perceptions of sex andreproduction.
Value of reproduction and family
In oriental cultures, reproduction is one of the highestvalues linked with the significant value of the family.This is clearly stated in the Confucian classic Thebook of rites :
Gentlemen (jun zi) [should] pay great atten-tion to the marriage that unites two familiesinto one in order to serve ancestors in thetemple of family and extend the family to
78 REN-ZONG QIU
future generations. Man and woman aredifferent, so there is affection betweenhusband and wife, then there is kinshipbetween father and son, then there is politicalrelation between king and his subjects (3).
When talking about the value of family, Japanesescholars emphasized the spiritual tie within or betweenfamily members (14). Actually, the spiritual tie is basedon blood tie and conjugation. According toConfucianism, conjugation between a husband andwife is the basis of the family and country. Anynonconjugal reproduction will weaken the blood tiebetween the members of a family and lead to itsinstability. And the value on reproduction and familyis closely related with morality.
Attitudes towards infertility and assistedreproduction
The desirable product of reproduction is a healthybaby. In Chinese culture healthy birth is of animperative value. The Confucianist, Xun Zi (next toConfucius and Mencius) argued that “Birth is thebeginning of a person, and death is the end of aperson. If you have a good beginning and good end,you fulfill the human Tao.” A good beginning andgood end have been interpreted as healthy birth andpeaceful dying; both very important values in theChinese culture as well as for other cultures in the FarEast. Chinese attitudes to infertility and assistedreproduction are influenced by three values: life-preserving or health-promoting, reproduction andpleasure. Of these three values, priority is usuallygiven to reproduction, and pleasure comes last.Confucianism rejects pleasure as a value of sex,despite the fact that in practice almost everybodypursues pleasure. Preservation of life or promotion ofhealth are desirable because they are in compliancewith filial piety: life and body are imparted by theparents, so the offspring has the responsibility ofpreserving it and keeping it healthy. Excessive sexualactivity is believed to lead to the shortage andweakening of jing or yang and then to infertility.
Living in such a pronatalist society, people whoexperience infertility while maintaining culturaltraditions are often under psychological and socialpressure. In a traditional family, the wife has a lowerstatus and an infertile wife has an even lower statuswith the risk of being divorced. The infertile husband
feels responsible for not continuing the biologicallineage. The infertile couple worry that they may bestigmatized in the community. As a result, they willmake every effort to seek treatment for their infertility.
In general, any intervention in natural reproduc-tion is not desirable because it disturbs the dao ofnature. However, disturbing the dao of nature is moreacceptable than being without an offspring.
Artificial insemination by donor (AID)
In a Confucian society, infertility is blamed on thewoman and the husband is permitted to marry asecond wife or borrow a wife. In the case of AID, thehusband is in a dilemma as he has to make a choicebetween sex without reproduction or reproductionwithout sex. A traditional Chinese will choose the latterand that is why AID is well accepted in China.
A couple in Shanghai married for many years butchildless went to a clinic for help. The physiciandiagnosed that the husband could not ejaculate andsuggested that they use AID. The wife gave birth toa boy. They were back home joyfully. But thehusband’s parents thought that the child did not looklike their son, and suspected that their daughter-in-law had had an affair. After the couple explained tothem that they had used AID, the grandparents stillrefused to accept the child. The result was the coupledivorced and the wife brought the child back to hermother’s home (15).
In another case, all family members agreed that theinfertile son’s wife could have sex with his brother forthe purposes of reproduction. In this case, the valuesconflict, but more weight is put on having offspringthan fidelity.
Another problem is that Chinese men are reluctantto donate sperm because they think sperm containjing or yuan qi which are indispensable for their healthand life. As a result, medical scientists and healthadministrators are concerned about incest since theavailability of sperm donors is disproportional to thedemand for AID and therefore in some cases spermfrom one donor is used for large numbers of insemina-tions.
In vitro fertilization, cryopreservation andtransfer
In vitro fertilization (IVF) is acceptable when thegametes of the couple are used. Sperm and embryocryopreservation and embryo transfer are not
Sociocultural dimensions of infertility and assisted reproduction in the Far East 79
objected to. However, there are concerns aboutwhether the environment in which the sperm or theembryo are preserved is rich with vital energy (jing oryuan qi), although there is no way to determine vitalenergy and its possible effect on ART procedures.
Intracytoplasmic sperm injection
The Chinese culture would not favour intracyto-plasmic sperm injection (ICSI) because in thehusband’s immature or possibly damaged spermato-zoa yang or jing or yuan qi will be deficient, and thismay lead to the birth of an unhealthy or congenitallydefective child. Despite this belief, some infertilecouples would probably take the risk of undergoingICSI, as this would give them the opportunity to havea child genetically linked to the father.
Surrogate motherhood
Surrogate motherhood is controversial. In the HongKong Special Administrative Region of China, thegovernment promulgated a regulation in whichcommercialization of surrogate motherhood andnongenetic surrogacy (in cases of homosexuals, singleparents and unmarried individuals) are banned. Theregulation provides that the surrogate mother cannotbe forced to give the child to its adoptive parents,because during gestation a mother-to-child relation-ship was developed. However, some scholars (16)suggested a comprehensive ban on surrogate mother-hood on the basis of an argument of “do no harm”.They argued that unlike sperm or oocyte donation,surrogate motherhood is not confidential and thatmight eventually harm the adoptive family. Moreover,the strong ties between the surrogate mother and thefuture child may eventually create problems for thesurrogate mother, adoptive parents and the child.Their suggestion was adopted by the ChineseMinistry of Health which prohibited surrogatemotherhood in the recently published (17) Measuresof administration of human assisted reproductivetechnologies (Article 22). Some experts have alreadyopposed this prohibition and have proposed thepermission of noncommercial surrogacy.
Commercialization
In many traditional cultures of the Far East the humanbody is sacred. Commercialization of body parts will
be considered as an insult to human dignity. However,the human embryo is not viewed as a person (althoughthere is a time limit, for example, for some research onembryos more than 14 days should be banned). Yet,in Measures of administration of human assistedreproductive technologies (Article 22), and theMeasures of administration of human sperm bank(17) the Chinese Ministry of Health also prohibitsbuying and selling of gametes, zygotes and embryos.The prevailing Chinese viewpoint is that even thoughgametes, zygotes, embryos and fetuses do not havethe moral status of a person, they should still not betreated as commodities.
References
1. Dao De Jing (Tao Te Ching). Shanghai, The Commer-cial Press, 1935, 2 :11.
2. Meng Zi. Four books and five classics. Beijing, China’sBookstore, 1985:85.
3. The book of rites (Li Ji). In: Meng Zi, ed. Four booksand five classics. Beijing, China’s Bookstore, 1985:324–326.
4. The book of changes (Yi Jing). In: Meng Zi, ed. Fourbooks and five classics , Beijing: China’s Bookstore,1985:1–55.
5. van Gulik RH. Sexual life in ancient China: apreliminary survey of Chinese sex and society from ca1500 BC till AD 1644. Chinese Translation. Shanghai,Shanghai People’s Press, 1995.
6. Liu DL, ed. Sex culture in ancient China. Yinchuan,Ningxia People’s Press, 1993.
7. Interior classics: plain questions. Beijing, ChineseMedical Science and Technology Press, 1998:1–8.
8. Tan YK. The development of obstetrics and gynecologyof traditional Chinese medicine. In: Li JW, Cheng ZF,eds. History of medicine. The encyclopedia of traditionalChinese medicine . Shanghai, Shanghai Press of Scienceand Technology, 1987:41–43.
9. Wan Q. Guang ci ji yao. In: Xia GC, ed. Infer tility.Beijing, People’s Health Press, 2000:6–7.
10. Sun SM. Qian jin yao fang [Important prescriptions ofa thousand pieces of gold] . In: Xia GC, ed. Infertility.Beijing, People’s Health Press, 2000:5.
11. The book of mountains and seas (San Hai Jing). In: XiaGC, ed. Infertility. Beijing, People’s Health Press,2000:3.
12. Cao YF. On the causes and symptoms of diseases. In:Xia GC, ed. Infertility. Beijing, People’s Health Press,2000:5.
13. Zuo Zhuan. In: Meng Zi, ed . Four books and fiveclassics. Beijing, China’s Bookstore, 1985:187.
14. Hoshimo K, ed. Japanese and western bioethics: studiesin moral diversity. Dordrecht, Kluwer AcademicPublishers, 1997.
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15. Qiu RZ. Chinese attitude towards intervention inreproduction (in collaboration with Hu XH). Presentedat the Vth International Congress of Andrology, May28, 1997, Salzburg, Austria.
16. Chen HW, Tao J. Moral exploration of whethersurrogate motherhood should be comprehensively
prohibited in Hong Kong. In: Julia Tao, Qiu Ren-Zong,eds. Value and society. Beijing, Chinese Social SciencesPress, 1997:137–155.
17. Ministry of Health. Measures of administration ofhuman assisted reproductive technologies. HealthNewspaper, March 6, 2001:3.
Section 3
Recent medical developments and unresolvedissues in assisted reproductive technologies
Gamete source and manipulation
HERMAN TOURNAYE
Gamete source, manipulation and disposition
Introduction
According to the World Health Organization (1),51.2% of couples are infertile because of a male factorand 39% of these men present with an abnormal semenanalysis for idiopathic reasons. Obviously, no specifictreatment is available for these men. The secondlargest category (23%) is men presenting with avaricocele. While varicocelectomy is the specifictreatment for this condition, meta-analysis of random-ized controlled studies has failed to show any benefitof this approach (2). The third largest category is mensuffering from male accessory gland infection (12%).But again this condition has been under debate andreports on its impact on male fertility have been incon-clusive (3).
Because many men have either no demonstrablecause for their abnormal semen profile or suffer fromconditions for which treatment is debatable, less than20% of men with reproductive failure have potentiallytreatable conditions for which a rational or proveneffective treatment is available (4). Furthermore, meta-analysis has shown that empirical treatments forunexplained male infertility not only confer no benefitbut may also have side-effects (5,6).
As improving the fertility status of one partnermay result in an increased fertility status of the coupleas a whole, in men with borderline semen profiles, anyimprovement in the female fertility status will have an
important impact on the couple’s fecundity.When treatment of the female partner has failed,
techniques of assisted reproduction are usuallyemployed. Their common rationale is to enhance theprobability of fertilization by bringing the spermatozoacloser to the oocyte(s). The choice of the most appro-priate assisted reproduction treatment for theindividual couple is often based on the quality of theejaculate or the source of the gametes.
Male gametes and assisted reproduction
Ejaculated spermatozoa
Ejaculated spermatozoa may be used either forintrauterine insemination (IUI), conventional in vitrofertilization (IVF) or intracytoplasmic sperm injection(ICSI).
The objective of IUI is to bypass the filteringeffect of the cervical mucus by placing thousands ofmotile spermatozoa directly into the uterine cavity bymeans of a catheter. After the semen is washed, it iscentrifuged over a density gradient or the sperm is leftto swim up in a medium. In this way, motile spermato-zoa can be selected and their motility characteristicscan be enhanced. Finally , a few hundreds orthousands to even a few million motile spermatozoacan be loaded into an insemination catheter with avolume not exceeding 0.5 ml in order to prevent uterine
84 HERMAN TOURNAYE
contractions. The numbers of spermatozoa in theejaculate together with the female fertility status andthe timing of insemination, are the most importantfactors in the success of treatment by IUI.
Apart from IUI, other techniques of artificialinsemination have been described. In “intrafallopianinsemination”, washed spermatozoa are placed directlyinto the fallopian tube on the side of the dominantovarian follicle, preferentially under sonographicguidance. A variant of this technique is “fallopiansperm perfusion” (FSP) in which a suspensioncontaining 10–100 x 106 motile spermatozoa is slowlyflushed through the uterine cavity and into thefallopian tubes. In “direct intraperitoneal insemina-tion” (DIPI), washed motile spermatozoa are intro-duced in the pouch of Douglas around the moment ofovulation by transvaginal puncture using a finebutterfly-type needle. A last variant is the “intra-follicular insemination” in which a small volume of asuspension containing washed spermatozoa is putinto a preovulatory follicle using transvaginalpuncture. According to several controlled studies,these alternative insemination techniques do notappear to be superior to standard IUI (7,8).
The objective of IVF is to bring the spermatozoaeven closer to the oocyte than is the case with IUI. InIVF, gamete transport, gamete interaction andfertilization take place outside the woman’s body.Since this technique involves several steps, each withtheir specific limitations in terms of success, IVF needsa relatively large number of oocytes and spermatozoa.The female partner undergoes ovarian stimulation toincrease the number of oocytes available for insemina-tion in vitro.
IVF was introduced in the late 1970s for thetreatment of women with problems of oocyte andsperm transfer caused by tubal dysfunction. Becauseonly a few thousands of motile spermatozoa wereneeded to obtain fertilization, IVF was also proposedas a treatment of infertility due to oligoastheno-teratozoospermia. While in normozoospermic males,60%–70% of the oocytes will be fertilized normally afterin vitro insemination, this percentage may drop to lessthan 50% when oligoasthenoteratozoospermia ispresent. Not only is the fertilization rate significantlydecreased, but complete fertilization failure of alloocytes may occur in up to one out of four couples(9). The cumulative conception rates and cumulativelive birth rates have been reported to be 28.0% (95%confidence interval [CI] 19.1%–40.0%) and 17.8% (95%CI 11.5%–26.9%), respectively, after three IVF treat-
ments and even after five IVF treatment cycles, thesefigures do not improve (10).
Several alternative techniques to in vitro fertiliza-tion-embryo transfer (IVF-ET) have been introduced.Gamete intrafallopian transfer (GIFT) and zygoteintrafallopian transfer (ZIFT) are among the mostpopular. In these techniques, oocytes and spermato-zoa or fertilized oocytes are transferred into thefallopian tube, respectively. However, meta-analysesof randomized controlled trials (RCTs) on thesealternative techniques do not show any benefit overclassical IVF-ET (11,12), especially in cases of maleinfertility in which fertilization is the major bottleneck.Considering the increased risk of side-effects fromlaparoscopic transfer in GIFT and ZIFT and the lackof any evidence that their results are superior to thestandard IVF technique, these alternative techniquesshould not be used as primary treatment options.
In contrast to IVF, ICSI uses only a singlespermatozoon to inseminate an oocyte. Thisspermatozoon is injected into the cytoplasm of theoocyte by means of a micromanipulator, thusbypassing capacitation and hyperactivation, recogni-tion of specific zona pellucida receptors, acrosomereaction and penetration of the zona pellucida andoolemma. Once introduced into the oocyte, thenucleus of the spermatozoon will decondense andform the male pronucleus.
Theoretically, ICSI needs only a geneticallyfunctional paternal genome, a functional microtubule-organizing centre (the paternally inherited spermcentrosome), and an oocyte-activating factor. Thefirst successful application of this invasive insemina-tion technique was reported in 1992 (13) and sincethen it has been used extensively worldwide for thetreatment of male infertility.
ICSI is highly efficient in cases of severe maleinfertility that would otherwise be untreatable. Thesuccess of ICSI, however, has led to its overuse. Anobvious reason for this is the avoidance of completefertilization failures. The risk of fertilization failure afterconventional IVF with normozoospermic semen hasindeed been a frustrating event ever since theintroduction of IVF. Unexplained failure of fertilizationafter IVF in normozoospermic males is observed inabout 10% of IVF cycles. In contrast, fertilizationfailure after ICSI occurs in less than 3% of cycles andis recurrent in only 15% of cases (14,15) .
In a meta-analysis of RCTs dealing with “border-line semen parameters”, more oocytes were foundfertilized after ICSI than after conventional IVF: the
Gamete source and manipulation 85
relative risk (RR) (calculated on a per-oocyte basis)was 2.2 with a 95% CI of 1.6–3.0 in favour of ICSI. TheRR (calculated on a per cycle basis) for a completefertilization failure was 10.8 (95% CI 3.1–38.1) and thenumber needed to treat (NNT) was 2.6 (95% CI of 1.5–10.1). However, when only studies using “highinsemination concentration” IVF were considered, theRR for an oocyte to become fertilized in vitro was 1.1(95% CI 0.7–1.7), again in favour of ICSI. The NNTwas 4.1 with a 95% CI of 1.4–4.9 (16). This meta-analysis clearly shows that ICSI significantlyimproved the probability of fertilization in couplessuffering from male infertility. However, given the wideconfidence intervals and the ongoing debateregarding the safety of ICSI, proposing ICSI to allcouples with borderline semen values may not be thebest first-line treatment option. Several authors haveproposed a split IVF/ICSI management scheme whenperforming assisted reproductive technology (ART)in couples with male infertility, while others prefer toperform at least one IVF procedure before startingICSI. In practice, the choice between the “straightICSI” approach, the “first-IVF” approach and the“split IVF/ICSI” approach will depend mainly ondifferences in defining the “borderline semen profile”,insemination procedures, patient selection, centreperformance, reimbursement policies and even patientpreference.
After five cycles of ICSI, a cumulative live birthrate of 60% has been reported in patients less than 38years old having their first course of ICSI treatment(17). Fertilization failure after ICSI using ejaculatedspermatozoa is rare (2.8% of ICSI cycles) and is duemainly to defective oocyte activation. From a clinicalviewpoint, fertilization failure after ICSI is related to asperm factor in half of the cases, including the absenceof motile spermatozoa or the injection of spermatozoawith severely abnormal morphology (14).
Ejaculated spermatozoa from anejaculatorypatients
When no ejaculate can be produced, several strategiesexist to obtain spermatozoa for assisted reproduction.
Retrograde ejaculation
In retrograde ejaculation, ejaculation does occur, butis directed into the bladder. Here, spermatozoa areexposed both to hypo-osmotic stress and to a low pH.When specific treatments are not available or
indicated, spermatozoa may be recovered frompostmasturbatory urine and subsequently used forassisted reproduction. The urine osmolality should beadjusted and alkalinization should be performed toimprove the quality of the spermatozoa. The numberand the motility pattern of the spermatozoa recoveredwill determine whether they may be used for IUI, IVFor ICSI (18).
Anejaculation
Anejaculation can be part of a general problem oferectile dysfunction. While there are several treatmentapproaches possible, including psychotherapy ormedical treatment, assisted reproduction may be usedin some cases.
Acute ejaculation occurs relatively frequentlyeven in patients undergoing ART. The production ofan ejaculate is for many patients a stressful eventwhich may induce the problem of anejaculation.Administration of sildenafil citrate may overcome theproblem of an unexpected, acute erectile dysfunction(19) .
Most patients with a chronic anejaculatoryproblem from a neuropathy or spinal cord injury whoneed assisted reproduction, will undergo either penilevibrostimulation (PVS)(20) or electrostimulation(21,22) in order to obtain an ejaculate. Vibro-stimulators are applied to the penis to induceejaculation. The best results are obtained using high-amplitude penile vibrostimulators which deliver anamplitude of at least 2.5 mm. Only vibrators intendedfor medical use will deliver this amplitude. To obtainejaculation with PVS, both the cauda and conus of thespinal cord must be intact up to the S-2 level.Ejaculation rates in spinal cord injured are around 60%,while in idiopathic anejaculation this figure is about70% (18) . Spermatozoa obtained by penile vibro-stimulation can be used for either IUI or IVF,depending on the quality of the sample obtained.
As an alternative, or when penile vibrostimulationfails, electrostimulation can be performed. In thistechnique, ejaculation is induced by introducing anelectrode in the rectum and using electrical pulses tostimulate the nerves and muscles involved inejaculation. Overall, in different categories of patients,electroejaculation is successful in about 90% ofpatients (18). Again, according to the semen quality,insemination, IVF or ICSI may be performed.
86 HERMAN TOURNAYE
Nonejaculated spermatozoa
Epididymal spermatozoa
In patients with obstructive azoospermia, fertility canbe restored by surgical correction, i.e. vasoepididy-mostomy, vasovasostomy or perurethral resection.When surgery has failed or is not indicated, as withpatients with congenital bilateral absence of the vasdeferens, for example, spermatozoa can be aspiratedfrom the epididymis and used for assisted reproduc-tion. Spermatozoa can be recovered by microsurgicalepididymal sperm aspiration (MESA) or percutaneousepididymal sperm aspiration (PESA). Before 1992 andthe introduction of ICSI, the first pregnancies withART using epididymal sperm were achieved withconventional IVF (23,24). However, the success rateof fertilization after conventional IVF with epididymalsperm was poor. The most important factors relatedto the success of IVF with epididymal spermatozoaare sperm maturity and the number of motile spermretrieved; often only a few spermatozoa showingprogressive motility are obtained after epididymalaspiration. ICSI, on the other hand, yields highfertilization and pregnancy rates when epididymalspermatozoa are used (25). Review of the literaturefrom different studies shows that the fertilization ratesreported after ICSI using epididymal sperm rangesfrom 39% to 65%, with clinical pregnancy rates rangingfrom 12% to 39% per ICSI cycle (26). These variationsare most probably due to differences in the age of thefemale partners and in the number of treatment cyclesincluded in the data. Epididymal sperm may becryopreserved and used for ICSI after thawing. Severalreports show similar outcomes after ICSI using eitherfresh or frozen-thawed epididymal spermatozoa (27–32).
Testicular spermatozoa
When no motile spermatozoa can be retrieved becauseof epididymal fibrosis, testicular sperm retrieval maythen be an alternative. Testicular sperm can beretrieved by different techniques (33): testicularsperm extraction or TESE (this refers to open excisionaltesticular biopsy), testicular sperm aspiration or TESA(refers to any method by which testicular sperm areaspirated percutaneously) or fine-needle aspiration(refers to any aspiration technique using needles of21 gauge or thinner).
Most azoospermic patients suffer from primarytesticular failure or nonobstructive azoospermia.
However, in a few cases, nonobstructive azoospermiamay be the result of hypogonadotrophic hypo-gonadism. These patients need hormonal stimulationby follicle stimulating hormone (FSH) and luteinizinghormone (LH) or pulsatile gonadotrophin releasinghormone (GnRH) to restore their fertility and they donot, in the first instance, need assisted reproduction.
Most patients with primary testicular dysfunctionresulting in azoospermia show a Sertoli cell-onlypattern in their testicular histology. Others havematuration arrest or have sclerosed and/or atrophiedseminiferous tubules. Notwithstanding these findings,a few seminiferous tubules may still show occasionalfoci of active spermatogenesis. The classificationproposed by Levin (34) has proven useful whendealing with men suffering from nonobstructiveazoospermia undergoing multiple testicular biopsies.When the main prevailing histopathology is germ cellaplasia (Sertoli cell-only syndrome), but some tubulesdo show active spermatogenesis, the terminology ofincomplete Sertoli cell-only syndrome is used. Thesame goes for maturation arrest: when full spermato-genesis is present in a few tubules, the condition isreferred to as incomplete maturation arrest. Hypo-spermatogenesis is an ill-defined condition withactive spermatogenesis in all tubules present, but withonly a few spermatozoa developing. Many men withhypospermatogenesis may have an obstruction as themain cause of their azoospermia, rather than a severetesticular dysfunction. The diagnosis of “nonobstruc-tive azoospermia” should be made according to thehistopathological findings, rather than on the basisof only clinical indicators such as FSH levels ortesticular size.
The sperm recovery rates in men with nonobstruc-tive azoospermia varies between 40% and 70%according to the recovery technique used (35–40) .Differences in recovery rates may also be due todifferences in the patient populations studied. Somestudies refer to nonobstructive azoospermia when nohistological diagnosis is obtained or they tend toinclude a majority of patients showing hypospermato-genesis. In the latter category of patients spermatozoawill always be found (39).
Often, testicular spermatozoa are recovered onlyafter examining and preparing multiple excisionalbiopsies (38). Even in about half the patients with anonmosaic 47,XXY Klinefelter syndrome, maturespermatozoa can be recovered from multiple testicularbiopsies (38,39). Multiple biopsies can be takenthrough several small incisions into the tunica
Gamete source and manipulation 87
albuginea or by one large opening through the tunicawhich provides a maximal exposure of the testicularmass of seminiferous tubules. With the latterapproach, using microsurgical inspection at a 40–80times magnification, the more distended tubules canbe selected for excision (38).
As for epididymal spermatozoa, cryopreservationof testicular sperm may be a method to avoid repeatedsurgery and even unnecessary controlled ovarianhyperstimulation in the female partner of a male withnonobstructive azoospermia due to primary testicularfailure. At present, however, the results are inconclu-sive as to whether the outcome after ICSI with frozen-thawed testicular spermatozoa is comparable to ICSIusing fresh spermatozoa. Some authors report similaroutcomes (36,41) , while others report a decrease insuccess rates (42–44).
Other sources of nonejaculatedspermatozoa
There have been reports on the recovery of sperm fromthe vas deferens (45,46) . This technique has beenreported to yield many spermatozoa and they may beespecially useful in patients with anejaculation inwhom vibrostimulation or electroejaculation hasfailed. However, both vasal sperm retrieval andretrograde epididymal sperm collection may result inthe collection of more dysfunctional senescent spermor sperm with damaged DNA, since in patients withobstruction the most distal sperm are the mostsenescent.
Immature gametes
Spermatogenetic cells
When no testicular spermatozoa can be recovered,more immature testicular spermatogenetic cells can beused for ICSI (47). There have been several reportson the use of spermatids to treat male infertility. Bothspermatids from ejaculates and from testicular biopsieshave been used. However, only one group hasreported fertilization and subsequent pregnancieswith ejaculated spermatids (48). Most pregnanciesreported after spermatid injection are pregnanciesobtained with elongated and round spermatids fromtesticular biopsies, often derived from patients withnormal spermatogenesis (49) . The number ofpregnancies reported so far is still limited.
A pregnancy has been reported after ICSI withsecondary spermatocytes, a spermatogenetic cell witha diploid DNA content undergoing the second meioticdivision (50).
If azoospermia is the result of an arrest inspermatogenesis at the primary spermatocyte state,then only diploid cells are available and ICSI is notfeasible. Yet, a recent paper reported ICSI withspermatids obtained after in vitro culture of primaryspermatocytes. Two out of five men with premeioticarrest of spermatogenesis developed spermatids invitro which were used for ICSI and a set of twins wasborn (51) . So far, these results have not beenconfirmed by others.
Testicular tissue
The seminiferous tubules contain spermatogonia,cells that have the capacity to renew themselves andto initiate meiosis at puberty. Only a small proportionof spermatogonia—the stem cells, have the potentialto renew themselves. Recently, research in mice hasshown that spermatogenesis can be re-initiated aftertransplanting testicular stem cells (52). It was alsoshown that the transplanted mice could reproduce invivo after transplantation. These experiments werealso performed using stem cells that had been frozenand thawed (53). These experiments, extrapolated toa human model, may have important applications.When an adult male undergoes sterilizing chemo-therapy, spermatozoa can be frozen to circumventsterility after treatment. However, such treatment is notpossible before puberty since no active spermato-genesis is present. Here, testicular tissue containingstem cells may be cryopreserved before any cytotoxictreatment. These stem cells can then be thawed whentheir donor has reached adulthood and can bereintroduced into his empty seminiferous tubules(autologous transplantation). Other applications maybe even more futuristic; it has been stated that it maybecome possible to develop human testicular stemcells to maturity in surrogate animals after transplanta-tion. So far, preliminary experiments have not beensuccessful. Transplantation of testicular stem cellsfrom hamsters, rabbits and dogs has failed to initiatespermatogenesis in recipient mice, probably becausethe phylogenetic gap between these species is toowide. However, the phylogenetic gap between greatapes and humans is smaller than that between rats andmice, a model in which xenotransplantation has worked.
88 HERMAN TOURNAYE
Oocytes and ovarian tissue
The female partner of an infertile couple requiring ARTneeds to undergo ovarian hyperstimulation to recovera larger number of oocytes. In most procedures, someloss of oocytes occurs at each stage—oocyte retrieval,fertilization, embryonic development in vitro, andimplantation. Therefore, attention has been directedtowards the possibility of the in vitro maturation ofoocytes which may circumvent the need for super-ovulation and the use of expensive drugs. It may alsoreduce the risks related to superovulation. However,oocyte retrieval will still be necessary. At present, theuse of immature oocytes for ART has been limited andsome pregnancies have been reported in patientsundergoing short ovarian stimulation followed by ashort in vitro maturation of the so-called immatureoocytes. The definition of “immature oocytes” can bediverse. In most studies, oocytes in their final stageof maturation are further matured in vitro, reducingovarian stimulation by a few days (54).
In vitro maturation may be useful where cryo-preservation is employed. Cryopreservation ofunfertilized mature oocytes (metaphase-II oocytes)has so far not been successful (55). Results of ARTare very variable and although pregnancy ratesranging from 1% to 10% per thawed oocyte have beenreported, oocyte survival and function is limited evenin those series of studies that focused on selectedpatients. When expressed per frozen oocyte, thesuccess rate in terms of a viable pregnancy is around1% per oocyte. Better results have been reported instudies using oocytes that survived the thawingprocedure.
Cryopreservation of immature oocytes may,however, become more successful, as these oocytesmay be less sensitive to damage during freezing orthawing. These oocytes, which are embedded in theovarian cortex, cannot be retrieved by ovarianpuncture and have to be recovered directly from theovarian cortex of an excised ovary. Collection ofimmature oocytes will probably not be an issue forpatients undergoing fertility treatment, but maybecome an important issue for young girls who needto have sterilizing chemo- or radiotherapy. If immatureoocytes can be retrieved from the ovarian cortex andcan be successfully cryopreserved, this may providea means to overcome this problem (56).
Cryopreservation of immature oocytes is still inan experimental phase and the techniques for freezingof ovarian tissue or the isolated follicles need to be
optimized (57). When ovarian cortex or the isolatedprimordial follicles are frozen, an 80% survival rate canbe obtained. However, these oocytes need to maturesubsequently to obtain their capacity to be fertilized.Currently, two possibilities are being investigated:either the cortex or the primordial follicles are maturedin vitro in order to obtain metaphase-II oocytes whichcan than be used for assisted reproduction, or theovarian cortex is autotransplanted into the recipientin the natural site (peritoneal cavity) or in another siteensuring easier retrieval of oocytes once in vivomaturation occurs. In the mouse and sheep, live younghave been obtained after transplantation. In thehuman, only transplantation to the peritoneal cavityor transplantation under the skin of the forearm hasbeen performed with limited results (58).
Artificial oocyte activation
When a spermatozoon fertilizes an oocyte, it liberatesa factor which induces the release of calcium from theoocyte. Since this release happens in a pulsatilefashion, this factor has been named oscilline. Oscillineis not present in round spermatids and, therefore,when ICSI is performed with these immature gametes,oocyte activation is deficient (50). This problem canbe bypassed by artificially activating the oocyte usingan electrical current to increase the inflow of calciumover the cell membrane, or by using a chemical suchas a calcium ionophore, which causes an increase inintracellular calcium that triggers further steps offertilization.
This factor may be deficient also in men withabsent spermatozoal acrosomes (globozoospermia orround-headed spermatozoa) (59). Again, artificialactivation may help their spermatozoa to fertilize anoocyte successfully with ICSI.
However, the use of a calcium ionophore hasraised a lot of concern since this compound is asuspected mutagen and has not been approved forhuman use (see below).
Ooplasmic transfer
In 1997, Cohen and co-workers introduced anooplasmic transfer procedure (60). With this tech-nique, small amounts of cytoplasm of donor eggs(5%–15%) are injected into oocytes that are assumedto be deficient in factors important for furtherembryonic development. The approach is empiricalsince it supposes that embryonic failure results from
Gamete source and manipulation 89
these deficiencies in the oocyte’s cytoplasm. Theinjected cytoplasm may contain mRNAs, proteins,mitochondria and other unknown factors or organelles.Recently it has been reported that offspring born afterART using these “upgraded” oocytes show mito-chondrial DNA heteroplasmy (61). About 30 babieshave been born worldwide following the applicationof this approach in selected patients (61) . Nocontrolled study has so far been reported establishingthe benefits of this technique.
Indications and contraindications, benefitsand eligibility of patients
Ejaculated spermatozoa as a source ofgametes
Spermatozoa for IUI and IVF
IUI is indicated in men with idiopathic oligozoo-spermia, asthenozoospermia, teratozoospermia or acombination of these conditions. The technique mayalso be useful in case of male infertility due toretrograde ejaculation, anejaculation or hypospadias.IUI is also possible in the treatment of cervical factorinfertility, immunological infertility and unexplainedinfertility.
Before intrauterine instillation, the ejaculate hasto be washed to prevent uterine contractions inducedby the presence of prostaglandins in the semen butwashing may increase the generation of reactiveoxygen species in the sample, which may adverselyaffect sperm function (62) . Using additionalprocedures, motile spermatozoa can be selected andtheir motility enhanced. In this way, a few hundredsor thousands to even a few million motile spermatozoaare concentrated in a small insemination volume notexceeding 0.5 ml. Thus ten times more spermatozoamay reach the uterine cavity as a result of using thistechnique compared to the normal physiology ofsperm migration. However, there is an importantqualitative difference: after in vitro sperm selectiontechniques, another, less functional, population ofspermatozoa will be selected than after selection invivo by the cervical mucus. For IUI, at least one millionprogressively motile spermatozoa should be obtainedafter preparation, otherwise the technique is not verysuccessful (63).
Commonly used methods for sperm preparationare the “swim-up” procedure and discontinuous
density gradient centrifugation. While the swim-upprocedure can be applied only on high-qualitysamples, density gradient centrifugation is used onsemen samples of lower quality in order to recover areasonable number of motile sperm. The swim-upprocedure is not used any more, as density gradientcentrifugation results in higher sperm recoveries andeven better IVF rates in certain categories of patients.Moreover, the swim-up procedure has a higher risk ofgenerating reactive oxygen species.
Two independent meta-analyses have beenpublished investigating the benefits of IUI (63,64) .In overall comparisons between IUI and naturalintercourse and/or intracervical insemination, IUI hasbeen shown to be effective in male factor infertility.In the larger meta-analysis by Cohlen, a significantincrease in fertility was found as a result of using IUIcompared with natural intercourse, with or withoutovarian stimulation.
Cohlen et al. (63) also performed a meta-analysisof four randomized controlled trials comparing IUI innatural cycles versus cycles with controlled ovarianhyperstimulation. The pregnancy rate was 12.6% instimulated cycles versus 7.3% in unstimulated cycles.Although there was a tendency for controlled ovarianhyperstimulation to increase fertility (OR 1.80) thedifference was not significant (95% CI 0.98–3.3). In thestudies using controlled ovarian hyperstimulationunder review, the multiple pregnancy rate was 5.5%(all twins) and the incidence of developing the ovarianhyperstimulation syndrome (OHSS) was 0.8%.
IVF is indicated for infertility caused by tubalblockage, severe endometriosis (not manageable bysurgery or after failure of surgery), polycystic ovariansyndrome with uncontrollable ovulation induction,the presence of antisperm antibodies in the male orfemale partner and oligoasthenoteratozoospermia inthe male partner. IVF may also be indicated in somecouples with unexplained infertility. However, for manyof these indications alternative treatments may existand therefore, the risks and benefits of each treatmentstrategy should be compared.
The lower limits for sperm numbers compatiblewith fertilization after conventional IVF are poorlydefined. In most centres, a cut-off value for thenumber of progressively motile spermatozoa aftersemen preparation is defined so as to allow conven-tional IVF. A minimum total number of rapid (type A,>25 µm/s) and slow (type B, 5–25 µm/s) progressivelymotile spermatozoa together is generally used (65).Payne et al. (66) used one of the lowest cut-off values
90 HERMAN TOURNAYE
of 200 000 motile spermatozoa obtained after a mini-Percoll preparation, but most programmes will prefer500 000 or more type A+B spermatozoa for conven-tional IVF.
Apart from the numbers, sperm morphologyaccording to the strict Tygerberg criteria is one of themost frequently used single semen parameters toscreen for conventional IVF. A literature reviewshowed that sperm morphology analysis accordingto the strict criteria represents the most effectiveindicator of male fertility potential in IVF. Fertilizationfailure will occur in most patients where there are fewerthan 5% morphologically normal spermatozoa in theejaculates (67) . Increasing the number of motilespermatozoa at insemination has been proposed toimprove fertilization in cases with borderline semencharacteristics, including those with sperm morphol-ogy below the 5% value (68,69). A recent reviewshows that in the studies where these high insemina-tion concentrations were used, the probability offertilization after IVF was better than that after ICSI(16) .
Spermatozoa for ICSI
With ICSI, the spermatozoon is injected directly intothe ooplasm and therefore specific gamete interactiondefects may be bypassed, including sperm dys-function at the level of the zona pellucida, zonapenetration or fusion with the oolemma. Since mostpatients with recurrent failure of fertilization afterconventional IVF present one or more of thesedisorders, ICSI may successfully alleviate these formsof infertility. Patients with severe oligozoospermiamay also benefit from ICSI even when conventionalinsemination in vitro is impossible. Basically, as longas the same number of motile spermatozoa can berecovered as there are oocytes to be injected, ICSI canbe performed with ejaculated spermatozoa. Therefore,an extensive search of the ejaculate should beperformed. ICSI is also successful when dealing withabsolute teratozoospermia. Patients with immuno-logical infertility may also benefit from ICSI sinceantisperm antibodies do not interfere with thefertilization process after ICSI (70) . When noprogressive motile ejaculated spermatozoa can beobtained for insemination in vitro, again fertilizationcan be achieved by ICSI. ICSI has also proved to be avaluable technique using frozen-thawed sperm fromcancer patients: even if sperm quality is impaired, ICSI
offers superior results and uses a minimal volume ofcryostored sperm (71).
However, fertilization failure after ICSI may stilloccur. Injecting immotile spermatozoa decreases theICSI fertilization rate (70). Therefore, an extensivesearch of the centrifuged semen pellet must be doneto recover motile spermatozoa and the collection andexamination of a second ejaculate may be necessary.When the second semen sample or its centrifugeddeposit does not contain motile spermatozoa, immotilebut live spermatozoa may be selected by a hypo-osmotic swelling test (HOS test). This test is,however, not useful in patients with 100% immotilesperm due to axonemal structural defects such asimmotile cilia syndrome. Patients with the immotile ciliasyndrome are sterile because their spermatozoa lackmotility, hindering natural gamete-interaction.Pregnancies have been reported after subzonalinsemination and ICSI using these spermatozoa(72,73); however, results after ICSI with thesespermatozoa remain poor and unpredictable, evenafter selection by an HOS test (74). The reason whyICSI results are so poor in these patients is not clear.Many of the ultrastructural defects may have conco-mitant defects affecting other microtubular structuressuch as the sperm centrosome and deficiencies at thislevel may be involved in fertilization failure or poorembryonic development (75,76).
In cases of necrozoospermia, viable spermatozoacan still be recovered by a testicular recoveryprocedure (77). Another category of patients withdeficient gamete interaction is those suffering fromglobozoospermia or round-headed sperm syndrome.In contrast to the immotile cilia syndrome, this is awell-delineated condition in which spermatozoa aredevoid of the acrosome and postacrosomal sheath.They cannot attach themselves to and penetrate thezona pellucida, neither can they attach themselves toor penetrate the oolemma of the oocyte. Again, sinceICSI may circumvent such gamete interaction defects,patients suffering from globozoospermia may benefitfrom the direct injection of their spermatozoa in theoocyte cytoplasm. A few pregnancies have beenreported after ICSI with round-headed spermatozoa(78,79), but the general results after ICSI withspermatozoa with no acrosome are poor. In thosepatients with ICSI failure, oocyte activation may bedeficient (59). Artificial oocyte activation with acalcium ionophore has been reported to overcome thisproblem (80).
Gamete source and manipulation 91
Epididymal spermatozoa as a gamete source
Epididymal spermatozoa may be used for ICSI inpatients with congenital bilateral absence of the vasdeferens, Young syndrome, failed reconstructivevasal surgery, azoospermia resulting from bilateralherniorrhaphy with accidental vas deferens occlusionand obstructions at the level of both ejaculatoryducts. Epididymal sperm retrieval methods have beenproposed as a means by which spermatozoa may beobtained in men with anejaculatory infertility.However, given the efficiency of assisted ejaculationin these men, surgical methods are only to beconsidered when penile vibrostimulation or electro-ejaculation has failed. Furthermore, it is preferable insuch patients to refrain from epididymal spermaspiration techniques because of their higher risk ofsubsequent iatrogenic obstruction (81).
Epididymal spermatozoa can be retrieved using anoperating microscope at a magnification of 40 to 80times (MESA) (24). An alternative technique is PESA.The latter technique has been described in detail byCraft and co-workers (82). By means of a percuta-neous puncture using a 19-gauge needle, epididymalsperm may be aspirated blindly from the epididymisunder local or regional anaesthesia. Its relativelynoninvasive character is the most importantadvantage of PESA; it can be easily performed on anoutpatient basis, it is quick and simple when comparedto MESA and is more cost-effective. It has beenargued also that there may be fewer complicationsafter PESA than after MESA (83). The sperm recoveryrate reported after PESA is comparable to that afterMESA (84). Both MESA and PESA may be repeatedin the same patient several times with good results interms of sperm recovery.
The main criticism of the PESA technique is thatblind percutaneous puncture may cause inadvertentdamage to the fine epididymal structures and produceuncontrolled bleeding causing postoperative fibrosis(81). Therefore, MESA may be the preferred methodto retrieve epididymal sperm in patients with obstruc-tive azoospermia in whom surgical repair still remainsan option. If no surgical correction is feasible, PESAis to be preferred. The epididymal spermatozoa thatare obtained can be easily cryopreserved for later usewithout jeopardizing the outcome after ICSI (29). If,however, previous investigations have shown thatmicrosurgical reconstruction is not possible, thenPESA may be performed since epididymal damage andfibrosis is not an important issue where reconstruction
is not possible. After MESA or PESA, epididymalsperm may not always be obtained (85). In this case,recovery of testicular spermatozoa may be attempted.
Testicular spermatozoa as a gamete source
All the indications for using epididymal spermatozoain ART are valid for testicular spermatozoa. Testicularsperm recovery is also indicated in men with absolutenecrozoospermia and has been proposed for an-ejaculatory patients as an alternative for penilevibrostimulation or electro-ejaculation. However, it ispreferable to refer these patients, especially those withspinal cord injuries, to specialized services whereassisted ejaculation can be performed. Vibro- orelectrostimulation are noninvasive techniques whichmay be performed without any anaesthesia inparaplegic men. Since scrotal haematoma may take along time to heal in such men, surgical sperm retrievaltechniques are indicated only where these non-invasive techniques fail to produce an ejaculate thatmay be used for ICSI. Even in these cases, vasdeferens aspiration may be preferable because of itslow risk of iatrogenic obstruction (46). The ejaculates,even when oligoasthenoteratozoospermic, can becryopreserved for later use. Testicular sperm retrievalmust be considered only when primary testicularfailure or obstruction is present in an anejaculatorypatient or when techniques of assisted ejaculationhave failed to produce an ejaculate that can be usedfor ICSI. An additional but important indication fortesticular sperm recovery is azoospermia in patientswith primary testicular failure.
Testicular spermatozoa may be obtained either byopen testicular biopsy or by fine-needle aspiration ofthe testis. Both methods are similar in terms ofoutcome (33); however , the numbers of spermobtained after open biopsies are much higher. For thisreason, open testicular biopsy may be preferredwhenever cryopreservation is desired. Alternativemethods of testicular aspiration have been describedyielding higher numbers of spermatozoa (86,87). Inthese aspiration techniques, needles with a largerdiameter are used in order to obtain tissue cylinders.Compared to fine-needle aspiration, these alternativemethods are less patient-friendly and need local orregional anaesthesia. Sometimes they may need to becombined with a small incision in the scrotal skin. Theirmain advantage is that cryopreservation is easy andefficient because of the higher numbers of spermobtained.
92 HERMAN TOURNAYE
In patients with normal spermatogenesis andobstructive azoospermia, all these techniques providea 100% sperm recovery rate (88). In patients withtesticular failure showing different degrees ofmaturation arrest, germ cell aplasia or tubular atrophyand sclerosis, spermatozoal recovery rates are around50% with excisional techniques.
TESA has been proposed in order to obtaintesticular spermatozoa from patients with non-obstructive azoospermia. However, several prospec-tive controlled studies have shown that the retrievalrate is significantly lower than with excisional biopsies(33,89,90).
Furthermore, in patients with a history of crypt-orchidism, testicular aspiration is contraindicated.These patients have a higher risk of developing atesticular cancer from carcinoma in situ cells and anexcisional biopsy must therefore be performed in orderto check for carcinoma in situ (91).
The recovery of testicular spermatozoa in thesedifficult cases is highly dependent not only on thesurgical technique used but also on the proceduresused in the laboratory to prepare the tissue samples.Sperm recovery may be facilitated by usingerythrocyte-lysing buffer (92) and enzymaticdigestion (93).
It is important to keep in mind that about 50% ofpatients suffering from azoospermia due to primarytesticular dysfunction may not benefit from thecombination of ICSI and testicular sperm recoverybecause no spermatozoa can be recovered from thetesticular mass even after extensive biopsies.Unfortunately, parameters such as testicular volume,preliminary semen analysis or serum FSH are not ableto predict successful sperm recovery (12,94). Inhibin-B, which is a marker for premeiotic germ cellproliferation, may be a better predictor in combinationwith serum FSH for testicular sperm recovery, althoughthe limited evidence available on this at present iscontradictory (95,96). In a small subgroup of patientssuffering from azoospermia because of a microdeletionat the Y chromosome, it was reported that nospermatozoa can be recovered when a deletion ispresent in the AZF-B region (97).
Another limitation of the efficiency of thecombination of ICSI and TESE is the decreased overallsuccess rate when compared to patients with normalspermatogenesis. Implantation rates do not exceed10% per embryo, especially in patients showingmaturation arrest with focal spermatogenesis (33). Thereasons for this finding are currently unclear, but may
be associated with deficient meiosis (98). However,no data are currently available showing that a higherproportion of embryos obtained in these patients isindeed aneuploidic.
Immature testicular gametes asa source
Recovery of immature testicular gametes has beenproposed as a means of overcoming infertility inazoospermic men where no spermatozoa could berecovered from the testicular tissue. Pregnancies havebeen reported after both the use of elongatedspermatids and round spermatids from testicularbiopsies or from ejaculates (49). Although thisapproach was introduced more than five years ago,the number of pregnancies reported after the use ofspermatids is still limited. Differentiating an elongatedspermatid in its final stage of spermiation from atesticular spermatozoon is not easy and requires adetailed microscopic examination (99). It has evenbeen assumed that in many so-called failed spermatidinjections, other testicular cells were actually injected(100). Most pregnancies reported after spermatidinjection are pregnancies obtained with elongatedspermatids recovered from testicular biopsies frommen with obstructive azoospermia showing normalspermatogenesis! It may thus be assumed thatspermatid ICSI is not a very successful approach fortreating infertility in azoospermic men with a primarytesticular dysfunction.
There is much debate concerning the pregnanciesreported after an adapted ICSI procedure usingsecondary spermatocytes (50) and with spermatidsobtained after a short in vitro culture of primaryspermatocytes (47), as no other groups have beenable to reproduce these results.
Banking testicular spermatogonia may be indica-ted for boys undergoing chemotherapy or extensiveradiotherapy. A study by Kliesch et al. (101)demonstrated that adolescent patients 14–17 years ofage are good candidates for semen banking, eventhough they may not have completed their puberty.From these results, it appears that semen cryo-preservation has a role to play, even for adolescents.Although testicular tissue or testicular cellsuspensions from prepubescent males may becryopreserved, this must be considered anexperimental procedure at present.
Gamete source and manipulation 93
Oocytes and ovarian tissue as agamete source
The use of immature oocytes and ovarian tissue is stillexperimental. Patients who may benefit from in vitromaturation of oocytes in their last stages of maturationare those who are at risk for developing OHSS. How-ever, many of these patients will suffer from polycysticovarian syndrome, and in these patients, in vitromaturation has not been very successful so far.
Patients who may benefit the most from thistechnology are women or girls who need to undergosterilizing treatments such as chemotherapy orbilateral ovariectomy. Since cryopreservation ofmature oocytes has not been successful to date,research has focused increasingly on bankingimmature oocytes. Although the technology is stillunder development, many ovaries have been cryo-preserved before starting sterilizing treatments.
Those needing unilateral ovariectomy by laparo-scopy may have their follicles banked after removalfrom the excised ovarian cortex or embedded in thinslices of ovarian cortex. The latter approach stillleaves the opportunity to autotransplant the slices,while follicle banking only leaves the possibility ofsubsequent in vitro maturation.
Patients at risk of having malignant cells in theirovaries, either from the primary tumour or frommetastases, may bank their ovarian tissue but, atpresent, only with a view of future in vitro maturation.
Another category of patients from whom ovariesare being banked are patients with Turner syndrome(45,XO karyotype). These patients have a progressivebut accelerated loss of primordial follicles and bankingtheir ovarian issue may be a means of preserving theirfuture fertility. However, this approach, althoughexperimental, may raise concerns regarding the risksfor congenital malformations in the offspring.
Artificial oocyte activation
Defective oocyte activation is an infrequent cause forfailed fertilization after ICSI. According to recentresearch using mouse oocytes and human spermato-zoa, artificial oocyte activation may overcome repeatedfertilization failures after ICSI (102).
When round-headed acrosome-less spermatozoaare used, fertilization after ICSI is poor and unpredic-table because of insufficient oocyte activation.Artificial oocyte activation with a calcium ionophorehas been reported to overcome this problem (80).
Artificial oocyte activation is necessary in order toobtain fertilization after microinjection of roundspermatids.
Ooplasmic transfer
The clinical indications for ooplasmic transfer are farfrom clear. There is no method as yet to detectcytoplasmic deficiencies in oocytes and ooplasmictransfer has so far been applied in selected patientswith a suspicion of ooplasm deficiencies because ofpoor early embryonic in vitro development after IVFor ICSI. The technique should be considered asempirical and experimental.
Risks
Ejaculated spermatozoa as a gamete source
When ejaculated spermatozoa are used for IUI orconventional IVF, the natural barriers controllingfertilization are still functional. The main risk with thesetechniques is the transmission of infectious agents.For many of these infectious agents an effectivetreatment is available. In contrast, the use ofspermatozoa from men with human immunodeficiencyvirus (HIV) or hepatitis C infection has raisedconsiderable debate since there are no vaccines toprovide protection against these infections that canbe given to their sexual partners.
Although at present it is still unclear whether theviral genome may be incorporated into the malegamete, it is assumed that the white blood cells withinan ejaculate are the main source of infection. Thesperm washing procedure may eliminate many viralparticles (103).
There have been many pregnancies resulting fromIUI or IVF using the spermatozoa of HIV-positivemales without any case of transmission of theinfection to the female partner being reported (104).These male partners have an undetectably low viralload and are under strict medical control. Often a man’ssemen is pooled after several ejaculations and the viralload is assessed on the frozen pool of semen. Whenno viral contamination can be detected, the risk oftransmission may be low in using frozen-thawedsemen from these men for ART.
Despite the low risk of transmission of the HIVvirus in these circumstances, the published series arestill too small to conclude that this approach will
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indeed be safe. At best it may be concluded that thisstrategy offers an important risk reduction. Becauseof the low numbers of spermatozoa used, it has beenargued that ICSI should be used with semen from HIV-positive or hepatitis C-positive men to limit the riskfor transmission of the infection to their partners.However, when the viral genome is incorporated intothe sperm’s genome, the transmission risk is real. Inthis case, preimplantation genetic screening may offera further risk reduction.
For ICSI, apart from the risks related to the sourceof the gametes used, the main important, but yetunproven, concern is the introduction of contamina-ting foreign material into the oocyte’s cytoplasmduring ICSI. The use of polyvinylpyrrolidone (PVP)to slow down sperm movement may constitute a riskdue to endotoxins. Although sound evidence is as yetunavailable to support this, PVP has been withdrawnfrom the market and replaced by products controlledfor endotoxin contamination. Microbiological conta-mination of semen is common but washing and furthersemen preparation may eliminate many of themicrobiological contaminants. On the basis of thecurrent literature, this hazard is assumed to be minimalor even nonexistent for bacteria (105) but for virusesother than hepatitis C or HIV such as the humanpapillomavirus (HPV), this issue is less clear (106).Theoretically, prions may be introduced during anICSI procedure (107). And although the technique isof a debatable reproducibility, it has been shown thatexogenous DNA could be integrated during ICSI inthe mouse, producing transgenic offspring (108) .More recently, foreign DNA was successfullyintroduced into nonhuman primate oocytes duringICSI, however, without producing transgenicoffspring (109). Therefore, it has been proposed thathuman spermatozoa should be exposed to a sequenceof “sanitizing” treatments before ICSI (109).
An important risk related to the gamete source forICSI is the status of the sperm genome. ICSI may beperformed with senescent ejaculated spermatozoa thatmay have accumulated DNA strand breakages fromoxidative damage, ageing or extended epididymalstorage (110) . Because of the genetic concernsrelated to DNA strand breakage and the fact thatspermatozoa with oxidative damage may successfullyfertilize by ICSI (111) , it is preferable to use viabletesticular sperm rather than nonvital dysfunctionalspermatozoa from the ejaculate (77). The ultimateselection of the spermatozoon to be injected in ICSIis made subjectively through the light microscope,
selecting a suitable motile spermatozoon on sight.Although no adverse effects in terms of outcome havebeen reported after microinjection of spermatozoa frompatients with morphologically abnormal spermatozoa,most of these studies have not correlated spermmorphology with ICSI outcome. Only a few studies,comprising a limited number of cases, have reportedon the outcome following injection of morphologicallyabnormal sperm (112,113). Both of these studiesshowed a reduced fertilization rate when abnormalsperm were used for ICSI. These findings are notsurprising since an increase in chromosomal aberra-tions has been observed, in spermatozoa fromoligozoospermic individuals, using fluorescence insitu hybridization (FISH)(98,114–116) .
Furthermore, up to 3% of patients witholigozoospermia are reported to have autosomalkaryotype abnormalities while the incidence of sexchromosome abnormalities in azoospermic men isreported to be 14% (116,117). The incidence ofkaryotype abnormalities may be inversely related tothe number of spermatozoa in the ejaculate (117). Bothazoospermic and oligozoospermic patients musttherefore be karyotyped before any ICSI treatment toprevent possible transmission of aneuploidy to theoffspring.
This increase in aneuploidy rate in infertile menwill probably at least partly explain the increase in sexchromosome abnormalities in the offspring of ICSIpatients (119) . Abnormal sperm decondensation afterICSI may also contribute to the problem of increasedde novo sex chromosome aneuploidy (120).
Finally, a distinct subpopulation of men whobenefit from ICSI treatment may have deletions at thelong arm of the Y chromosome (121). These Yqdeletions will be passed on to the next male generationby ICSI (122,123). Autosomal Y homologues or otherunknown recessive gene defects may exist and manygenes related to spermatogenesis may be interlinkedin gene networks. Apart from Yq deletions, mutationsin the androgen receptors, including an increasednumber of CAG repeats in the androgen receptor gene,have been reported to cause male infertility (124,125) .At present, all of the inheritance patterns of maleinfertility are far from having been elucidated but moreevidence is arising that hereditary traits may beinvolved in many candidate patients for ICSI (126).
Globozoospermia and immotile cilia syndromes arenow increasingly assumed to be hereditary disorders.Apart from reproductive disorders, ICSI candidatepatients may have a slightly higher prevalence of
Gamete source and manipulation 95
potentially heritable nonreproductive disorders as well(127).
In patients with less than five million spermatozoain their ejaculate, a cytogenetic analysis and Y-deletion screening should be performed beforeembarking on an ICSI treatment (128) . Not-withstanding genetic counselling, many patients maystill prefer to use their own gametes, hence taking arisk of transferring hereditary male infertility to theirsons. There have been several cytogenetic studiesperformed in ICSI candidate patients that have shownthat female partners of those males with severeoligozoospermia necessitating ICSI may themselveshave increased aneuploidy rates (more than 1% afterexcluding mosaicism) (129–132). These findings arehard to explain but may be related to a bias in theselection of the patients under investigation and callfor further study.
Epididymal spermatozoa as a gamete source
The risk when using epididymal spermatozoa for ICSImay be twofold. First, there is the risk related to thetechnique used to retrieve the spermatozoa. Blindpercutaneous puncture (PESA) may cause epididymaldamage and fibrosis although this is not an importantissue where surgical reconstruction is not possible.Second, there are the risks related to the source of thegametes. Senescent spermatozoa with DNA strandbreaks may be retrieved and used for ICSI and caremust be taken to select motile epididymal spermatozoa.
Patients with congenital absence of the vasdeferens are known to have mutations or deletions inthe cystic fibrosis transmembrane conductanceregulator (CFTR) gene (133). Screening for CFTRgene mutations must be performed before embarkingon ICSI in these patients. There are currently morethan 600 different gene mutations known andscreening for the most frequent mutationsrepresentative of a given population should beperformed on the wives of men with congenitalabsence of the vas deferens (CBAVD). When thefemale partner is found to carry a mutation, pre-implantation genetic diagnosis should be proposedif the male partner, too, is a carrier.
Patients with anejaculation may be exposed tospecific risks related to the techniques of assistedejaculation. If spinal cord lesions are located at thelevel of T-6 or higher, a risk of developing autonomousdysreflexia exists, with dangerous elevation of theblood pressure. Therefore, prophylactic administra-
tion of 10–40 mg sublingual nifedipine may benecessary.
Testicular spermatozoa as a gamete source
It is important to keep in mind that at least 50% ofpatients suffering from azoospermia due to primarytesticular dysfunction may not benefit from testicularsperm recovery because no spermatozoa can berecovered even after extensive biopsies. Unfortunate-ly, parameters such as testicular volume, preliminarysemen analysis or serum FSH are not able to predictsuccessful sperm recovery. Many patients may thusbe at risk to undergo repeated attempts at retrievalwithout success.
An important issue is the adverse effects of sucha procedure including testicular haematoma, oedemaand postoperative testicular fibrosis, which may occurwhen multiple excisional testicular biopsies are taken(134,135) . There are concerns that this fibrosis mayresult in a decline in testosterone output from thetestis. Although this concern is only borne out by thefindings of a small series (136), patients should beinformed about this possible adverse effect. Lessinvasive methods, such as fine-needle aspiration, maycause less damage to the testicular tissue butprospective controlled studies have shown that thismethod is not useful in some patients since thechances for recovering spermatozoa are about threetimes lower than with the other techniques (33,36,94).
Possibly more promising may be microsurgicalsperm retrieval (137). This approach may facilitatefinding the best area of the testis without removingmuch testicular tissue and may, as such, lower the riskof side-effects (40).
Some authors have reported that scheduling thetesticular recovery procedure one day before the ovumpick-up (138) or the use of sperm motility stimulantsmay facilitate the retrieval of motile spermatozoa fromthe tissue (139). Both strategies may, however, resultin additional risks. Testicular spermatozoa may bemore prone to accumulate DNA strand breakage duringovernight incubation than ejaculated spermatozoa.Pentoxifylline, on the other hand, may induceembryonic toxicity (140).
As with men with severe oligozoospermia, menwith nonobstructive azoospermia have an increasedrisk of aneuploidy and Yq deletions. An additionalimportant risk related to the use of testicularspermatozoa may be an increase in aneuploidy,
96 HERMAN TOURNAYE
especially in men with testicular failure (98). This maynot only reduce the implantation rates but may alsocause an increase in aneuploidy in the offspring. Atpresent, there is only limited information available onthe offspring of men with testicular failure undergoingICSI with testicular sperm and these data do not showany increase.
Immature testicular gametes as a source
Although pregnancies have been reported after theuse of elongated spermatids and round spermatidsfrom testicular biopsies or from ejaculates, the use ofsuch immature haploid germ cells gives rise to a lot ofconcern and confusion (141). Reports often refer toICSI performed with testicular spermatozoa andelongated spermatids since the distinction betweenboth cell types is not always possible after enzymaticdigestion of the testicular tissue and observation ofthe wet preparation. A classification system has beenproposed for observations made without fixation andstaining (49). Furthermore, it is difficult to distinguishround spermatids from diploid germ cells by theirmorphological appearance (99) and thus injection ofdiploid cells is not impossible (100).
There are also concerns relating to genomicimprinting (142) as this may not be completed in theseimmature cells. However, in a mouse model it has beenshown that genomic imprinting is completed at thespermatid stage (143) and that normal viable youngwith normal behaviour can be obtained after roundspermatid injection up to the fifth generation (144).Since mouse offspring obtained after injection ofsecondary spermatocytes were found to be fertile, itwas concluded that imprinting may be completed bythe second meiotic division or may even be completedwithin the oocyte’s cytoplasm (145). So far, therefore,the results from animal models in which ICSI isperformed with immature germ cells do not call forconcern but it is not clear whether these results canbe extrapolated to the human.
Oocytes and ovarian tissue as a gametesource
The post-treatment transplantation of ovarian tissueobtained pretreatment in cancer patients, riskstransplantation of malignant cells as well. This is notan issue when the immature gametes are matured andused in vitro . Currently, all these techniques areexperimental and not very promising. The use of
human immature oocytes for ART has been limited.From experimental animal models it appears that usingimmature oocytes matured in vitro , starting fromprimordial follicles, may not be without risks. Onepaper has reported the birth of one mouse aftercomplete in vitro maturation and ART. The offspring,however, had severe developmental problems (146).
Artificial oocyte activation in ART
Artificial oocyte activation with a calcium ionophorehas been promoted to overcome fertilization failure inICSI with acrosome-less spermatozoa and roundspermatids. However, whether this is a safe approachis unknown. The calcium ionophore treatment causesa massive calcium release in the oocyte and may thusactivate several secondary messenger-signallingpathways in the oocyte. In addition, calcium iono-phore has been shown to be mutagenic.
Ooplasmic transfer
The number of babies born after ooplasmic transfer islimited and no scientific evidence is available showingany benefit from this method. The genetic modifica-tion of the germline introduced by this techniqueraises a lot of concerns. However, the advocates ofthis technology consider the risks to be minimal sinceonly small amounts of foreign mitochondrial DNA arebeing transferred. They also refer to the finding thatmitochondrial DNA heteroplasmy may occurspontaneously without apparent problems (61). It hasbeen reported, however, that the active donormitochondria are unevenly distributed throughout theembryonic cells and subsequently betweenembryonic and extraembryonic tissues (61) . Theimplications of this finding remain unclear. Finally, bytransferring small amounts of donor cytoplasm,theoretically, prions too may be transferred to therecipient ovum.
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105. Michelmann HW. Influence of bacteria and leukocyteson the outcome of in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI). Andrologia , 1998,30:99–101.
106. Brossfield JE et al. Tenacity of exogenous humanpapillomavirus DNA in sperm washing. Journal ofAssisted Reproduction and Genetics, 1999, 16:325–328.
107. Lacey RW, Dealler SF. Vertical transfer of prion disease.Human Reproduction, 1994, 9:1792–1800.
108. Perry ACF et al. Mammalian transgenesis byintracytoplasmic sperm injection. Science, 1999, 284:1180–1183.
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111. Twigg JP, Irvine DS, Aitken RJ. Oxidative damage toDNA in human spermatozoa does not precludepronucleus formation at intracytoplasmic sperminjection. Human Reproduction, 1998, 13:1864–1871.
112. Mansour RT et al. The effect of sperm parameters onthe outcome of intracytoplasmic sperm injection.Fertility and Sterility , 1995, 64:982–986.
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117. Yoshida A, Miura K, Shirai M. Chromosome abnormal-ities and male infertility. Assisted Reproduction, 1996,6 :93–99.
118. Van Assche E et al. Cytogenetics of infertile men.Human Reproduction, 1996, 11 :1–24.
119. Bonduelle M et al. Seven years of intracytoplasmicsperm injection and follow-up of 1987 children.Human Reproduction , 1999, 14:243–264.
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124. Tut TG et al. Long polyglutamine tracts in theandrogen receptor are associated with reduced trans-activation, impaired sperm production, and maleinfertility . Journal of Clinical Endocrinology andMetabolism , 1997, 82:3777–3782.
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128. Rowe PJ et al. WHO manual for the standardisedinvestigation of the infertile couple. Cambridge,Cambridge University Press, 2000.
129. Van der Ven K et al. Increased frequency of congenitalchromosomal aberrations in female partners of couplesundergoing intracytoplasmic sperm injection. HumanReproduction, 1998, 13:48–54.
130. Scholtes MCW et al. Chromosomal aberrations incouples undergoing intracytoplasmic sperm injection:influence on implantation and ongoing pregnancyrates. Fertility and Sterility , 1998, 5:933–937.
131. Peschka B et al. Type and frequency of chormosomeaberrations in 781 couples undergoing intracytoplasmicsperm injection. Human Reproduction , 1999, 14:2257–2263.
132. Gekas J et al. Chromosomal factors of infertility incandidate couples for ICSI: an equal risk of constitu-tional aberrations in women and men. HumanReproduction, 2001, 16:82–90.
133. Lissens W et al. Cystic fibrosis and infertility causedby congenital bilateral absence of the vas deferens andrelated clinical entities. Human Reproduction, 1996,11:55–78.
134. Schlegel P, Su LM. Physiological consequences oftesticular sperm extraction. Human Reproduction,1997, 12:1688–1692.
135. Ron-El R et al. Serial sonography and colour flowDoppler imaging following testicular and epididymalsperm extraction. Human Reproduction , 1998,13:3390–3393.
136. Manning M, Junemann KP, Alken P. Decrease intestosterone blood concentrations after testicularsperm extraction for intracytoplasmic sperm injectionin azoospermic men. Lancet, 1998, 352:37.
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138. Angelopoulos T et al. Enhancement or initiation oftesticular sperm motility by in vitro culture oftesticular tissue. Fertility and Sterility, 1999, 71:240–243.
139. Tasdemir I, Tasdemir M, Tavukcuoglu S. Effect ofpentoxifylline on immotile testicular spermatozoa.Journal of Assisted Reproduction and Genetics, 1998,15:90–92.
140. Tournaye H et al. In vitro use of pentoxifylline inassisted reproductive technology. Human Reproduction,1995, 10:72–79.
141. Aslam I et al. Can we justify spermatid microinjectionfor severe male factor infertility? Human Reproduc-tion Update , 1998, 4 :213–222.
142. Tesarik J, Mendoza C. Genomic imprinting abnormal-ities: a new potential risk of assisted reproduction.Molecular Human Reproduction, 1996, 2:295–298.
143. Shamanski FL et al. Status of genomic imprinting inmouse spermatids. Human Reproduction, 1999,14:1050–1056.
144. Tamashiro KLK et al. Bypassing spermiogenesis forseveral generations does not have detrimentalconsequences on the fertility and neurobehavior ofoffspring: a study using the mouse. Journal of AssistedReproduction and Genetics, 1999, 16:315–324.
145. Kimura Y, Yanagimachi, R. Development of normalmice from oocytes injected with secondary spermato-cyte nuclei. Biological Reproduction , 1995, 53:855–862.
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102 JEAN-NOEL HUGUES
Ovarian stimulation for assisted reproductivetechnologies
JEAN-NOEL HUGUES
Gamete source, manipulation and disposition
Introduction
Within the past decade, a better understanding of thehormonal control of human folliculogenesis and asimultaneous development of DNA technologiesproviding new products with high purity and goodclinical efficacy have allowed most physicians to useovarian stimulation in every clinical situation wherethe main goal is to achieve pregnancy. Indeed, ovarianstimulation has been advocated as a common practicenot only in the treatment of infertile couples withamenorrhoea or anovulation but also for coupleswhose infertility was related to either tubal, male orunexplained factors. For these reasons, controlledovarian hyperstimulation (COH) has increasinglybecome a new tool in many situations.
The concept of controlled ovarianhyperstimulation
The concept of COH emerged from the practice of invitro fertilization (IVF). Although Louise Brown wasborn following in vitro fertilization-embryo transfer(IVF-ET) in a natural cycle, it soon became clear thatthe pregnancy rate was greatly improved if more thanone embryo was replaced in the uterus (1,2). Thus,the aim of any regimen for controlled ovarianstimulation was to obtain as many follicles as possible
from which good quality eggs could be collected. How-ever, the simultaneous risks of ovarian hyperstimula-tion syndrome (OHSS) and multiple pregnancies haveled to the adoption of a compromise betweenpregnancy rates and multiple follicular development,and restriction in the number of embryos transferred(3). However, such a policy is not fully applicable tointrauterine insemination (IUI) and major concernsremain about the risk of multiple pregnancies whenovarian stimulation is performed in a context of in vivofertilization. This critical issue will be discussedthroughout this review.
Controlled ovarian stimulation protocols
Clomiphene citrate
The antiestrogenic properties of clomiphene citratehave been used and have proved to be very effectivefor the induction of follicular development in anovula-tion since 1962. However, the clinical benefit of thiscompound is confined to WHO Group II anovulationpatients with endogenous ovarian steroidogenesis.In this situation, the ovulation and pregnancy ratesachieved with this compound have justified its useas a first-line therapy in this type of anovulation.Nevertheless, some clinical and biological featuresmay be relevant to predict the effectiveness of
Ovarian stimulation for assisted reproductive technologies 103
clomiphene citrate to achieve ovulation or pregnancy(4,5).
As administration of clomiphene citrate alone mayinduce a limited increase in the number of pre-ovulatory follicles, it may be worthwhile for themanagement of IUI in normally ovulating patients.However, its antioestrogenic action could, theore-tically, interfere with endometrial receptivity and withimplantation (6) and, as discussed below, the rationaleto use clomiphene citrate in this indication iscontroversial.
The use of clomiphene citrate in combination withgonadotrophins was first recommended for patientsundergoing IVF. However, the effectiveness of sucha regimen has been hampered by the risk of a prematurespontaneous luteinizing hormone (LH) surge whichoccurs in about 20% of stimulated cycles and leadsto IVF cancellation or impaired oocyte quality (7).Therefore, gonadotrophin releasing hormone (GnRH)agonists, by preventing an untimely LH surge, haveoffered an effective alternative to this regimen and thisapproach has been used since the mid-1980s. Therecent marketing authorization of GnRH antagonists,which induce an immediate suppression of endo-genous LH secretion, has provided the opportunityof reconsidering the role of clomiphene citrate therapyin ovarian stimulation. The clinical effectiveness ofthis new regimen is now being tested.
GnRH analogues
A GnRH analogue is a peptide in which the primarystructure of GnRH has been altered by the deletion orthe substitution of one or more amino acids. A largenumber of structural analogues of GnRH have beensynthesized, including both agonists and anta-gonists.
GnRH agonists (GnRH-a)
While GnRH agonists display a high in vitro bio-potency, results from experimental and clinical studieshave shown that repeated daily in vivo administrationof these compounds induces a biphasic pattern ofgonadotrophin secretion. Indeed, the first GnRH-ainjections induce a sharp release of both gonado-trophins (the so-called “flare-up effect”) followed bya state of pituitary desensitization related to bothdownregulation of the GnRH receptor and intracellularuncoupling. This leads to a progressive reduction ingonadotrophin synthesis which is maintained during
GnRH-a administration. Both the intensity andduration of the pituitary desensitization are dose-dependent, at least for LH (8,9). However, it is wellrecognized that, during this period of desensitization,LH radioimmunoassays do not actually reflecthormonal bioactivity. After cessation of GnRH-aadministration, a refractory period to endogenousGnRH is observed, the duration of which is dependenton both the dose and the formulation of the GnRH-a.
These properties of GnRH-a have been applied inclinical practice with two main regimens of adminis-tration.
The short-term GnRH-a protocol
This regimen takes advantage of the initial rise (flare-up) of serum gonadotrophins on follicular recruitmentand of the subsequent pituitary desensitizationinduced by daily agonist administration. Gonado-trophin administration is started in the early follicularphase. Its clinical efficacy has been previously estab-lished (10–13). Several adjustments to this protocolhave been suggested:
• a shorter period of GnRH-a administration, for 3days (ultra-short protocol) (14) or for 7 days (15),on the assumption that suppression of the endo-genous LH surge may be obtained through a veryshort course of GnRH-a administration;
• pretreatment with progestogens during the lutealphase of the cycle preceding IVF in order toprogramme the patient’s cycle and the timing ofoocyte retrieval (16,17).
The long-term GnRH-a protocol
With this regimen, both pituitary and ovariandesensitization are induced by GnRH-a administrationin the early follicular or mid-luteal phase of the cyclepreceding the planned IVF. Once desensitization isobtained, ovarian stimulation with gonadotrophins isstarted and GnRH-a injection is continued until humanchorionic gonadotrophin (hCG) is administered.
GnRH-a administration is now used routinely forall patients undergoing IVF-type procedures althoughthe early studies advocating the superiority of GnRH-a over conventional stimulation regimens wereperformed in patients who were poor or abnormalresponders (18). A meta-analysis of randomizedstudies has shown that GnRH-a reduces IVF cancella-tion rates, increases the number of oocytes recovered
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and improves the clinical pregnancy rates per cycleand per embryo transfer (19).
In clinical practice, the long-term protocol is themost traditional and widely used regimen, probablybecause it is more convenient for programming IVF.However, controversial conclusions have been drawnfrom studies comparing the respective effectivenessof long-term and short-term GnRH-a protocols. Someauthors have reported a better outcome for patientstreated with the long-term GnRH-a regimen (20–22),advocating that the initial flare-up effect of the GnRH-a causes a rise in serum LH, androgens and proges-terone (P) levels that might be deleterious for oocytequality. In contrast, others have published goodclinical results with the flare-up regimen (23,24).Discrepancies between these results may be relatedto several biases in patient selection rather than to theregimen itself, since no significant difference wasfound in a meta-analysis of seven trials comparingboth regimens (19). It must be pointed out that theshort-term GnRH-a regimen may provide someeconomic advantages in terms of reducing bothagonist and gonadotrophin doses because the longprotocol requires a more prolonged stimulation andadministration of higher doses of exogenous gonado-trophins than the short one.
Whatever regimen is used, the long-term protocolwith GnRH-a for IVF cycles does not exclude someminor concerns in clinical practice. Within the pastdecade, several issues have been addressed withregard to this protocol.
One of these issues concerns pituitary desensi-tization. The main parameters of desensitization(rapidity, intensity and duration) are criticallydependent on numerous factors in the GnRH-aprotocol including: which analogue is used; the timeof its first administration in the cycle; the dose andduration of administration; and the formulation (seereview in 25). As far as the most appropriate time ofGnRH-a administration is concerned, downregulationseems to be achieved more rapidly when the GnRH-ais started in the midluteal phase. A combination ofnorethisterone acetate or a combination of oral contra-ceptive with GnRH-a has proved to be effective inpreventing ovarian cyst formation (26,27). Althoughit has been suggested that ovarian response togonadotrophins could be reduced in patients whosepituitary downregulation is delayed (28), the outcomein terms of pregnancy rates is still not clear (29–31).
Another issue is related to the duration of thedesensitization phase prior to ovarian stimulation.
Using leuprolide acetate for 15 days prior to ovulationinduction, Scott et al. (32) did not observe any impactof the duration of the hypoestrogenic state on theovarian reponsiveness to gonadotrophins and thesuccess of IVF. According to these authors, apart fromthe increased cost, there is no reason to believe thata patient should be stimulated as soon as pituitarydesensitization and ovarian quiescence are achieved.This observation allows greater flexibility in schedul-ing ovulation induction cycles but seems to contra-dict other evidence in the literature which indicatesthat the implantation rate is higher in amenorrhoeicpatients (33) as discussed below.
The slight increase in serum P levels observed atthe time of hCG administration in up to 20% ofstimulated cycles has caused some concern. A criticalthreshold P serum level of 3.1 nmol/ml on the day ofhCG administration has been proposed, above whichthe pregnancy rate may be adversely affected (25).This subtle premature rise in serum P is presumed toimpair endometrial receptivity rather than oocytequality (34–37) and a recommendation has been madefor the cryopreservation of embryos for subsequenttransfer in these situations (38). However, severalother studies have not found a relationship betweenlate follicular P levels and IVF outcome (25). Further-more, the mechanisms that account for the prematureelevation of P, despite suppressed endogenousgonadotrophins by GnRH-a, are still unclear. As apituitary escape from the suppressive effect of GnRH-a is unlikely, serum P elevation could result fromexposure to a large amount of exogenous gonado-trophins (39) through an increased follicle stimulatinghormone (FSH)-induced LH receptivity (40). Thecontribution of the adrenal gland to both P andandrogen production cannot be excluded and this maybe reduced by simultaneous dexamethasone adminis-tration, but it is still uncertain whether this actuallyimproves the IVF outcome (41,42). At the presenttime, serum P cut-off levels on the day of hCG, as ameans of making a clinical decision with respect to thepossible cancellation of the IVF cycle and thecryopreservation of all embryos for future transfer,should be questioned (43).
GnRH antagonists
GnRH antagonists are synthetic analogues of GnRHthat compete with endogenous GnRH for pituitarybinding sites but are unable to induce GnRH receptorcross-linking, a process that appears to be necessary
Ovarian stimulation for assisted reproductive technologies 105
to effect calcium ion-mediated gonadotrophin release(44). Clinical advantages of GnRH antagonists overGnRH agonists are the absence of the initial stimula-tion of gonadotrophin release (flare-up effect) and, asa consequence, a more direct, immediate and rever-sible suppression of gonadotrophin secretion whichallows their use without the need for a desensitizationperiod.
To date, three generations of antagonists havebeen used. The first- and second-generationcompounds exhibited high potency in the suppressionof ovulation in rats but induce histamine release,resulting in transient systemic edema and inflamma-tion at the injection site (first generation) or localreactions only (second generation). The thirdgeneration of GnRH antagonists has negligiblehistamine-release properties and comparable anti-ovulatory activity to that of the second generation.
In initial clinical studies, GnRH antagonists wereused to prevent a premature LH surge during themenstrual cycle (45,46) and, subsequently, duringovarian stimulation for IVF. There are two regimensusing GnRH antagonists.
Multiple-dose GnRH antagonist administration
In this protocol, daily injections of low-dose antago-nist are given from day six of ovarian stimulation usingexogenous gonadotrophins, which is when multi-follicular development and estradiol secretion maytrigger an endogenous LH surge (47). A multiple dose-finding study performed with orgalutran, one of twoavailable antagonists, clearly demonstrated that theoptimal daily dose is 0.25 mg (48). Indeed, this dosageis able to adequately prevent the endogenous LHsurge before hCG administration and simultaneouslymaintain a residual basal LH secretion compatible witha high rate of estradiol secretion, mature oocytecollection and pregnancy. The short half-life of theantagonist with this dose requires a daily adminis-tration up to the time of hCG administration (49). Asimilar study using 0.25 mg cetrotide has confirmedthat this dose is adequate to prevent an endogenousLH surge (50).
Single-dose GnRH antagonist administration
The injection of a single and large dose of GnRHantagonist in the late follicular phase has proved tobe effective in postponing the spontaneous LH surgein normo-ovulatory women (46). On this basis, several
clinical studies have been performed using cetrotidein IVF cycles (51,52). In a comparative study, a 3 mgdose was selected as a safer choice since a “protectionperiod” of at least four days can be obtained (53).When this dose was injected on day eight of thestimulated cycle, or earlier if the ovarian response wasmore rapid, no LH surge was observed. Moreover ,in some cases where plasma LH levels were above10 IU/L at the time of GnRH antagonist injection, theLH surge was completely blunted (52,53). Whenovarian stimulation needed to be prolonged over thethree days following the first GnRH antagonistinjection, a second large dose or additional daily 0.25mg doses of the drug were required, due to the rela-tively short half-life of the antagonist (53). In everysituation, oocyte retrieval was performed in theabsence of follicular rupture, demonstrating theeffectiveness of this regimen in the prevention of theendogenous LH surge.
While the primary goal of GnRH antagonistadministration—the prevention of the LH surge—was achieved in these studies, some concern remainsabout the overall effectiveness of the protocol.Indeed, at least in multicentre studies (54,55), thenumber of ovarian follicles, collected oocytes andpregnancy rates tended to be lower than thoseobtained with the long-term GnRH-a protocol. Reasonsfor these differences in the effectiveness of the twoprotocols are still poorly understood and may bepartly related to the regimen of GnRH antagonist.However, it is likely that other factors, such as theabsence of ovarian quiescence before ovarian stimula-tion, and the regimen of exogenous gonadotrophins,also contribute to the relatively lower effectivenessof GnRH antagonist protocols. Finally, if the resultsof these studies are adjusted according to eachcentre, differences between protocol effectivenesswere limited, attesting that a learning period is requiredto adequately control stimulation protocols employ-ing GnRH antagonists. Furthermore, programming theIVF cycle through steroid administration during thecycle preceding IVF may not only be convenient formost centres but could also be effective in improvingthe size of the cohort of recruited follicles. The benefitof a programming cycle is currently under considera-tion.
Nevertheless, several advantages have beenclearly identified with these protocols. The compli-ance of patients with the GnRH antagonist protocolswas excellent due to the shortened exposure to GnRHanalogue administration and to the good clinical
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tolerance of this third generation of antagonists.Furthermore, the amount of exogenous gonado-trophins needed for ovarian stimulation was reducedas well as the occurrence of hyperstimulationsyndrome (54,55). Finally, the overall cost of thisregimen was significantly lower than that of the GnRH-a protocol.
The new GnRH antagonists also permit the designof more gentle stimulation schemes, with the returnto the use of clomiphene citrate, minimal stimulationor even natural cycles (56,57).
Gonadotrophins
FSH preparations
Human menopausal gonadotrophin (hMG), extractedfrom the urine of menopausal women, has been usedsuccessfully for many years for ovarian stimulation.It is a mixture of both FSH and LH with low specificactivity and also contains other urinary proteins (58)which can induce allergic reactions (59).
According to the “two cells–two gonadotro-phins” theory, both FSH and LH are required toachieve steroidogenesis. Therefore, for patientswhose anovulation is related to hypogonadotrophichypogonadism, hMG preparations must be used thatensure adequate estradiol production and endometrialmaturation for embryo implantation.
However, although LH is necessary for thecalandrogen production, the amount of LH required forfollicular development and steroidogenesis is minimal.Indeed, when LH secretion is suppressed after long-term GnRH-a administration, FSH alone is sufficientto ensure adequate steroidogenesis and endometrialdevelopment. Furthermore, there has been someconcern about the theoretical possibility thatexcessive amounts of LH could compromise success-ful maturation of the oocyte. Two recent meta-analyses of randomized trials, comparing hMG andFSH for IVF (60,61), concluded that the clinicalpregnancy rate per cycle was greater with the use ofFSH than with hMG if no pituitary desensitization wasundertaken. However, for patients assigned to longor short GnRH-a protocols, the difference between theefficacy of FSH and hMG treatments was less andonly significant in the case of FSH (60). These datastrongly suggested that the choice of gonadotrophinpreparations used for ovarian stimulation during IVFtreatment should take into account the GnRHanalogue regimen that is used. Finally, a meta-analysis
performed in patients with polycystic ovary syndrome(PCOS), showed that the rate of OHSS was signifi-cantly reduced when using FSH instead of hMG (62) .
The need for an improved product combined withadvances in purification techniques led to a highlypurified human urinary FSH (u-hFSH), which containsmore than 95% pure FSH with a specific activity of9000 IU FSH/mg. Nevertheless, this preparation stillhas the inherent disadvantages of all urine-derivedpreparations which require the collection of largequantities of urine, leading to unreliable supply and,most importantly, batch to batch inconsistency.
Recombinant DNA technologies were used in theearly 1990s for the production of recombinant humanFSH (r-hFSH) with the insertion of alpha and beta FSHsubunits into genetically engineered mammalian cells(Chinese hamster ovary [CHO] cells). The mostsignificant advantage of this technology is that themanufacture of r-hFSH is independent of urinecollection, ensuring the consistent availability ofbiochemically very pure FSH preparation (>99%) withminimal batch to batch variation (63). The purificationprocedure consistently yields an FSH preparationwith a very high specific activity of >10 000 IU FSH/mg and a low level of degradation or oxidation (64).
Two r-hFSH preparations are currently available:follitropin alpha and follitropin beta. While themanufacturing and purification procedures for thesetwo preparations are different (65), it is uncertain towhat degree these factors are clinically relevant. Thereis some evidence that r-hFSH preparations haveclinical advantages over u-hFSH or highly purified u-hFSH. Several comparative studies have demons-trated significant advantages for r-hFSH in terms ofefficacy as assessed by the number of oocytesretrieved as well as efficiency judged by FSHconsumption and the duration of treatment (66–71).Pregnancy rates in individual studies were marginallyhigher after r-hFSH than after u-hFSH (72) whencomparable numbers of embryos were transferred.However, when pregnancies after the transfer of frozenembryos were assessed, a statistically significantdifference in pregnancy rates was observed in favourof r-hFSH (73). Furthermore, a meta-analysis of 12randomized trials comparing 1556 patients receivingr-hFSH and 1319 patients receiving u-hFSH in IVF andintracytoplasmic sperm injection (ICSI) programmes(74) showed that the pregnancy rate per started cyclewas significantly higher with r-hFSH. Thus it may beconcluded that clinical practice should favour the useof r-hFSH over urinary preparations.
Ovarian stimulation for assisted reproductive technologies 107
For these reasons, urinary products have beenprogressively replaced by r-hFSH preparations inEurope, despite the increased cost. The use of r-hFSHresults in a higher pregnancy rate with a lower doseof drug over a shorter period of administration.Furthermore, two recent cost-effectiveness studies inthe USA and the UK have shown r-hFSH to besignificantly more cost-effective than u-hFSH in termsof ongoing pregnancy (75). Neither social costs northe costs of patients’ time away from work and travelexpenses were incorporated into the models. It isassumed that as fewer attempts are required with r-hFSH, the social, employment and travel costs wouldbe lower than with u-hFSH. However, this requiresfurther study.
LH preparations
Following the development of r-hFSH for use inassociated reproductive technology (ART), a reliablerecombinant DNA LH preparation, free from thepotential problems associated with human sourcematerial, has been developed. The biological activityof this r-hLH preparation has been demonstrated inthe rat seminal vesicle weight gain bioassay and in aprimate model of IVF. In both cases, the biologicalresponses to r-hLH and hMG were shown to be similar.Clinical studies were undertaken to investigate boththe efficacy and the safety of r-hLH for patients withhypogonadotrophic hypogonadism (76). It was foundthat daily injections were well tolerated and produceda dose-related effect on estradiol production andendometrial thickness. A daily injection of 75 IU r-hLHseems to be the minimal dose to achieve adequatefollicular maturation.
The issue of the need for LH in normal womensimultaneously treated with GnRH analogues is stillto be addressed. In IVF cycles programmed with along-term GnRH-a protocol, r-hFSH administration issufficient to produce adequate folliculogenesis in mostcases (77). Preliminary studies have also shown thataddition of LH (225 IU) in this situation does notimprove the parameters of ovarian stimulation and thecycle outcome (78). However, while it is likely thatonly a subset of patients would benefit from LHtherapy, a study comparing different doses of r-hLHin addition to r-hFSH is needed. No data are availableabout the use of LH in IVF cycles treated with GnRHantagonists.
Finally, in vitro studies have suggested that LHcould be involved in the control of follicular growth
during the late follicular phase of the cycle (79) .Therefore, clinical studies are in progress to evaluatethe potential effects of r-hLH in the reduction of thenumber of developing follicles in hyperstimulatedcycles.
Dose of gonadotrophins
There has been no systematic investigation of theoptimal dose of FSH needed for controlled ovarianstimulation. A daily dose of 150 IU or 225 IU of urinaryor recombinant preparations is usually recommendedwith subsequent adjustments from day six or sevenof stimulation, according to the ovarian responseassessed by serum estradiol levels and/or ultrasound.More recently, the introduction of r-hFSH with ahigher efficiency than urinary preparations has led tothe comparison of several starting doses of FSH in a100–225 IU range (80,81). Although the design ofthese studies was not strictly comparable, it seems that150–200 IU is the standard starting daily dose forpatients with no evidence of ovarian dysfunction.
Triggering of ovulation
Human chorionic gonadotrophin
Due to its similarity to LH, urine-derived hCG (u-hCG)has been used clinically in anovulatory women forabout 40 years to trigger ovulation and luteinizationand to support the corpus luteum. In patients enrolledin IVF protocols which include GnRH-a, u-hCG is usedas a surrogate LH surge. Despite the widespread useof u-hCG, commercial preparations suffer from thesame disadvantages as other urine-derived gonado-trophins. They require the collection of largequantities of urine from which the extracted startingmaterial is of poor quality, leading to unreliablepharmaceutical activity and unpredictable adverseimmunological reactions (82).
The advent of recombinant DNA technology hasalso permitted the development of a recombinant formof hCG (r-hCG) which is pure, and whose productionis independent of urine collection. One product, fromgenetically engineered CHO cells, is now commerciallyavailable and preliminary studies have estimated that250 µg r-hCG correspond to 5000 IU u-hCG. Tworecent studies comparing u-hCG and r-hCG in womenundergoing ovulation induction for ART, concludedthat the final oocyte maturation was similar (83) or
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better (84) following the administration of therecombinant preparations. Moreover, in both studies,serum P concentrations on day one and days six andseven post-hCG, and serum hCG concentrations at allpost-hCG time points, were statistically higher in thegroup treated with r-hCG preparations. Furthermore,the incidence of adverse events was significantlyhigher in the u-hCG group while the incidence ofinjection-site reactions was significantly lower in ther-hCG group. Therefore, r-hCG seems to havesignificant advantages compared to u-hCG.
Recombinant LH
Although human LH produced by DNA recombinanttechnology has similar pharmacokinetic character-istics to the pituitary-derived hLH, r-hLH has aterminal half-life of about ten hours compared to the30 hours of u-hCG (85). This difference between thetwo preparations may be important in the preventionof OHSS which is likely linked to the long half-life ofu-hCG.
In humans, r-hLH has been tested for triggeringfinal follicular maturation before IVF. The firstpregnancy using this approach was reported in 1996(86). More recently, a large multicentre, double-blindstudy has been undertaken to compare differentdoses of r-hLH in 258 patients enrolled in a regularIVF protocol following pituitary desensitization withGnRH-a. Each dose of r-hLH, from 5000 to 30 000 IU,appeared to induce an adequate final follicularmaturation with a percentage of mature and fertilizedoocytes similar to that found with u-hCG. However, asecond dose of 15 000 IU of r-hCG, two days after thefirst injection, appeared to be required to adequatelysupport the luteal phase. As this observation wasmade in patients whose low residual secretion ofendogenous LH was induced by pituitary desensi-tization, it deserves confirmation in cycles withoutdesensitization with treatment protocols includingGnRH antagonists. This study also confirmed that theduration of the exposure to LH/hCG is a majordeterminant for the development of OHSS.
GnRH agonist
The endogenous LH surge induced by GnRH-a worksthrough an indirect mechanism that relies on thepatient’s own pituitary response to GnRH. The GnRH-a induced LH surge has a sharper profile with a higherpeak value but a shorter duration than the natural LH
surge (87) . Consequently, in clinical practice,triggering ovulation with GnRH-a may be consideredin women at risk of OHSS or multiple pregnancy andin cycles where pituitary desensitization has not beenpreviously performed. The efficacy and safety of theLH surge induced by GnRH-a was first investigatedin WHO Group II anovulatory PCOS patients (87–90). These studies showed that the risks of OHSS andmultiple births were not totally blunted and demons-trated a high incidence of luteal phase deficiency.Therefore, luteal phase support is likely to be requiredwhen this ovulation triggering regimen is applied.Furthermore, in normally ovulating patients whoseovarian stimulation was performed before IUI, GnRH-a administration was reported to improve the preg-nancy rate and to abolish the risk of OHSS (91) .Finally, preliminary results have been published inpatients whose endogenous LH surge was preventedby GnRH-a administration (92). An LH surge wassuccessfully elicited by administration of triptorelin(one bolus of 0.1 mg) but no pregnancy was reported.Altogether, these studies show that triggeringovulation through GnRH-a administration may beuseful for patients or cycles at risk of OHSS andmultiple pregnancy, but a further evaluation of theoutcome of this treatment is needed.
Luteal phase support
Progesterone (P) and estradiol (E2) play central rolesin the maintenance of human reproduction. Steroidproduction peaks about four days after ovulation andcontinues at this level for about a week, falling aboutfive days before the next menstrual period (93).During this time, P is secreted in a pulsatile fashionand P production is 40-fold the maximal E2 production.Until the luteo-placental shift occurs at about sevenweeks of gestational age, the ovary’s production ofthese hormones is critical to pregnancy maintenance(94).
In stimulated cycles, the luteal phase differs fromthe natural one because hormone production frommultiple corpora lutea is supraphysiological. More-over, the luteal phase may be shortened in relation toa sharper decline in serum P and E2 than in naturalcycles. For this reason, the principle of luteal supportwas widely adopted and this policy was furtherreinforced with the advent of GnRH-a use in the late1980s (95) . Nevertheless, the supraphysiologicalsteroid levels following ovarian stimulation may also
Ovarian stimulation for assisted reproductive technologies 109
have adverse effects on uterine receptivity, even whenluteal length is adequate. Indeed, advanced endo-metrial maturation and increased uterine contractionshave been observed in high-responding women (96–97) with a risk of a lower pregnancy rate (98).
In stimulated IVF cycles, steroid production duringthe first week after ovum retrieval is likely to be well-timed and sufficient. Therefore, the start of exogenoussteroid support does not seem to be critical. Incontrast, the timing of P administration is critical inovum donation programmes where the only source ofP is exogenous. The highest pregnancy rates are likelyto occur when two-day-old embryos are transferredon the fourth or fifth day of P therapy (99).
While P alone is recommended in a conventionalluteal support regimen, E2 supplementation shouldalso be considered. Indeed, even if E2 does not directlymediate luteinization, it may be required to stimulateP receptor replenishment. For this reason, hCGadministration has been advocated for its stimulatingeffect on E2 and P secretion by the corpora lutea.Meta-analysis has shown that hCG injections seemto be more effective than P alone in terms of pregnancyrates in GnRH-a cycles (100). However, the increasedrisk of OHSS following repeated hCG administrationduring the luteal phase may explain why the use ofhCG has not been widely adopted. Furthermore, if thesuperiority of hCG over P is related to its ability tostimulate E2 production, adding exogenous E 2 to Psupplementation must be considered as a saferalternative. This issue has been recently addressedin a study performed in high-responding patientstreated with a long-term GnRH-a protocol (101).Patients who received both E2 and P had higherimplantation rates and lower spontaneous abortionrates than those who did not. Therefore, lutealsupplementation with both steroids may be a betteralternative than the use of repeated hCG injections,at least in patients at risk of OHSS.
Several routes of P delivery have been proposed,including oral, intramuscular and transvaginal.
Although the development of micronized formula-tions of natural P has resulted in preparations withimproved absorption and bioavailability, the systemicP levels that can be achieved with these preparationsfollowing oral ingestion (100 mg) are too low toprovide adequate endometrial support (102). Thismay be related to a first-pass effect following oraladministration of P and its extensive hepatic metabolicdegradation (103). Several clinical trials of oralsupplementation with natural P in IVF cycles (200 mg
three times daily) have confirmed the inadequacy ofthis route compared with the other routes of adminis-tration (104–106).
Intramuscular administration of P significantlyincreases its bioavailability (107). The usual intra-muscular dose varies from 25 mg to 100 mg daily,sometimes in divided doses. Serum peak levels arewell above the physiological range and endometrialmaturation is “in phase”; this is associated with goodclinical results (108). Furthermore, a comparison oforal micronized P with intramuscular P resulted insignificantly higher implantation rates with the lattertreatment (105). However, the intramuscular route alsohas several drawbacks: it is inconvenient, un-comfortable for the patient and it may produce somelocal side-effects, such as marked inflammation at theinjection site.
The vaginal route offers several importantadvantages over intramuscular dosing as it avoids thefirst-pass hepatic metabolism and ensures sustainedplasma P concentrations. Progesterone absorption isfurther influenced by the formulation used (tablets,suppositories, creams, oil-based solutions or, morerecently, slow-release polycarbophil gel) (109) .Compared with intramuscular P, higher doses ofvaginal P are often necessary to achieve adequateserum P levels but, using sustained-release formula-tions, lower doses (45–90 mg) applied once a day oreven once every other day, might be effective(104,110–111). As shown by endometrial biopsiesperformed in the midluteal phase, most endometriawere in phase after the use of vaginal micronized P(112), even though serum P levels were less thannormal (113) . This suggests that vaginally adminis-tered P exerts a pronounced local effect on theendometrium, the so-called “first uterine pass effect”.While comparison between vaginal and intramuscularP administration provided contradictory results (109) ,a recent study in a donor ovum programme showedan improvement in the cycle outcome with the use ofsustained-release formulations (114). The vaginalroute has proved to be a valuable route for drugdelivery in infertility treatment.
Monitoring of treatment
The main objectives of monitoring treated cycles areto control follicular maturation, to time hCG adminis-tration and to predict the outcome of the cycle.Another purpose of ovarian monitoring is to prevent
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OHSS by cancelling cycles at risk for high ovarianresponse or, alternatively, to detect poor ovarianresponse and adjust ovarian stimulation accordingly.This approach is valid for an IVF cycle and, to a lesserextent, for programming an IUI cycle.
The combination of serum E2 determination andultrasonography has long been accepted as the mostwidely used mode of follow-up during COH.
In the early development of IVF when GnRHanalogues were not available, clinical studiesemphasized the need for monitoring serum E2concentrations and different serum E2 patterns werecorrelated with cycle outcomes (115,116) . However,the level of serum E2, although a functional indicatorof folliculogenesis, is not always correlated withfollicular growth (117). Due to the considerable varietyof protocols used in ART cycles, no description of acommon and optimal E2 pattern is available. Never-theless, there is some evidence that, whatever theprotocol used, a plateau of plasma E2 values for morethan three days is associated with a poor outcome ofthe ART cycle. Conversely, measurements of plasmaE2 are helpful in predicting excessive ovarian responseand in deciding subsequent doses of gonadotrophinor the cancellation of the cycle or the ET.
Serum E2 levels were used as an early marker ofovarian responsiveness to exogenous gonadotro-phins. On the fourth day of treatment, assessment ofserum E2 levels may predict the subsequent ovarianresponse to exogenous gonadotrophins (118) . Simi-larly, evaluation of E2 response to the endogenousgonadotrophin flare-up induced by GnRH-a in theshort-term protocol, was designed as a “lupronscreening test”(119,120). Both the E2 pattern and themaximal E2 response following the first injections ofGnRH-a have been correlated with the subsequentovarian response to COH (121). These data underlinethat a single determination of plasma E2 may be ahelpful predictor of a poor or high ovarian responseand useful for the tailoring of gonadotrophin adminis-tration.
Determination of plasma E2 is also recommendedfor the assessment of whether or not pituitarydesensitization induced with a long-term GnRH-aprotocol is effective at the ovarian level. Indeed, asplasma LH immunometric evaluation may not ade-quately reflect the state of pituitary desensitization,it is commonly stated that plasma E2 must be lowerthan 180 nmol/ml to ensure that ovarian activity isactually suppressed. In every situation, it is recom-mended that ovarian stimulation is started with FSH
only when ovarian activity has been suppressed,whatever the duration of GnRH-a administrationrequired to obtain suppression of ovarian activity.
Finally, the recent availability of GnRH antagonistsin ART cycles provides the opportunity of reconsider-ing the role of plasma E2 determinations during thestimulation phase of the ART cycle. Indeed, adminis-tration of a GnRH antagonist may alter the pattern ofplasma E2 response (54). However, it is still not clearif a decrease in serum E2 levels after GnRH antagonistinjection is responsible for the lower pregnancy ratesometimes observed with this protocol. Plasma E2determination is a valuable tool for monitoring ARTcycle treatment while the value of plasma LH measure-ment seems to be strictly limited to cycles stimulatedwithout the addition of GnRH analogues.
Additionally, ultrasound measurement of folliculargrowth plays a key role in the assessment of theadequacy of follicular maturation and of the correcttiming of hCG administration. In most clinical studies,triggering of ovulation by hCG is recommended whenat least three large (>16 mm) follicles have beenvisualized on ultrasound. Furthermore, measurementof endometrial thickness through a vaginal probeallows an indirect assessment of E2 secretion. Withthe extensive use of GnRH-a protocols, it has beenemphasized that patient follow-up could be simplifiedby using only ultrasound determination of bothfollicular growth and endometrial maturation and thisapproach seems effective in triggering ovulation with-out reducing the pregnancy rate (122). This minimalmonitoring is more cost-effective and especiallyrelevant in low-resource settings.
Clinical indications for ART
Intrauterine insemination
The rationale for performing IUI is to increase thenumber of highly motile spermatozoa with a highproportion of normal forms at the site of fertilization.While in the past, the whole ejaculate was placed inthe uterus, new semen preparation techniques derivedfrom IVF procedures and able to remove prosta-glandins, bacteria and immunocompetent cells, haveled to the recommendation that a direct transfer ofmotile spermatozoa after sperm preparation andconcentration in a small volume of medium is to bepreferred. Several studies have shown that IUI is moreeffective than intravaginal or intracervical insemina-
Ovarian stimulation for assisted reproductive technologies 111
tions with unprepared semen (123).Indications for IUI include:
• physiological and psychological dysfunctions,such as hypospadias, vaginismus, retrogradeejaculation and poor erectile function;
• cervical hostility related to poor quality mucus orpersistently negative postcoital tests;
• male infertility: a minimal amount of total motilesperm cells (at least one million) should be insemi-nated for optimal results (124) and it is presumedthat a certain degree of normal morphology ofspermatozoa is also required to achieve pregnancy.Treatment should be restricted to IUI alone,because induction of ovulation has little additionalbeneficial effect (125);
• unexplained infertility in both the male and thefemale partner.
While both IUI and COH independently increasethe probability of conception (126,127), COH seemsto be a more contributory factor than IUI by over-coming some subtle cycle disorders. In male and inunexplained infertility, it has been recommended thatthree to six cycles of IUI are undertaken and, if un-sucessful, the couple can be offered IVF/ICSI.
Intracytoplasmic sperm injection
Intracytoplasmic sperm injection is primarily indica-ted in the most severe forms of male infertility withvery low sperm count, poor motility and/or highteratospermia, and in males with obstructive or idio-pathic azoospermia by using epididymal or testicularsperm. ICSI is also currently used in couples who havefailed to provide an embryo through routine IVFprocedures. These topics are discussed elsewhere inthis volume.
Eligibility of patients
Determinants of ovarian response
Age
The age of the female partner is the single mostimportant factor determining spontaneous fertility andthe effect of age is enhanced when considering theoutcome of all forms of fertility treatment. Age is aparticularily strong factor when the outcome of ART
treatment is considered (128,129). As reported inmany countries (130,131) , pregnancy rates are fairlyconstant (at around 25% live births per cycle) up tothe age of 34 years, when there is a steep decline. Nopregnancies have been recorded among women overthe age of 46 years. While many factors may contri-bute to the deleterious effect of age, there is compellingevidence that ovarian function is altered. Not only isthe number of follicles available decreased withadvancing age but oocyte quality is reduced and theincidence of aneuploidy increased. Therefore, theageing ovary is a major concern in infertility treatment,particularly when COH must be achieved. Theassessment of ovarian function is a key issue beforeperforming COH.
Duration of infertility
While the duration of infertility is a major factordetermining the likelihood of spontaneous pregnancyoccurring in untreated infertile patients (132), it is stilluncertain whether reduced effectiveness of ovarianstimulation is related to the duration of infertility orto the age of the woman, which are clearly closelylinked.
Weight
Obesity is often associated with menstrual disordersand anovulation (133). As the impact of weight gainon the reproductive system is multifactorial, therespective roles of abnormalities such as hyperandro-genism, hyperinsulinism or estrogen production fromadipose tissue is still a matter of debate. Furthermore,obesity itself may be a factor affecting ovarianresponse. Indeed, in women with no ultrasoundevidence of PCOS, a higher dose of clomiphene citrateis needed to obtain ovulation (134) and the responseto gonadotrophin induction of ovulation is inverselyrelated to body mass index (135). Moreover, PCOSpatients with moderate obesity have a bluntedresponse to gonadotrophin therapy compared withtheir nonobese counterparts (136) and require a moreprolonged stimulation and a higher dosage of FSH(137). It is likely that the pharmacokinetic profile ofART drugs is different in overweight compared to leanpatients and may partly explain the need for higherdoses. Weight reduction is beneficial in restoringovulation or in reducing drug dosage. Weightreduction in obese patients reduces hyperandro-genism and hyperinsulinaemia, both factors influ-
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encing the ovarian response to FSH. Therefore, it ispresumed that obesity is responsible for the relativeovarian insensitivity to infertility treatment.
Smoking
Epidemiological studies have shown that 38% of non-smokers conceive in their first ART cycle comparedwith 28% of smokers, with smokers being 3.4-fold morelikely to take more than one year to conceive thannonsmokers (138). Both active and passive smokinghave been associated with elevated FSH concentra-tion (139). It has been postulated that impaired fertilityand delayed conception among women who smokeresult from interference with gametogenesis or fertili-zation, failure of implantation and early miscarriage(138). As far as ovarian function is concerned, somestudies have shown that smoking women, in parti-cular, young women, had a higher basal and post-clomiphene citrate test serum FSH (139–141). Otherstudies have shown a detrimental association betweencigarette smoking and ovarian response to stimula-tion. Women who smoke required a significantlyhigher dosage of gonadotrophins than nonsmokers(141–143). Hence smoking may further increase thecost of ovarian stimulation and this must be empha-sized to the infertile couples in whom the femalepartner is a smoker.
Management of poor ovarian responsiveness
Diminished or poor ovarian response to COH occursin about 9%–24% of patients (144) and is still achallenging issue. One of the main reasons may berelated to the lack of a universally accepted definitionof “poor responders”.
The original definition of poor responders wasbased on low peak E2 concentrations (<1000 pmol/ml)during ovarian stimulation with 150 IU hMG (145).The low pregnancy rate in these patients was attribu-ted to the low number of recruited follicles and retrievedoocytes. Later, the definition evolved with the adventof more aggressive stimulation protocols to peakserum E2 values greater than 1700 pmol/ml and lessthan four dominant follicles on the day of hCGadministration.
Another approach involved patients withoutprevious experience of stimulatory ART cycles butwhose diminished ovarian reserve could predict a poorresponse to gonadotrophins. Indeed, several tests of
the functional ovarian reserves seem reliable forpredicting a low response to standard protocols(146,147).
These tests include:
• day three determination of basal serum FSH (148–150), E2 (151,152), inhibin B (153) or the FSH/LH ratio (154);
• dynamic tests, such as the clomiphene citratechallenge test (155,156), the GnRH-a stimulationtest (119,120,157) and the exogenous FSH ovarianreserve test (158);
• imaging techniques, such as measurement ofovarian volume (159,160), antral follicle count(161,162), and measurement of ovarian stromalbood flow with colour Doppler (163,164).
Several stimulation protocols have been proposedto improve the outcome in poor responders. Theseinclude:
• varying the dose or the day of the cycle forinitiating stimulation with gonadotrophins (165–169);
• pituitary desensitization with a GnRH-a longprotocol followed by stimulation with a high doseof gonadotrophins (170);
• initiating GnRH-a and gonadotrophins together ina short-term protocol (171,172) ;
• cotreatment with growth hormone or growthhormone-releasing hormone (173–176);
• cotreatment with estrogens or combination oralcontraceptives (177,178);
• using clomiphene citrate for stimulation (179,180);
• natural IVF cycles (181).
However, while some of these protocols mayimprove the ovarian response to stimulation, none ofthem were able to significantly improve the pregnancyrate. Other approaches have been shown to be moresuccessful in improving the outcome of IVF cycles.All recommend the reduction of GnRH-a or manipu-lation of the agonist differently, for example:
• a “micro-dose” GnRH-a flare-up regimen: after apretreatment with oral contraceptives, patientsreceived microdose of GnRH-a (20–40 µg ofleuprolide twice daily) in the early follicular phaseand started gonadotrophins on the third day(182–184);
Ovarian stimulation for assisted reproductive technologies 113
• reducing the dose of GnRH-a when ovariandesensitization is achieved has been proposed asa “mini-dose” long protocol (185). Dosage ofGnRH-a may be reduced by half or a fifth withoutrisk of a premature LH surge (186);
• the “stop-lupron” protocol which involvesstopping GnRH-a administration with the onset ofmenses and stimulation with high-dose gonado-trophin therapy (187,188).
With these protocols, some advantage wasobserved in terms of pregnancy and it is possible thatthey may be an effective approach in those cases inwhich the use of GnRH-a is presumed to be respon-sible for the poor ovarian response to gonadotro-phins.
From these data, it is clear that the different causesof poor ovarian response should be taken intoconsideration when deciding what protocol is the mostsuitable and in what circumstances the cycle must becancelled. As an example, in young, poor-responderpatients with normal serum FSH basal values, it hasbeen reported that a low response to gonadotrophinsdoes not adversely affect the IVF cycle outcome(189,190). Conversely, the least favourable situationis clearly that of patients with a low ovarian reservein relation to their advanced age, or ovarian dysfunc-tion. They do not benefit from the use of ICSI (191)and should be considered as candidates for oocytedonation.
Management of PCOS
This is one of the more common endocrine disorderswith a very heterogeneous definition, from the singlefinding of polycystic ovarian morphology detected byultrasonography to a complete form with clinicalsymptoms such as obesity, hyperandrogeny, cycledisorders and infertility (192). It is estimated to be themajor cause of anovulatory infertility (accounting for73% of cases) and hirsutism (193). There is evidencethat ovarian hyperandrogenism is the main factorresponsible for persistent anovulation (194) and it islikely that the hyperinsulinaemia usually observed inthese patients may contribute to the infertility.
The strategy for ovulation induction in PCOSanovulatory women must take into account that therisks of hyperstimulation and multiple pregnancy aremarkedly enhanced with gonadotrophin therapy.Therefore, clomiphene citrate administration has been
recommended as the first-line therapy in thesepatients. Indeed, clomiphene citrate induces ovulationin about 70%–85% of patients although only 40%–50% conceive (195). While a large range of dailydoses has been studied, it must be emphasized thatan exuberant response may be observed with 50 mgin some patients and, in the USA, the maximal doseapproved by the FDA is 100 mg/day for five days. Theuse of clomiphene citrate is currently recommendedfor only six months because of the putative increasedrisk of ovarian cancer.
Gonadotrophin therapy is indicated for womenwith anovulatory PCOS who have been treated withclomiphene if they have either failed to ovulate or havea response to clomiphene that is likely to reduce theirchance of conception (for example, negative post-coital tests). To prevent the risks of overstimulationand multiple pregnancy, traditional protocols havebeen replaced by either low-dose step-up, step-downregimens or by a sequential step-up, step-downprotocol. Several studies have shown that these regi-mens are effective and safe by reducing the numberof leading and medium-sized follicles (196–198). Therisks of multiple pregnancy and OHSS are furtherreduced if ovulation is triggered with a single injectionof hCG and in the absence of more than two follicleslarger than 16 mm or more than four follicles larger than14 mm. In overstimulated cycles, hCG is withheld andthe patient advised to refrain from unprotected sexualintercourse. Many published series support the notionthat carefully conducted ovulation induction therapyresults in a good cumulative conception rate in womenwith PCOS (199).
Different gonadotrophin preparations have beenused to induce ovulation in PCOS anovulatory women.Two meta-analyses were carried out on the use of FSHversus hMG treatment. The first concluded that FSHis associated with a reduction of moderate-to-severeOHSS (62) . The other (60) showed that treatment withFSH results in a 50% higher pregnancy rate in IVFcycles. In spite of the well-known drawbacks of meta-analyses, it may be concluded that FSH is moresuitable in PCOS patients to reduce the risk of OHSS,which is still a major concern with this therapy.
As hypersecretion of LH is a classical endocrinefeature of PCOS and may result in reducing theconception rate (200), particular attention has beenpaid to the possible advantages of adding GnRH-aprior to ovarian stimulation. However, prospectiverandomized studies have indicated that GnRH-aprovide no benefit over gonadotrophin alone and do
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not reduce the tendency to multifollicular develop-ment, cyst formation and OHSS (201,202). Forpatients resistant to ovulation regimens, IVF therapyhas been advocated as another modality but thepersistent risk of OHSS justifies recommending carefuladministration of FSH.
Finally, reducing hyperinsulinaemia through theadministration of insulin-sensitizing agents such asmetformin, is effective in decreasing serum androgensin both obese and nonobese PCOS patients (203),improving spontaneous ovulation (204) and theovarian responsiveness to clomiphene citrate in obesePCOS patients (205).
Risks of COH
The side-effects of COH still remain the challengingissue of ovulation induction. Some of them are moreserious, OHSS being the most serious complication.Others are longer-term side-effects with a specialconcern regarding the risks of neoplasia and themorbidity and mortality associated with multiplebirths.
OHSS
The worldwide incidence of severe OHSS has beenestimated at 0.2%–1% of all ART cycles (206) and theassociated mortality at 1:45 000–1:50 000 per infertilewomen receiving gonadotrophins (207). However, thefrequency of this life-threathening situation dependson many factors such as criteria used for diagnosis,identification of patients at risk, the type of medicationand the use of preventive measures. For example, afterIVF, the overall incidence is reported to be 0.6%–14%(208). Thus, clinicians have to balance the risks andbenefits of medical intervention when consideringtreatment options.
While the pathogenesis of OHSS has not beencompletely elucidated, it is likely that the increasedcapillary permeability triggered by the release ofovarian vasoactive substances under hCG stimulationplays a key role in this syndrome. Factors belongingto the renin–angiotensin system, cytokines andvascular endothelial growth factor (VEGF) are alsoinvolved in this process (209) and awareness of thesemechanisms may provide opportunities for the designof specific treatment regimens. While there is noconsensus about the management of OHSS, it isagreed that prevention of this syndrome is the main
objective.Individualizing ovulation induction protocols may
lead to better control of ovarian hyperstimulation.Several factors may be taken into account including ahistory of exaggerated response to gonadotrophinsin previous cycles and ultrasonographic appearanceof PCOS.
Using step-wise regimens and, if needed, earlycancellation based upon serum E2 and ultrasoundfindings, withholding hCG administration or cancel-ling oocyte pick-up have been proven to be efficientin reducing the occurrence of OHSS. However, theseapproaches take a heavy emotional and financial tollon patients and do not resolve the issue of the infertil-ity. Therefore, other less drastic prevention measureshave been proposed such as “coasting”.
Coasting consists of stopping gonadotrophinstimulation for one or more days and seems to be avaluable method to reduce the incidence and severityof OHSS in patients at risk (210–212) withoutcompromising the cycle outcome (213,214).
As the incidence and duration of severe OHSS isgreatest for patients who conceive (215), cryopreser-vation of all embryos has been proposed as analternative way to minimize hCG exposure withoutcancelling oocyte retrieval (216). Subsequent transferof cryopreserved-thawed embryos in a programmedcycle with steroid substitution yields a good preg-nancy rate (217). However, as the obstetric outcomeof pregnancies complicated by severe OHSS could beworsened (218), interruption of pregnancy when life-threatening situations occur may be need to beconsidered.
An attempt to distinguish between early OHSS(three to seven days after hCG) related to high estro-gen levels and late OHSS (12–17 days after hCG)associated with clinical pregnancy could help to betterdefine the preventive effects of these therapeuticapproaches (219).
Neoplasia
Breast and ovarian neoplasia are of multifactorialetiology and infertility is one of the factors consideredto increase the risk. A linkage between the drugs usedin ART and breast or ovarian cancers has not yet beenfully established (220).
Ovarian cancer
Ovarian cancer represents the sixth most common
Ovarian stimulation for assisted reproductive technologies 115
cancer in women and is the most fatal gynaecologicalmalignancy with a 5-year survival rate of about 40%(221). However, the incidence of ovarian cancer varieswidely among countries (222) and a large number ofidentifiable factors have been associated withincreasing risk of ovarian cancer, including environ-mental, hormonal and genetic factors. Parity and oralcontraceptive use have well-documented protectiveeffects as does tubal ligation and hysterectomy. Theexplanation for these protective effects possiblyinvolves decreased ovulation, at least in older infertilewomen (223). Conversely, infertility and “incessantovulation” have been documented as risk factors forthe development of ovarian cancer (224). As a resultof this consistent association, it has been hypothe-sized that the hyperstimulatory effects of fertilitymedication may be linked to the genesis of some casesof ovarian cancer. However, inability to conceive isby itself a risk factor for ovarian cancer independentof nulliparity (225). Therefore, the fundamentalquestion is whether the use of drugs for the inductionof ovulation independently increases a woman’s riskof ovarian cancer over and above that predicated byinfertility alone or infertility in conjunction with lowparity.
After the first report in 1971 of a possible relation-ship between incessant ovulation and ovarian cancer(226), it was suggested that epithelial inclusion cystsin the ovarian surface epithelium, which occur inassociation with ovulation, may be the source of suchneoplasms. The first case of invasive epithelial ovariancancer associated with ovulation induction wasdescribed in 1982 (227) and was followed by severaladditional case reports, cohort and case–controlstudies (228). Concern about the risk of ovariancancer and the use of fertility medications wasrecently highlighted in a series of publications (229,230) which reported that infertile women using fertilitydrugs are three times more at risk for invasiveepithelial ovarian cancer than women without a historyof infertility. Conversely, in these studies, infertilewomen not using fertility drugs were reported to haveno increased risk. However, critics of these reportshave cited selection bias, wide confidence intervals,lack of a uniform etiology of infertility and temporalincompatibility between licensing of modern fertilitydrugs and treatment for infertility in the subjects inthese studies (231). In addition, no attempt was madeto control for confounding factors such as infertilityitself or family history of ovarian cancer.
In a well-designed and executed large case–cohort
study (232), infertile women using clomiphene citratehad a threefold increased risk of developing anyovarian neoplasm but, when infertile clomiphenecitrate users were compared with infertile nonusers,no statistically significant increased risk wasobserved. Nevertheless, the use of clomiphene citratefor more than 12 ovulatory cycles was associated withan increased risk of developing an ovarian neoplasm.However, if the relationship between clomiphenecitrate use and ovarian cancer had been truly causal,a more evident dose–response relationship wouldhave been expected.
The possibility of a relationship between infertilitysecondary to underlying ovarian pathology andovarian cancer has been also suggested (233). It isalso possible that follicular hyperstimulation maydrive an already existing epithelial ovarian neoplasmto become clinically apparent. However, evidenceagainst this hypothesis is provided by other studiesthat have shown epithelial ovarian carcinomas to beinsensitive to gonadotrophins (234).
Finally, IVF procedures including not only ovarianhyperstimulation but also repeated minor trauma forovum pick-up, were associated with some cases ofovarian cancer. However, comparison betweenstimulated and natural cycles for IVF in women couldnot find any excess risk for ovarian cancer in thetreated group (235). By contrast, a significant associa-tion was detected between a diagnosis of unexplainedinfertility and invasive epithelial ovarian cancer.
Breast cancer
Breast cancer is the leading cancer in women and theuse of oral contraceptives and hormone replacementtherapy as risk factors remain controversial. Manystudies have failed to observe excess risk for breastcancer among infertile women (236). Furthermore, noexcess risk for breast cancer can be attributed toovulation induction. On the contrary, some antiestro-genic agents, such as clomiphene citrate, could beconsidered protective because of their similarity totamoxifen (237). However, a diagnosis of breastcancer during or shortly after infertility treatmentshould warrant close medical follow-up.
Multiple births
The medical, social and financial risks caused bymultiple birth needs to be addressed in terms of policyand practice. Iatrogenic multiple pregnancy occurs
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after ovulation induction with clomiphene citrate andgonadotrophins, with reported incidence figures of5%–10% and 16%–40%, respectively (238). The mostcommon result is twinning but the greatest relativeincrease consists in triplet and quadruplet preg-nancies. ART has affected the rate of multiple birthsin two ways: first, the procedures themselves have adirect impact on the incidence of multiple pregnancy;second, the number of couples undergoing infertilitytreatment has increased dramatically. As far as theprocedures are concerned, it is obvious that the useof more aggressive ovarian stimulation for IVF hasresulted in more oocytes being collected and a greaternumber of embryos being transferred. Nevertheless,recent adoption by several countries of a restrictivetransfer policy has led to a significant reduction inhigh-order multiple pregnancies (239).
Paradoxically, some major concern remainsregarding the policy of ovulation induction forchronic anovulation or in preparation for IUI. Indeed,as the results of IUI from natural cycles proved to beinferior to those from gonadotrophin-stimulatedcycles (240), ovulation induction is currently per-formed in normally ovulating patients. As a conse-quence, multiple pregnancies after ovulation inductionalone or associated with IUI, have accounted for themajority of all multiple pregnancies related to infertilitytreatment (241) . This is partly due to the developmentof a large number of leading follicles (more than twoor three) (242) . However, careful monitoring ofstimulated cycles can reduce, but not totally eliminate,this risk. Indeed, according to an extensive retro-spective study (243), the peak serum E2 concentrationand the total number of follicles are independentpredictors of the risk of high-order multiple pregnancy.However, as recently shown (244), the number offollicles with a diameter of 12 mm or more seems to bemore predictive of multiple birth than that of mature(>16 mm) follicles. Therefore, the current guidelinesfor ovulation induction, based upon the number oflarge-sized follicles, may be inadequate for reducingthe incidence of high-order multiple pregnancies.Nevertheless, in clinical practice, the best way tominimize the risk of multiple pregnancies is to usemuch milder stimulation regimens, to carefully controlfollicular development with both hormonal and ultra-sound assessments, and to cancel the cycle in casesof overstimulation. The ovarian stimulation policymust also take into account other parameters such asthe patient’s age, duration of infertility, previous parityand etiology of infertility, all factors that interfere with
the potential risk of multiple pregnancy followinginduction of ovulation (245). Development of newovarian imaging technologies may be helpful inimproving the reliability of ovarian monitoring. Thisstrategy could limit the use of IVF procedures as analternative way to avoid the risk of high-order multiplepregnancy (243).
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183. Schoolcraft W et al. Improved controlled ovarianhyperstimulation in poor responder in vitro fertiliza-tion patients with a microdose follicle-stimulatinghormone flare, growth hormone protocol. Fertilityand Sterility, 1997, 67:93–97.
184. Surrey ES et al. Clinical and endocrine effects ofmicrodose GnRH agonist flare regimen administeredto poor responders who are undergoing in vitro fertil-ization. Fertility and Sterility, 1998, 69:419–424.
185. Feldberg D et al. Minidose gonadotropin-releasinghormone agonist is the treatment of choice in poorresponders with high follicle-stimulating hormonelevels. Fer tility and Sterility, 1994, 62:343–346.
186. Olivennes F et al. A protocol using a low dose ofgonadotrophin-releasing hormone agonist might be thebest protocol for patients with high follicle stimulatinghormone concentrations on day 3. Human Reproduc-tion, 1996, 11 :1169–1172.
187. Faber BM et al. Cessation of gonadotropin-releasinghormone agonist therapy combined with high-dosegonadotrophin stimulation yields favorable pregnancyresults in low responders. Fer tility and Sterility, 1998,69:826–830.
188. Dirnfeld M et al. Cessation of gonadotropin-releasinghormone analogue (GnRH-a) upon down regulationversus conventional long GnRH-a protocol in poorresponders undergoing in vitro fertilization. Fertilityand Sterility, 1998, 72:406–411.
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191. Moreno C et al. Intracytoplasmic sperm injection asa routine indication in low responder patients. HumanReproduction, 1998, 13:2126–2129.
192. Balen AH et al. Polycystic ovary syndrome: thespectrum of the disorder in 1741 patients. HumanReproduction, 1995, 8 :2107–2111.
193. Franks S. Medical progress article: polycystic ovarysyndrome. New England Journal of Medicine, 1995,333 :853–861.
194. Gilling-Smith C et al. Hypersecretion of andro-stenedione by isolated theca cells from polycysticovaries. Journal of Clinical Endocrinology andMetabolism, 1994, 79:1158–1165.
195. ESHRE 1997 Female infertility: treatment optionsfor complicated cases. The ESHRE Capri workshop.Human Reproduction , 1997, 12:1191–1196.
196. White DM et al. Induction of ovulation with low-dosegonadotrophins in polycystic ovary syndrome: ananalysis of 109 pregnancies in 225 women. Journalof Clinical Endocrinology and Metabolism , 1996,81:3821–3824.
197. Fauser BC, Donderwinkel PFJ, Schoot DC. The step-down principle in gonadotrophin treatment and therole of GnRH analogues. Baillière’s Clinical Obstetricsand Gynaecology , 1993, 7:309–330.
198. Hugues JN et al. Sequential step-up and step-down doseregimen: an alternative method for ovulation inductionwith FSH in polycystic ovary syndrome. HumanReproduction , 1996, 11 :2581–2584.
199. Fauser BCJM, Van Heusden AM. Manipulation ofhuman ovarian function: physiological concepts andclinical consequences. Endocrine Reviews, 1997, 18:71–106.
200. Homburg R et al. Influence of serum LH concentra-tions on ovulation, conception and early pregnancyloss in polycystic ovary syndrome. British MedicalJournal, 1998, 297:1024–1026.
201. Homburg R et al. Gonadotropin-releasing hormoneagonist reduces the miscarriage rate for pregnanciesachieved in women with polycystic ovary syndrome.Fer tility and Sterility, 1993, 59:527–531.
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203. Velazquez EM et al. Metformin therapy in polycysticovary syndrome reduces hyperinsulinemia, insulinresistance, hyperandrogenia and systolic blood pressurewhich facilitate normal menses and pregnancy.Metabolism, 1994, 43:647–654.
204. Morin-Papunen LC et al. Metformin therapy improvesthe menstrual pattern with minimal endocrine andmetabolic effects in women with polycystic ovarysyndrome. Fertility and Sterility , 1998, 69:691–696.
205. Nestler JE et al. Effects of metformin on spontaneousand clomiphene-induced ovulation in the polycysticovary syndrome. New England Journal of Medicine,1998, 338:1876–1880.
206. Smitz J et al. Incidence of severe ovarian hyperstimula-tion syndrome after GnRH agonists/HMG superovula-tion for in vitro fertilization. Human Reproduction,1990, 5:933–937.
207. Brinsden PR et al. Diagnosis, prevention and manage-ment of ovarian hyperstimulation syndrome. BritishJournal of Obstetrics and Gynaecology, 1995, 102:767–772.
208. Rizk B. Ovarian hyperstimulation syndrome. In:Brinsden, RP and Rainsbury, PA, eds. The Bourn Halltextbook of in vitro fertilization and assisted concep-tion. London, Parthenon, 1992:369–383.
209. Elchalal U, Schenker JG. The pathophysiology ofovarian hyperstimulation syndrome—views and ideas.Human Reproduction, 1997, 12:1129–1137.
210. Sher G et al. Prolonged coasting: an effective methodfor preventing severe ovarian hyperstimulationsyndrome in patients undergoing in-vitro fertilization.Human Reproduction, 1995, 10:3107–3109.
211. Dhont M, Van der Straeten F, de Sutter P. Preventionof severe ovarian hyperstimulation by coasting.Fertility and Sterility , 1998, 70:847–850.
212. Fluker MR, Hooper WM, Yuzpe AA. Withholdinggonadotropins (coasting) to minimize the risk ofovarian hyperstimulation during superovulation and invitro fertilization-embryo transfer cycles. Fertility andSterility, 1999, 71:294–301.
213. Benadiva CA et al. Withholding gonadotropinadministration is an effective alternative for theprevention of ovarian hyperstimulation syndrome.Fertility and Sterility , 1997, 67:724–727.
214. Tortoriello DV et al. Coasting does not adverselyaffect cycle outcome in a subset of highly responsivein vitro fertilization patients. Fertility and Sterility,1998, 69:454–460.
215. Forman R et al. Follicular monitoring and outcomeof in vitro fertilization in gonadotropin-releasinghormone agonist treated cycles. Fertility and Sterility,1991, 55:430–440.
216. Amso NN et al. The management of predicted ovarianhyperstimulation involving gonadotropin-releasinghormone analog with elective cryopreservation of all
pre-embryos. Fertility and Sterility, 1990, 53:1087–1090.
217. Queenan JT et al. Cryopreservation of all prezygotesin patients at risk of severe hyperstimulation syn-drome does not eliminate the syndrome but the chancesof pregnancy are excellent with subsequent frozen-thaw transfers. Human Reproduction, 1997, 12:1573–1576.
218. Abramov Y, Elchalal U, Schenker JG. Obstetricoutcome of in vitro fertilized pregnancies complicatedby severe ovarian hyperstimulation syndrome: a multi-center study. Fertility and Sterility, 1998, 70:1070–1076.
219. Mathur RS, Akande AV, Keay SD. Distinction betweenearly and late ovarian hyperstimulation syndrome.Fer tility and Sterility, 2000, 73:901–907.
220. Modan B et al. Cancer incidence in a cohort ofinfertile women. American Journal of Epidemiology,1998, 147 :1038–1042.
221. Heintz APM, Hacker NF, Lagasse LD. Epidemiologyand etiology of ovarian cancer: a review. Obstetricsand Gynecology, 1985, 66:127–135.
222. Parazzini F et al. The epidemiology of ovarian cancer.Gynecologic Oncology Journal, 1991, 43:9–23.
223. Hankinson SE et al. A quantitative assessment of oralcontraceptive use and risk of ovarian cancer. Obstetricsand Gynecology, 1992, 80:708–714.
224. Nasca PC et al. An epidemiologic case–control studyof ovarian cancer and reproductive factors. AmericanJournal of Epidemiology , 1984, 119:705–713.
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227. Bamford PN, Steele SJ. Uterine and ovarian carcinomain a patient receiving gonadotrophin therapy. BritishJournal of Obstetrics and Gynaecology, 1982, 89:962–964.
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126 HENRY E. MALTER, JACQUES COHEN
Intracytoplasmic sperm injection: technical aspects
HENRY E. MALTER, JACQUES COHEN
Gamete source, manipulation and disposition
Introduction
What is micromanipulation?
No reproductive specialist could have predicted thatthe emerging field of experimental micromanipulationwould have such an impact on assisted reproductionin less than a decade after the first relatively simple,but elegant, applications appeared. Since then,thousands of babies have been born worldwide frommicromanipulative methods aimed at alleviating maleinfertility, enhancing implantation and prediction ofnormal development in embryos derived from fertile,but genetically affected, individuals. Some existingand larger laboratories have three or more completestations for micromanipulation. Rather than certainembryologists subspecializing in the area of micro-manipulation, which was the practice in the first fewyears, most embryologists now aim to becomeproficient in one or more techniques. The mainemphasis in this review will be on micromanipulationof gametes, particularly intracytoplasmic sperminjection (ICSI) and handling of embryos. Micro-manipulation is practised on all stages of gametes andpreimplantation embryos, since the applications aremostly diagnostic or potentially therapeutic. In thiscontext, it becomes increasingly difficult to discussmicromanipulation as a separate subject, as thesetechniques have become ubiquitous laboratory tools,
covering such diverse areas as ovum freezing viazygote reconstitution, cryopreservation of isolatedtesticular spermatozoa and cytoplasmic transfer forreversal of cytoplasmic and potential nuclear in-competence as well as the other better-known tech-niques. Only the procedures that are not consideredexperimental will be discussed below.
Intracytoplasmic sperm injection
Review and problems
ICSI has been in use for the successful treatment ofmale factor infertility for almost a decade. Thetechnique involves the direct injection of a singleimmobilized spermatozoon into the cytoplasm of amature oocyte. Direct sperm injection was developedin invertebrates, rodents and large animals (1–4) .However, few births were reported in those studies.This has led to criticism, particularly from basicscientists who refer to this as “ART before science”(5). Other attempts to microsurgically fertilize ovaincluded zona drilling and subzonal sperm insertion(6,7). Though those studies led to many births inanimal models, application in the human was onlypartially successful due to physiological differencesand low rates of normal fertilization (8). The adventof microsurgical fertilization is an example of the
Intracytoplasmic sperm injection: technical aspects 127
limitations of animal modelling prior to clinicalapplication, since early methods that appeared safeand promising in the mouse were very limited in thehuman, whereas the ICSI method that now appearssafe in the human, seems problematic in studiesinvolving rodents and primates (9–11) . The first birthsfrom ICSI were reported by Palermo and colleagues in1992 (12). Since that time, use of the technique hasspread rapidly due to its relative simplicity and highrate of success in achieving apparently normal fertiliza-tion in cases of previously intractable male infertility.
Spermatozoa for ICSI are obtained throughstandard preparation and washing of ejaculated orelectro-ejaculated semen. In the case of azoospermia,a variety of techniques for microsurgical spermaspiration or isolation from the epididymis or testiscan be used (13,14). Sperm suspensions are diluted,if necessary, to an appropriate concentration withculture media and combined with media containingpolyvinyl pyrrolidone (PVP) to increase viscosity andfacilitate handling of the spermatozoa, though theefficacy and safety of PVP use for this purpose hasbeen questioned (15,16). Mature oocytes are obtainedfollowing standard techniques and denuded of coronacells by exposure to hyaluronidase; the use of thisenzyme is considered safe, but detailed follow-up ofthe effects of different concentrations and alterna-tives on pregnancy outcome are lacking (17,18).Micromanipulation for ICSI requires a standardholding pipette and a bevelled, sharpened injectionpipette with an outer and inner diameter of seven andfive micrometers, respectively. For injection, a single,preferentially motile and overtly morphologicallynormal spermatozoon is selected from the PVP dropand immobilized using the injection pipette. Theeffects of sperm morphology on pregnancy outcomeand congenital malformation is unknown. Alternativesfor immobilization are mediation by a piezo actuator,laser application and pipetting (19). The efficacy andsafety of immobilization has been questioned (20).The severity of mechanical immobilization mayincrease the rate of fertilization by mature and immaturespermatozoa (21,22). The tail of the spermatozoon ispositioned at a ninety-degree angle to the injectionpipette, which is lowered and drawn across the tail.This results in plasma membrane permeability and aloss of motility, both of which have been associatedwith an improvement in fertilization (23,24) . Theimmobilized sperm cell is aspirated tail-first into theinjection pipette and transferred to the drop contain-ing the oocyte. The oocyte is held with the holding
pipette and positioned such that the polar body is notadjacent to the “3 o’clock” entry point of the injectionpipette. The spermatozoon is positioned at thebevelled terminus and the injection pipette is gentlyadvanced through the zona pellucida and into theplasma membrane of the oocyte. The membrane willeither spontaneously break due to this penetration orcan be broken by gentle manipulation of the injectionpipette (22) . When the membrane has broken,cytoplasm can exhibit flow back into the injectionpipette. The sperm cell is then carefully expelled intothe oocyte cytoplasm and the pipette is withdrawn,completing the procedure. It should be noted that theposition of the polar body in relation to the depositedsperm may affect embryo morphology, developmentrate and pregnancy (25).
In a recent report on over 3700 ICSI cycles, thesurvival rate following the ICSI procedure was 94%with a normal fertilization rate of 75% with ejaculatedspermatozoa and 69.8% with surgically retrievedspermatozoa (26). The clinical pregnancy rate followingICSI was 43.8%. Complete fertilization failure followingICSI is rare and has been linked to oocyte activationfailure or incomplete sperm decondensation (27,28) .Timing of the procedure may be important and failurehas been linked to the inability of embryologists totime cytoplasmic maturity (Cohen and Garrisi,unpublished observations). Down-regulation andsynchronization of cohorts of follicles may avoid theneed for cytoplasmic timing (29). Noninvasive assaysfor maturity are unfortunately not available (30).
Concerns over the use of ICSI fall into two maincategories based around fertilization abnormalitiesand genetic issues. Despite recent animal work, theICSI technique was essentially developed through itsclinical application in the human. This is occasionallythe case with clinical assisted reproduction techniques(ART) since the available rodent or large animal“model” systems often differ markedly from the humanand are therefore inappropriate for all but the mostrudimentary studies. For example, successful ICSI inthe mouse was only recently developed and requiresspecialized piezo-manipulation systems to allow fornontraumatic membrane penetration (31). It appearsthat reproductive specialists were particularly motivatedonce ICSI was applied to the human and showed suchhigh fertilization rates; they probably based the safetyof the procedure on preceding technology (partialzona dissection and subzonal sperm insertion) thatused microsurgical fertilization to expose the humanoocyte membrane to spermatozoa, but had low clinical
128 HENRY E. MALTER, JACQUES COHEN
success rates. These methods had reasonablyaccepted standards for preclinical research in animalmodels (6,7) . Besides the physical differencesbetween animal and human work, the fertilizationprocess differs markedly between the mouse andhuman due to the persistence of a functional maternalcentriole in the mouse (32,33). As discussed above,some ultrastructural studies were undertaken onhuman oocytes following failed ICSI (27,28) .However, the functional processes of the ICSItechnique were not carefully studied until the recentdevelopment of a successful primate model system inthe rhesus macaque with fertilization and implantationrates similar to those in the human (34–37).
Ultrastructural and other analyses of the eventsof fertilization and early development following ICSIin the macaque monkey have revealed an interestingphenomenon. Following ICSI, decondensation andremodelling of the sperm chromatin is delayed andstructurally distinct, and this apparently leads to adelay in the onset of DNA synthesis in the first cellcycle (10,11). The ICSI process bypasses the normalevents of sperm–ovum interaction and fusion. One ofthe key events during this interaction is the membranefusion and exocytosis of the sperm acrosome, a cap-like membrane that overlays the sperm head plasmamembrane. Following ICSI, the intact acrosome andassociated perinuclear theca must be removed andprocessed by the oocyte cytoplasm. These eventsapparently result in an extension of the normal spermhead remodelling process as well as the creation ofan asymmetry in chromatin decondensation. Due tothe persistence of the perinuclear theca at the base ofthe acrosome, access to and remodelling of the apicalportion of the sperm chromatin is perturbed leadingto a situation where the posterior portion of the spermchromatin is decondensed while the apical portionremains intact. This delay in chromatin decondensa-tion apparently leads to a delay in subsequent nuclearremodelling processes including the recruitment ofnuclear pore constituents and to a delay in DNAreplication (by both paternal and maternal pronuclei)and the first cell cycle following fertilization (10,37).Despite these observations, made during aberrantsperm head processing, the macaque oocyte canultimately process the unusual acrosome-related struc-tures and complete sperm chromatin decondensationsuccessfully. Macaque zygotes fertilized by ICSI orin vitro fertilization are indistinguishable at 20 hourspostfertilization (10). Human ICSI embryos possiblyexhibit slower cleavage as well however, their
performance later does not reflect this initial delay (38,Garrisi and Cohen. unpublished). The authors of themonkey studies speculate that the delay andasymmetry in chromatin processing seen followingICSI could potentially result in abnormal chromosomebehaviour during the first cell cycle and/or disturb-ances to gene expression. Nonrandom positioning ofchromosomes in human sperm has been describedwith evidence that the X chromosome exhibits a biasfor the apical portion of the sperm head (39) . This hasbeen of particular interest since there may be a slightincrease in the incidence of sex chromosome abnor-malities in either human embryos, fetuses or offspringfollowing ICSI (see below). Also, a bovine study hasindicated that perturbations to replication during earlyembryogenesis can lead to subsequent disturbancesof gene expression (40). However, a direct relationshipbetween the unusual events observed during ICSIfertilization in the macaque and any chromosomal,genetic or epigenetic effect has yet to be demonstrated.Furthermore, it is still unclear as to what extent thesituation in the macaque is duplicated under normalconditions in the human. Problems with this model andinterpreting these particular findings may be relatedto physical differences between procedures, theconsequences of captivity on physiology andbehaviour, the use of exogenous hormone prepara-tions from other species, the limited number ofoffspring obtained, and the restricted funds that existfor studying primate embryology.
Another genetic concern with the application ofICSI is the fact that men with nonobstructive azoo-spermia and extreme oligospermia are at increased riskof harbouring genetic lesions related to infertilityincluding Y chromosome deletions (41,42). Whilesuch men can successfully father children throughICSI, the genetic trait related to their infertility may betransmitted to their male offspring (43,44). Thisphenomenon is not a congenital malformation, sincethose are obvious in the newborn, but a predisposition(45,46).
Application criteria
While the standard in vitro fertilization procedure hasproven efficacious in the treatment of mild male factorinfertility, it has become obvious that, when semenquality is impaired, the incidence of fertilization issignificantly reduced (47,48). The ICSI procedure hasproven to be consistently successful in achievingfertilization across a large spectrum of male factor
Intracytoplasmic sperm injection: technical aspects 129
issues including the most severe oligozoospermia,and with ejaculates completely lacking in normal forms(49,50).
One factor that seems to be directly correlated withsuccessful fertilization following ICSI is sperm motility(51–54). An analysis of ICSI cycles with failedfertilization revealed a lack of motile sperm as the mostcommon cause (53). When exclusively immotile spermare used for ICSI, fertilization and outcome arecompromised. Apparent sperm motility deficienciescan result from a variety of conditions, most of whichare addressable, including infection and obstructivenecrozoospermia. However, genetic causes, such asimmotile cilia syndrome, can also be present resultingin spermatozoa with inherently nonfunctional flagella(52). ICSI results with this patient population areparticularly poor (53). In the absence of a clear geneticdefect, a consistent lack of motile sperm in multipleejaculates is a rare occurrence. When only nonmotilesperm are present in multiple ejaculates, an attemptto surgically isolate motile testicular sperm isindicated. If necessary, viable immotile sperm can beselected via the hypo-osmotic swelling test formembrane integrity (55), or by pipetting the tail andmeasuring its plasticity. There is some evidence thatICSI results with immotile epididymal or testicularsperm are somewhat better than those with immotileejaculated sperm (56).
The ICSI technique has proven to be a particularlypowerful tool in the treatment of men who are overtly“azoospermic” through either a physical (obstructive)or physiological (nonobstructive) cause (57). Micro-surgical techniques for the retrieval of viable spermfrom either the epididymis (MESA) or testis (TESE)have been combined with ICSI with consistentsuccess (58,59). It has been estimated that there issome level of spermatogenesis present in at least 60%of azoospermic men and surgical sperm isolationfollowed by ICSI has been successful even in casesclassified as Sertoli cell-only syndrome (12,60). ICSIhas also been successful with cryopreserved sperma-tozoa derived from surgical isolation techniques,although motility issues often complicate this aspect(60,61). Testicular tissue and isolated spermatozoahave a high ability to survive cryopreservation,particularly in cases of obstructive azoospermia(62,63). The use of ICSI following cryopreservationof extremely dilute sperm samples has been facilitatedby micromanipulation techniques for the “storing” ofisolated, individual spermatozoa in evacuated zonapellucidae (64). The use of such animal zonae has been
met with certain criticism, as it has been postulated towork as a vehicle for pathogens. Animal zonaeobtained in a sterile fashion are devoid of pathogensand passive absorbance of compounds is theoretical.There are many other compounds and solutions usedin IVF and ICSI that may potentially “label”spermatozoa. Such labels may not penetrate the eggduring natural conception and IVF, though there is noproof that exogenous DNA cannot enter the egg inrare conditions (perhaps this is a pathway forevolution in nature). ICSI has been postulated to be agood experimental vehicle for loading DNA ontospermatozoa and creating transgenic animals (65,66).Although in these studies, the transgenesis wasmediated and labels were tagged onto the spermatozoapurposefully, DNA is present in many laboratorysolutions such as sera and albumins, hence the needfor protein-free and sterile conditions during theoperation of PCR techniques. It is unknown whethersuch potential agents can tag spermatozoa primed forinjection during ICSI.
As mentioned previously, certain genetic risksincluding Y chromosome deletions and sexchromosome abnormalities are increased in individualsexhibiting extreme forms of male infertility, particularlyin cases of apparent azoospermia (12). Anotherdistinct risk with surgical retrieval involves the wellcharacterized connection between cystic fibrosis (CF)mutations and congenital bilateral aplasia of the vasdeferens (67) . Men with idiopathic obstructiveazoospermia are also at increased risk for harbouringCF mutations (68).
A final treatment methodology based on ICSI isthe use of immature male germ cells to achievefertilization. Several pregnancies have been reportedfollowing the injection of what are described as roundspermatids of ejaculatory or testicular origin, althoughthe success rate is extremely low (69,70). Further-more, the requirement for using such immaturespermiogenic cells is questionable since it is thoughtthat a true maturational arrest does not occur at thisstage of spermiogenesis (71). Theoretically, if roundspermatids are present in a biopsy or ejaculate, thenlater stages including elongated spermatids andmature spermatozoa should also be present. Birthshave also been reported following elongated spermatidinjection; however, the overall success of thesetechniques is also much reduced from that of ICSI withmature spermatozoa (72,73). Finally, concerns havebeen raised about the potential for epigeneticproblems derived from insufficient oocyte activation
130 HENRY E. MALTER, JACQUES COHEN
by spermatid injection and issues of nuclear maturityin these cells (74). There is evidence that spermatidsfrom azoospermic males may be deficient in oocyte-activating factors and this may partially explain thepoor fertilization and development rates followingspermatid injection (75) . Furthermore, it is not knownif the haploid genomes of immature spermatogeniccells are equivalent to those of mature spermatozoaand therefore a potential exists for incorrect epigeneticprogramming (69). We concur generally with thecomments against round spermatid injection made byothers (76).
Risk–benefit analysis
ICSI is still the only commonsense alternative to malefactor infertility treatment. There are no otheralternatives either known, such as in vitro fertilization,or to be developed that show any promise. It is in thislight that a risk–benefit analysis should be discussed.What are the risks? One concern would involvepotential consequences in future generations. Evenfrom animal models, there are no clues as to whathappens to the next generation. Animal models arealso hampered since there are no good models forhuman male infertility. The closest model is perhapsthe cheetah, and obviously that species cannot beused for clinical work. The primate work discussedabove shows many cell biological variations thatoccur after ICSI and that may be consideredanomalous, but it appears that these phenomena areovercome during further development. The sameresearch team has now found, apparently, that thereare also more subtle differences between thesemonkeys born after ICSI showing apparently greaterlevels of developmental aberrations (G. Schatten,personal communication). What about monkeys aslaboratory models for ICSI? They live in captivity, areusually fertile, but are not out-bred like humans. Inaddition, they receive hormone preparations forfollicular stimulation that are not just exogenous, butprepared from blood or urine from other species. Arewe to believe that none of these important criteriashould be considered when assessing models forICSI? Similar criteria can be applied to the mouse modelwhen this becomes available for evaluating ICSI. Hereagain, there are important differences that are similarto the ones described for monkeys, but in addition,conventional ICSI using a piercing needle cannot beapplied in the mouse. Instead, one has to apply a piezoactuator to pierce the membrane. Such piezo actuators
are damaging to mouse development when used atcertain settings (T.Schimmel, unpublished observa-tions).
Considering the above, and considering theclinical evaluations of ICSI to date, the risk–benefitscale weighs heavily towards benefit. There is a slightincrease in congenital anomalies, particularly concern-ing sex chromosome disorders and male-determinedgenetic diseases. In some subgroups there could bean incidence of 10% or more of Y deletions. Evenconsidering that this is a mild congenital error, manypatients show little interest in this fact.
Conclusions
ICSI is indicated as a treatment in essentially all casesof severe male factor infertility where some spermato-zoa can be obtained either via ejaculation or surgicalisolation. A lack of sperm motility is one factor thatcan compromise success and a careful evaluation anddiagnosis of the cause of such motility deficits isindicated. The use of immature spermatogenic cellsfor ICSI has been reported although success rates arevery low and this methodology remains controversial.Genetic counselling for patients with male factorinfertility is strongly suggested due to general andspecific risk factors present in this population. Itremains to be determined whether ICSI is a replacementfor IVF in patients with nonmale factor infertility, butmore importantly, whether it should be a replacementfor IVF.
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134 ANDRÉ VAN STEIRTEGHEM
Intracytoplasmic sperm injection: micromanipulation inassisted fertilization
ANDRÉ VAN STEIRTEGHEM
Gamete source, manipulation and disposition
Assisted hatching: overall outcome
Different assisted hatching (AH) procedures havebeen developed to help embryos escape from their zonaduring blastocyst expansion. These include mechanicalincision of the zona, chemical zona drilling with acidicmedium, laser-assisted hatching and piezo technology(1). These different procedures for AH will bereviewed in this chapter.
The clinical relevance of AH within an assistedreproductive technology (ART) programme remainscontroversial and elusive since reports on only a veryfew randomized controlled trials (RCT) are available.The discussion in this chapter will be limited to thesereports.
Using chemical zona drilling, Cohen and Feldbergreported in 1991 (2) the results of an RCT including69 couples in the study group and 68 couples in thecontrol group. In this study, the implantation rate ofzona-drilled embryos was 28% (66/236) which wasbetter (p<0.05) than the 22% implantation rate of zona-intact embryos (50/226).
In an RCT involving 137 couples in whom thefemale partner had normal basal serum folliclestimulating hormone (FSH) concentrations, theimplantation rate of zona-drilled embryos (28%; 67/239) was not statistically different from the implanta-tion rate of zona-intact control embryos (21%; 49/229)(3).
The hypothesis as to whether or not AH couldrescue poor-prognosis embryos (i.e. those showingthick zonae, low developmental rates and excessivefragmentation) was tested in 163 patients randomizedin a control group and a study group in which embryoswere selectively zona-drilled. The implantation rate inthe study group was 25% (70/278), significantly(p<0.05) higher than the implantation rate of controlembryos (18%; 51/285). In addition, selective AHappeared most effective in women over 38 years ofage and in those with elevated basal FSH levels (3).
In 1996, two prospective randomized trialsdemonstrated clearly that no benefit resulted from AHfor an unselected group of patients undergoingembryo transfer (ET), whether using partial zonadissection (PZD) (4) or acidic Tyrode zona drilling (5).It can be concluded that AH might be of value inincreasing embryo implantation rates in humans, butonly in selected cases.
The benefit of AH in the older age group remainsuncertain since only one RCT has evaluated whetherAH improved implantation rates and pregnancy in thisage group (6). Patients >36 years of age were in astudy group with hatching (n=41) or a control groupwithout hatching (n=48). No significant differenceswere observed in the rates of implantation (11.1%versus 11.3%), clinical pregnancy (39.0% versus41.7%) or ongoing pregnancy (29.3% versus 35.4%)between the two groups.
ICSI: micromanipulation in assisted fertilization 135
A prospective but uncontrolled pilot study on 19patients reported that high pregnancy rates per cycle/transfer (53%) and implantation rates (33%) could beachieved when enzymatic pronase treatment of thezona pellucida of Day 5 blastocysts was carried out(7). This hypothesis was also tested after transfer ofzona-free Day 3 embryos (8). Women below the ageof 40 years undergoing a first intracytoplasmic sperminjection (ICSI) cycle were randomized to receivezona-free embryos (27 women) and zona-intactembryos (25 women). The pregnancy rate was notsignificantly improved when the zona pellucida wasremoved. A second group of patients included women40 years of age and more and/or who had had at leasttwo previous failed in vitro fertilization (IVF)/ICSIattempts; they were randomized in a 3:4 ratio (30 zona-free, 41 zona-intact). Zona removal resulted in asignificantly higher pregnancy rate when comparedwith controls (23% versus 7.3%). The authorsconclude that complete removal of the zona pellucidacan improve pregnancy rates in women with poor IVF/ICSI prognosis.
When reviewing the outcomes of ART, twophenomena have been identified which appear toinfluence monozygotic twinning, i.e. ovulationinduction (9) and zona pellucida architecture andmanipulation (10). ICSI and AH are both zona-breaching procedures and the subject of monozygotictwins in the context of zona pellucida micromanipula-tion needs to be carefully addressed. Reviewing alarge number of transfer cycles (n=3546), the Cornellgroup assessed the occurrence of monozygotic twinsand a possible relationship with zona pellucidamanipulation and did not find a different monozygotictwinning rate between zona-manipulated and zona-intact subgroups. The authors concluded, however,that studies with greater statistical power are needed(11).
The association between AH and monozygotictwinning was assessed in a case–control study designby the Division of Reproductive Health of the Centersfor Disease Control on a sample of IVF-ET cyclesinitiated in 1996 in clinics in the USA (12). Cases werethose pregnancies for which the number of fetal heartsobserved on ultrasound exceeded the number ofembryos transferred. These pregnancies wereconsidered to contain at least one monozygotic setof twins. Cases were compared with two controlgroups: other multiple-gestation pregnancies (>2 fetalhearts but number of fetal hearts <number of embryostransferred); and singleton pregnancies (1 fetal heart).
Women with a case pregnancy were more likely to havereceived embryos treated with AH procedures thanwere women in either control group. After appropriateadjustment for confounding variables (patient age,number of embryos transferred, prior cycles, infertilitydiagnosis, ICSI and whether embryos were cryo-preserved in the cycle), odds ratios and 95% confi-dence intervals for use of AH were 3.2 (1.2 and 8.0)compared with other multiple-gestation pregnancies,and 3.8 (1.8–9.8) compared with singletonpregnancies.
ICSI
Since the birth of Louise Brown in July 1978, it hasbecome clear that conventional IVF is an efficient ARTprocedure for couples with female factor infertility,especially tubal disease, and for couples withunexplained infertility (13,14); however, it soonbecame apparent that it yielded generally poorpregnancy rates for couples with male factor infertility(15). In this study, IVF results were compared in agroup of couples with male factor infertility and asimilar group with tubal factor infertility. In cases withmale infertility, more oocytes were recovered but feweroocytes were fertilized; fewer ETs were performed, theaverage number of embryos per transfer was lower andthe total pregnancy rate was also lower at 13% versus23%. From this and other studies it could be concludedthat in male infertility the results of IVF weredisappointing. A number of couples with severelyimpaired semen could not be accepted for IVF; thisincluded of course couples with obstructive andnonobstructive azoospermia.
Several procedures of assisted fertilization wereexplored. The clinical results of partial zona dissectionand subzonal insemination were, for both procedures,initially encouraging but with wider experience theyproved to be inconsistent and rather disappointing(16–19). A major turning point in assisted fertilizationoccurred in 1992 when our group reported the firstpregnancies and births after ICSI (20). ICSI involvesinjection using micromanipulation procedures of asingle spermatozoon directly into the cytoplasm of theoocyte through the intact zona pellucida. It soonbecame apparent that ICSI was superior to PZD orsubzonal insemination (SUZI), in that the fertilizationrate was consistently better and more embryos withimplantation potential were produced (21,22) . SinceJuly 1992, ICSI has been the only procedure used in
136 ANDRÉ VAN STEIRTEGHEM
our Centre when some form of assisted fertilization isnecessary (23).
Success rates
ICSI has become well established worldwide as aneffective form of treatment for couples with male factorinfertility, including azoospermia. In the last availablereport from the Human Fertilisation and EmbryologyAuthority (HFEA) in the UK (1997/98), there were9295 ICSI cycles, alongside 24 889 conventional IVFcycles, indicating that 27% of ART in the UK is carriedout for severe male factor infertility. In that year, thereported birth rate was 20.7% per cycle for ICSIcompared to 14.9% for IVF. However, in that samereport the multiple birth rate was over 25% and theage of the female partner was a major determinant ofsuccess: for women over 40 years of age the successrate per cycle was 5% or lower while in women in theirearly thirties the success rate was 20%–25% (24).
The results of the survey carried out by the ESHREICSI Task Force were recently reviewed by Tarlatzisand Bili (25). In this worldwide survey over a three-year period (1993–1995), the number of centresundertaking ICSI increased from 35 to 101, and thenumber of ICSI cycles per year increased from 3157 to23 932. Less than 10% of oocytes were damaged bythe procedure and the normal fertilization ratesobtained with ejaculated, epididymal and testicularspermatozoa for 1995 were 64%, 62% and 52%,respectively. An ET was possible in 86%–90% ofcouples, the viable pregnancy rate was 21% forejaculated, 22% for epididymal, and 19% for testicularsperm, with an incidence of multiple gestations of 29%,30% and 38%, respectively. In this survey there wasno difference in the results of ICSI according to theetiology of the azoospermia.
Our own group (26) reviewed the outcome of thefirst seven years of ICSI practice (1991–1997) whichinvolved 7374 cycles involving 74 520 metaphase-IIoocytes injected with a single sperm. In only 3.1% ofscheduled cycles the procedure could not be carriedout because there were no oocytes or spermatozoaavailable for the microinjection procedure. Thedamage rate of oocytes after ICSI was 9.1%. Thenormal fertilization rate was higher after ICSI withejaculated spermatozoa (67.0%) than after ICSI withepididymal or testicular spermatozoa (between 56.6%and 59.8%). It was extremely exceptional that none ofthe injected oocytes fertilized normally. The morphol-ogical quality of the embryos was also better after ICSI
with ejaculated sperm but the percentages of embryosactually transferred or frozen as supernumeraryembryos was similar for the four types of spermatozoaand varied between 59.6% and 65.7% of the two-pronuclear oocytes. The transfer rates and overallpregnancy rates were similar for the different typesof sperm used. Reviewing the data on ICSI outcomesin a group of Belgian couples, less than 37 years ofage, who had their first ICSI cycle between 1992 and1993, the per cycle delivery rate was as high as 31%but the real cumulative pregnancy rate was 60% after6 cycles of treatment. Again, female age had apowerful effect on success rates (27).
Safety of ICSI
Since the introduction of ICSI there has been majorconcern about its safety and the health of the ICSIoffspring. The direct injection of a single spermato-zoon into a mature oocyte bypasses the naturalphysiological processes of normal sperm selectionand raises concern over the potential risk of congeni-tal malformations and genetic defects in children bornafter ICSI. When ICSI with nonejaculated spermato-zoa was introduced, more concern was expressed.This concern related to the safety of the ICSItechnique itself, to the chromosomal or geneticconstitution of the sperm used, and to the possibilityof incomplete genomic imprinting at the time offertilization when testicular spermatozoa are used.Recent work indicated that poor quality semencontained spermatozoa with compromised DNAintegrity (28), but this did not compromise theirfertilizing ability at ICSI (29) , further highlighting theimportance of assessing ICSI outcome.
When ICSI was introduced in Brussels, we furtherenhanced our extensive follow-up procedures for ARTpregnancies and children. Before starting ICSI, thecouples are asked to participate in this prospectivefollow-up study, which includes karyotyping bothpartners, genetic counselling, prenatal karyotypeanalysis (now amended, after careful information ofthe different risks, to optional karyotyping in the firsttwo years postnatally) and participation in a prospec-tive clinical follow-up study of the children. Thisincludes completing a standardized questionnaire andreturning it to the research nurses, and—wherepossible—visiting the Centre for Medical Geneticswith the child after birth. All couples referred forassisted conception were evaluated for possiblegenetic risks (personal history, family history,
ICSI: micromanipulation in assisted fertilization 137
medication, alcohol abuse, smoking, socioeconomicstatus and possible environmental or occupationalrisk factors). A karyotype was routinely performed forthe couple. At birth, written data concerning thepregnancy outcome were obtained from the obstet-rician or the paediatrician in charge. A detailedphysical examination was carried out on babies bornat our University Hospital. Whenever possible, babiesborn elsewhere were examined at two months in ourCentre by a paediatrician–geneticist. Further follow-up examinations were done at 12 months and two yearsto assess physical, neurological and psychomotordevelopment. At approximately two years, Bayleytests were performed in order to score the psycho-motor development of the children. Further psycho-motor evaluation and social functioning arescheduled at a later age. This extensive follow-upprogramme is a collaborative study of the Centres forReproductive Medicine and Medical Genetics of theVrije Universiteit Brussel (26,30–35) .
Prenatal diagnosis in ICSI pregnancies
The available results of prenatal diagnosis after ICSIare summarized in Table 1. Seven studies report on2175 fetal karyotypes. There were 42 de novochromosomal aberrations (16 sex chromosomalaneuploidies and 26 autosomal aneuploidies orstructural aberrations) and 31 inherited aberrations.In our own, so far unpublished, series on 1473 fetalkaryotypes, we concluded that there is a statisticallysignificant increase in sex chromosomal aberrationsand structural de novo aberrations as compared to acontrol neonatal population.
These results are used in our practice to informthe patients during genetic counselling about the riskof chromosomal aberrations in ICSI fetuses. Currently,in our own practice, about half of the patients choose
to have amniocentesis or chorionic villus sampling.In a survey of counselling about prenatal diagnosisto 107 women pregnant as a result of ICSI, Meschedeet al . (42) reported that among these patients therewas a strong preference (82%) for noninvasiveprenatal diagnosis (ultrasound, serum markers) whileonly 17% made use of amniocentesis or fetal bloodsampling.
The question has been raised as to whetherinvasive prenatal testing involves additional risks forthe patients undergoing ICSI. The pregnancy out-come was compared in 576 pregnancies after invasiveprenatal diagnosis with that of 540 pregnancieswithout it. Amniocentesis was recommended forsingleton pregnancies and chorionic villus samplingfor twin pregnancies. Prenatal testing did not increasethe preterm delivery rate, the low-birth-weight rate, orthe very low-birth-weight rate, as compared withcontrols. The fetal loss rate in the prenatal diagnosisgroup was comparable to that of the control group(43) .
Congenital malformations in ICSI children
It should first of all be stressed that the data in theliterature do not give a full picture of the outcome ofICSI pregnancies. In the ESHRE survey (44), 94 centresfrom 24 countries provided data on 14 000 cycles oftreatment, from oocytes collected to embryostransferred. A total of 24 centres completed the follow-up survey for the children but only two centresreported major congenital malformations. All volun-tary surveys on IVF outcome are incomplete regardingsuch parameters as complications during pregnancyand perinatal outcome. Furthermore, the comparisonbetween surveys is difficult since the methodologyused to collect data varies from one survey to anotherincluding such points as the way in which major or
Table 1. Karyotype analyses in prenatal diagnoses after ICSI
De novo chromosomal aberrationsReferences Fetuses Inherited structural
Sex chromosomal Autosomal aberrations
36 115 – – 537 71 6 3 –38 101 – 1 339 209 – 6 140 57 1 – 141 149 – 2 235 1473 9 14 19
138 ANDRÉ VAN STEIRTEGHEM
minor malformations are categorized (45).Table 2 summarizes relevant reports of groups in
the USA (46), Denmark (39), Sweden (47), Australiaand New Zealand (48), and Belgium (35).
When the number of children in these surveys arecategorized in terms of originating from singleton,twin, triplet or higher-order pregnancies, it becomesevident that the overall percentage of children bornwho do not originate from singleton pregnancies is44% (4244 out of 9521 children); this percentagevaries from 32.6% to 60.8% according to the survey.Most of these children are from twin pregnancies. Themean percentage of children from triplet or higher-order pregnancies is 5.5% (524 out of 9521 children);this percentage varies greatly among centres, in onecentre it is as high as 13.2% (46) and in the othercentres between 2.5% and 4.3%. The problemsgenerated by multiple births after ART arising fromthe practice of replacing multiple embryos has beenwell documented (49,50). It is more than obvious thatthis excessive number of multiple pregnancies willresult in problems appearing either immediately or laterin life. It is therefore without any doubt the objectivefor all ART centres that the multiple pregnancy rateshould be reduced substantially in the future.
As indicated in Table 2, perinatal mortality in thedifferent surveys varies from 1% to 3%. The major andminor congenital malformation rate cannot becompared between the different surveys because ofthe differences in methodology used in these surveys(45).
In Denmark, a national cohort study of 730 infantsborn after ICSI included all clinical pregnanciesobtained after ICSI registered in Denmark betweenJanuary 1994 and July 1997 at five public and eightprivate fertility clinics (39). The frequency of multiplebirth, caesarean section rate, gestational age, pretermbirth, and birth weight were comparable with previousstudies. The perinatal mortality rate was 1.37% for
children born at a gestational age of 24 weeks or more.Major birth defects were reported by the parents in2.2% of liveborn children and in 2.7% of all infants.Minor birth defects were found in nine liveborn infants(1.2%).
A Swedish study (47) reported the malformationrate in 1139 infants born after ICSI in two IVF clinicsin Göteborg using data from the medical records, theSwedish Medical Birth Registry and the Registry ofCongenital Malformations, and compared the resultswith all births in Sweden and also with births afterconventional IVF. An identified anomaly was seen in87 children (7.6%), 40 of which were minor. The oddsratio for ICSI children having any major or minorcongenital malformation was 1.75 (95% CI 1.19–2.58)after stratification for delivery hospital, year of birthand maternal age. In a population study from Swedenon all infants born after IVF between 1992 and 1997,hypospadias was more frequent in ICSI children (51) .This may be related to paternal subfertility with agenetic background. The groups from Göteborg alsoexamined the obstetric outcome of pregnancies afterICSI (41). Deliveries occurred in 75.9% and earlyspontaneous abortion, late spontaneous abortion andectopic pregnancy in 21.4%, 1.0% and 1.2% ofpregnancies, respectively. Multiple birth occurred in21.3% (almost all twins) of deliveries, and preterm birthoccurred in 15.7% of all deliveries. Preterm birth wasnot related to sperm origin or quality but was relatedto multiple birth. The prematurity rate was 8.4%, 42.8%and 100% for singletons, twins and triplets, respec-tively. The perinatal mortality rate was 11.7 per 1000born infants; 7.6% of infants had a malformation, 40of which were minor. They concluded that the obstetricoutcome of ICSI pregnancies was similar to that ofconventional IVF and was not influenced by spermorigin or quality.
The current details of the major malformations inthe Brussels Free University (Vrije Universiteit Brussel
Table 2. Liveborn children and congenital malformation rate in intracytoplasmic sperm injection children
Reference Liveborn children Children from Prenatal Major and minormultiple mortality congenital malformations
Total Singleton Twins Triplets* pregnancies (%)
46 2059 708 980 271 60.8 16 22 major/11 minor39 721 473 230 18 34.4 1.4% 2.2% major/1.2% minor47 1139 736 400 3 35.4 NA 47 (4.1%) „serious‰48 2762 1861 782 119 32.6 3.0% 2.5% minor35 2840 1499 1228 113 47.2 1.7% 3.4% major/6.3% minor
* Tr iplet or higher-order liveborn
ICSI: micromanipulation in assisted fertilization 139
VUB) survey can be summarized as follows (35): majormalformations were found in 18 terminated preg-nancies and in eight stillbirths among a total of 49stillbirths after 20 weeks. There was one additionalmalformation detected prenatally, i.e. a child with aholoprosencephaly detected at 15 weeks of pregnancy;this child died at birth. The major malformation ratewas 3.4% (96/2840 live-born children), with 3.1% inchildren from singleton pregnancies and 3.7% inchildren from multiple pregnancies. Defining the totalmalformation rate as (affected live births + affected fetaldeaths + induced abortions for malformations) dividedby (live births + stillbirths), the figures are (96 + 8 +18) divided by (2840 + 49) or 4.2% (Brussels FreeUniversity, unpublished). The major congenitalmalformation rate was also similar between childrenborn after ICSI with ejaculated sperm (3.5%) andnonejaculated (epididymal or testicular) sperm (3.4%)and in children from singleton (3.1%) or multiplepregnancies (3.7%).
Further medical and developmental outcomeof ICSI children
In 1998, two publications in The Lancet reported onthe further development of ICSI children. An Australianstudy (52) compared the medical and developmentaloutcome at one year of 89 children conceived by ICSIwith 84 children conceived by routine IVF, and with80 children conceived naturally. Developmentalassessment was done with the Bayley Scales of InfantDevelopment from which a mental development indexwas derived. The incidence of major congenital ormajor health problems in the first year of life was similarin the three groups. The mental development indexwas lower for ICSI children (especially boys) at oneyear of age than for IVF or naturally conceivedchildren; more ICSI children showed mildly orsignificantly delayed development in this test, whichassesses memory, problem-solving and languageskills (generally in the predominant language of thecountry). In the same issue of The Lancet, our owngroup (53) reported that at two years of age the mentaldevelopment, as tested by the Bayley MentalDevelopmental Index, of 201 ICSI and 131 non-ICSIIVF children was similar between the ICSI and IVFgroups and comparable to that for the generalpopulation. Our conclusion was that there was noindication at this point that ICSI children have slowermental development than the general population. In alater case–control study from the UK, Sutcliffe et al.
(54) compared 123 ICSI children and 123 childrenconceived naturally when they were between 12 and24 months old. Only singleton children were recruited;children were matched for social class, maternaleducational level, region, sex and race but not maternalage. The mean mental age and the mean Griffithsquotients were comparable; only eye–hand coordina-tion was lower in the study group. There was nodifference in the numbers of major and minor mal-formations in the children from the study and controlgroups.
As suggested in a commentary in The Lancet (55) ,further case–control studies taking into accountparental background and other confounding variables,such as language spoken at home, are needed beforefinal conclusions can be drawn in this area.
Conclusions and suggestions for furtherstudies
As the database of ICSI offspring grows larger, theavailable evidence on the short-term health of theseoffspring is generally reassuring. The major issueremains the high prevalence of multiple pregnanciesand the short- and long-term consequences ofprematurity.
Several issues need to be further addressed inrelation to different aspects of ICSI outcome, includingthe role of prenatal testing during ICSI pregnancies,the significance of malformations among terminatedpregnancies and stillbirths, the outcome of ICSIpregnancies in cases where nonejaculated sperm hasbeen used, the incidence of abnormalities in childrenafter replacement of frozen-thawed ICSI embryos, andthe long-term follow-up of ICSI children.
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142 HELEN M. PICT ON, ROGER G. GOSDEN, STANLEY P. LEIBO
Cryopreservation of oocytes and ovarian tissue
HELEN M. PICTON, ROGER G. GOSDEN, STANLEY P. LEIBO
Gamete source, manipulation and disposition
Introduction
The concept of oocyte storage
Oocyte freezing has the potential to be an importantadjunct to assisted reproductive technologies (ART)in humans and domestic animals. However, the easeand success of cryopreservation programmes forsperm (1) and embryos (2) contrast markedly with theproblems associated with freezing mammalian oocytes(3). The results of numerous studies suggest that thesurvival of human oocytes after cryopreservation canbe affected by their stage of maturation, their qualityor by biophysical factors resulting from the cryo-preservation procedure used (4). For example, thematurity, quality and size of the oocyte are particularlyimportant characteristics affecting the outcome ofcryopreservation. However, oocyte freezing has beenslow to be adopted clinically as the number of oocyteswhich survive the freeze-thaw process is extremelyvariable and fewer than 1% of fertilized cryopreservedoocytes have developed to term, even when fertilizedby intracytoplasmic sperm injection (ICSI).
Human oocytes can be stored as either (i) denudedindividual oocytes; or (ii) cumulus-enclosed oocytes.The approach selected usually depends on the stageof nuclear maturity of the oocyte prior to cryo-preservation. For example, where mature metaphaseII (MII) oocytes are harvested for storage the gametes
are commonly denuded prior to freezing to confirmtheir nuclear status. In contrast, it is physiologicallyfar more appropriate to leave full-grown, germinalvesicle (GV) oocytes enclosed within their cumuluscells during the freezing process for optimal in vitromaturation (IVM) after thawing. Each approach hasadvantages and limitations.
Mature metaphase II oocytes
Metaphase II oocytes are collected as part of theexisting practice in assisted reproduction and oocytecryopreservation can be easily incorporated into thecurrent ART protocols. At this stage in their develop-mental pathway, the oocytes have undergone nuclearand cytoplasmic maturation, the first polar body hasbeen expelled and the chromosomes are condensedand arranged on the delicate MII spindle. Freezing ofMII oocytes has been the subject of numerous earlypublications (5–9) and probably even more unreportedstudies. Despite this intense interest, the results inhumans have been generally disappointing and, todate, only a few dozen live births using cryopreservedoocytes have been reported. Several reasons can beoffered—mature human oocytes have a short fertilelifespan, they are exquisitely sensitive to chilling andhave little capacity for repairing cryoinjury beforefertilization. Nevertheless, a number of recent reports
Cryopreservation of oocytes and ovarian tissue 143
show improved oocyte survival and developmentalpotential with viable pregnancies after oocytecryopreservation by slow freezing techniques (Table1). Other recent studies (10,11) give hope of successwith vitrification as an alternative to slow freezingprotocols. Together these reports have regeneratedclinical interest in the cryopreservation of fully grownhuman oocytes.
Immature germinal vesicle oocytes
An alternative approach to MII oocyte cryopreserva-tion is the storage of GV stage oocytes. These cellscan be harvested from Graafian follicles aftergonadotrophin stimulation using ultrasound-guidedfollicular aspiration with modified needles and lowerpressure (20,21). At the time of recovery, GV oocytesare full-size but their chromatin remains at thediplotene stage of prophase I and they therefore donot possess a spindle apparatus. Unlike MII oocytes,immature GV oocytes require a period of maturationto induce the required nuclear and cytoplasmicchanges before they are competent to undergofertilization and support early embryo development.
Alternative approaches to oocytefreezing·ovarian tissuecryopreservation
In view of the limited success with the cryopreserva-tion of oocytes collected from preovulatory follicles,recent research has focused on the development ofan alternative strategy of storing oocytes at the
earliest follicle stage—the primordial follicle. A numberof options are available for primordial follicle andoocyte freezing. These include (i) storage of denudedprimordial oocytes from isolated primordial follicles;(ii) storage of intact primordial follicles; and (iii) storageof thin slices of the ovarian cortex. Biopsies of ovariancortex obtained by laparoscopy, laparotomy oroophorectomy can yield tens to hundreds of primordialand primary follicles depending on the mass of tissueand age of the patient from which the tissue washarvested (22). Despite the apparent difficulties offreezing complex tissues as compared with singlecells, the storage of ovarian tissue has provedsurprisingly successful and a number of reports havedemonstrated that human primordial follicles cansurvive cryopreservation after cooling to –196°C inliquid nitrogen (23–25). Furthermore, the banking ofprimordial follicles in situ offers the potential to restorenatural fertility by autografting when the thawedtissue is returned to the body at either orthotopic orheterotopic sites (24, 25). The suitability of ovariantissue for freezing is enhanced by the developmentalplasticity of the tissue as the ovary is capable offunctioning even when its complement of follicles hasbeen severely reduced such as naturally occurs duringageing, after partial ablation or after injury. Unlikecryopreservation of isolated cells, freeze-storage oftissue presents new problems because of the complex-ity of tissue architecture and cryopreservationprotocols must strike a balance between the optimalconditions for each different cell type. The characteris-tics that influence the sensitivity and suitability ofeach of these three stages of oocyte development forcryostorage are shown in Table 2.
Table 1. Details of the methodology, survival and pregnancy rates obtained after oocyte cryopreservation [adapted from (12)]
Authors/reference Years Type of Freezing Number frozen Stage of freezing and Pregnancies/CPAs method (% survival) method of fertilization deliveries
Porcu et al. (13) 1997 PR Slow 12 (33) MII/ICSI 1/1Tucker et al. (14) 1998 PR Slow 311 (24) MII/ICSI 5/3Polak de Fried et al. (15) 1998 PR Slow 10 (30) MII/ICSI 1/1Young et al. (16) 1998 PR Slow 9 (89) MII/ICSI 1/–Tucker et al. (17) 1998 PR Slow 13 (23) GV/ICSI 1/1Porcu et al. (18) 2000 PR Slow 1502 (54) MII/ICSI 16/9Kuleshova et al. (10) 1999 EG+S Vitri 17 (65) MII/ICSI 1/1Yoon et al. (11) 2000 EG+S Vitri 90 (63) MII/ICSI 3/1Fabbri et al. (19) 2001 PR+S Slow 1769 (54) MII/ICSI –
CPAs: cryoprotective agents; DM: dimethylsulfoxide; PR: 1.2-propanediol; EG: ethylene glycol; S: sucrose; Slow: slow freezing prog ramme;Vitri: vitrification programme; GV: germinal vesicle; MII: metaphase II; ICSI: intracytoplasmic sperm injection
144 HELEN M. PICT ON, ROGER G. GOSDEN, STANLEY P. LEIBO
The principles and practice of oocytecryopreservation
Developing protocols that optimize the survival,fertilization and developmental rates of fully grown GVand MII stage oocytes following exposure to theextreme chemical and physical stresses associatedwith cryopreservation has proved to be a majorchallenge. Cryopreservation of biological specimenscauses complex changes in structure and cellularcomposition, and no single approach has yet provedto be universally effective. In addition, there aresignificant stage- and species-specific differencesbetween freezing oocytes and embryos. A number ofparameters of normal oocyte physiology have beenhighlighted as potential targets for injury that mayresult from various cryopreservation methods (Table2). Changes in any of these parameters will contributeto loss of developmental competence of the storedoocytes through cellular injury or even to irreversibleloss of viability during the cryopreservation process.
Cryopreservation protocols for oocytes andovarian tissue can be broadly classified as “equili-brium” (slow freezing) or “nonequilibrium” (rapidfreezing) according to the cooling rates and cryo-protective agents (CPAs) used. However, the basicconcepts of these two protocols are the same, as theyboth aim to protect the cells from the effects ofintracellular ice crystal formation, cellular dehydrationand drastic changes in solute concentrations at bothhigh and low temperatures. Fundamentally, oocyte
cryopreservation requires that cells tolerate threenonphysiological conditions: (i) exposure to molarconcentrations of CPAs; (ii) cooling to subzerotemperatures; and (iii) removal or conversion of almostall liquid cell water into the solid state.
Exposure to cryoprotectants
The first and essential step in any cryopreservationprotocol for isolated oocytes, follicles or samples ofovarian cortex is to equilibrate the cells with a CPA.Various compounds act as CPAs to protect cellsagainst freezing injury. CPAs share common featuresas they are completely miscible with water, arenontoxic even at high concentrations, and easilypermeate cell membranes. Cryoprotectants are thoughtto protect cells by stabilizing intracellular proteins, byreducing or eliminating lethal intracellular iceformation, and by moderating the impact of concen-trated intra- and extracellular electrolytes (26). Oneof the keys to the success of oocyte cryopreservationappears to be achieving adequate permeation of CPAsacross the oocyte membrane. This necessitatesoptimization of protocols for each cell or tissue typeas post-thaw survival of ovarian tissue is profoundlyaffected both by the type of cryoprotectant used andthe equilibration time required for CPA uptake andremoval (27,28) .
As first proposed by Mazur in 1963 (26), one majorfactor that influences the response of a cell to freezingis the ratio of its surface area to volume of the cell. In
Table 2. Comparison of the characteristics that influence cryosensitivity and suitability for cryostorage [reproduced withpermission from (3)]
Material Primordial oocyte Full-size immature Full-size mature (MII stage) oocyte(GV stage) oocyte
Availability Abundant, always present Scarce, only from antral follicles Scarce, only at mid-cycle
Ease of collection Easy, e.g. biopsy Oocyte retrieval Oocyte retrieval
Size <50 øm 80–300 øm (species dependent) 80–300 øm (species dependent)
Support cells Few, very small Numerous corona/cumulus Numerous corona/cumulus
Nuclear status Resting prophase I, GV, has nuclear membrane Resting MII, on temperaturenuclear membrane sensitive spindle, no nuclear membrane
Zona No Yes Yes
Cortical granules No Central Peripheral
Intracellular lipid Little May be abundant May be abundant
Metabolic rate Low Low Low
Surface:volume ratio High Low Low
GV: germinal vesicle; MII: metaphase II
Cryopreservation of oocytes and ovarian tissue 145
general, the larger the cell, the slower it must be cooledto survive freezing. For example, a human oocyte witha diameter of 120 µm has a volume of 9.05 x 105 µm3
and a surface area of 4.5 x 104 µm2. By comparison, ahuman spermatozoon has a volume of 28 µm3 and asurface area of 120 µm2 (29). Thus, the flattened,paddle-shaped sperm cell has a surface area to volumeratio of 4.3, whereas the spherical oocyte has a surfacearea to volume ratio of only 0.05. Consequently, humanoocytes require much longer to reach osmotic equili-brium when exposed to CPAs than do spermatozoa.Furthermore, optimum cooling rates for spermatozoaare much higher than those for oocytes (30).
Additionally, at temperatures near 0°C, care mustbe take to avoid extreme fluctuations in cell volumeduring CPA equilibration as abrupt volume excursions(31) can immediately damage cells and also make themmore susceptible to stress during subsequent coolingor thawing procedures. At the same time, the durationof exposure to these potentially toxic chemicalsshould be minimized. Cryoprotectant toxicity can bereduced by lowering the temperature of exposure, butthis may necessitate a longer exposure time. Althoughmany investigators attribute cellular damage duringfreezing solely to the toxicity of the CPAs, others arguethat cellular damage is due entirely to osmotic shock(see below).
Cooling to subzero temperatures
When oocytes are frozen in molar concentrations ofCPAs, their survival is strongly dependent on coolingrate, and the specific optimum cooling rate that yieldsmaximum survival is dependent both on the type andconcentration of the CPA. Cell survival is also equallydependent on warming rate. The optimum warmingrate depends both on the CPA and its concentration,as well as on the cooling rate that preceded it.Cryobiological studies have shown that differenttypes of cells, even when frozen in the same solution,exhibit different optimum warming rates. These factsare especially relevant to the cryopreservation ofovarian cortex, since this tissue comprises manydiverse types of cells and each type has its owncharacteristic size, shape and permeability properties.Therefore, cooling and warming conditions that areoptimum for one cell type within the ovarian cortexmay be harmful to others. Because of the complexityof ovarian architecture, survival of frozen tissues isdependent not only on cooling and warming rates, butmore importantly, is affected by the rate and method
by which CPAs are removed from cryopreservedtissues (32–34).
Osmotic events during cell cryopreservation
When aqueous solutions are frozen, water is removedin the form of ice, causing the cells to becomeincreasingly concentrated as the temperature falls.The reverse occurs during thawing. Furthermore asthe cells are frozen, they must respond osmotically tolarge changes in extracellular fluid concentrations.The efflux of water during slow (<2°C/min) freezingcauses oocytes to undergo osmotic dehydrationleading to contraction (28). It has also been arguedthat cells can be damaged because of long exposureto high electrolyte concentrations, excessive celldehydration and the mechanical effects of external ice.But these interpretations are not universally held.
Although cells in suspension can tolerateexposure to very high concentrations of CPAs,whether the cells survive the freeze-thaw process ornot is dependent on how they are removed from theCPA solution. When frozen cells are warmed rapidly,the melting of the cell suspension is equivalent torapid dilution of the CPA that became concentratedduring the freezing process. The rapid influx of waterinto cells or tissues as the extracellular milieu beginsto melt can cause osmotic shock at subzero tempera-tures (35). Sensitivity to osmotic shock is therefore afunction of the cell’s permeability to water and solutes.This shock can be reduced by use of an osmotic buffer,such as sucrose, as a nontoxic, impermeable subs-tance (36,37) . Tissues are even more sensitive toosmotic effects than cell suspensions, because cellsin the interior of a piece of tissue can respondosmotically only when the neighbouring cells havealso responded.
Cryopreservation protocols
Equilibrium freezing protocols for oocytes andovarian tissue
For the most part, the cryopreservation proceduresused for equilibrium freezing of oocytes and ovariancortex are very similar to the procedures designed forcleavage stage embryos. Denuded and cumulus-enclosed oocytes are usually frozen in straws orampoules after being equilibrated in an aqueoussolution containing an optimal concentration of 1–1.5
146 HELEN M. PICT ON, ROGER G. GOSDEN, STANLEY P. LEIBO
M cryoprotectant and an osmolyte such as sucroseat a concentration of 0.1–0.5 M. The CPAs mostcommonly used for mature oocyte cryopreservationare propylene glycol, ethylene glycol and dimethyl-sulfoxide (DMSO) (Table 1). Following CPA exposure,the temperature is then slowly lowered and ice crystalgrowth is initiated (“seeded”) in the solution. Theampoules or straws are seeded at –7°C, and cooled at0.3–0.5°C/min to approximately –40°C, then at 10ºC/min to –150°C, and finally transferred into liquidnitrogen for storage. It has been shown that embryosand spermatozoa do not deteriorate even when storedfor decades in liquid nitrogen (38,39).
An effective method for the preservation ofhuman ovarian cortex involves the equilibration ofthin slices (<1 mm thick) of ovarian cortex for 30minutes at 4ºC in freezing solution containingcryoprotectant plus sucrose (27,28,40,41). Thisapproach provides a maximal surface area for rapid CPApenetration, as evidenced by nuclear magneticresonance spectroscopy (28). Oocytes and ovariantissues can be stored in liquid nitrogen at –196ºC foras long as required. Exceptionally, Harp et al.(42) andGunasena et al. (43) cooled ovarian specimens at0.5°C/min to approximately –55ºC and then plungedthem into liquid nitrogen, whereas Salle et al. (44)cooled at 2ºC/min to approximately –140ºC.
Most procedures stipulate that oocytes orovarian cortex are thawed rapidly by being swirled ina water bath at ~20°C or 37°C, and the CPA isprogressively diluted from the tissue by repeatedrinses with fresh medium.
Nonequilibrium protocols: vitrification
Vitrification refers to the physical process by whichan aqueous solution forms an amorphous glassy solid,rather than crystallizing. A number of differentmethods have been used to vitrify human oocytes andpreimplantation embryos. These approaches that havebeen developed for use with animal embryos andoocytes have met with varying degrees of successwhen used for human tissues. The methods includethe use of conventional straws (45,46) , the open-pulled straw method (47), the cryoloop (48) andvitrification of cells using electron microscope gridsas a support (49). Typically, high concentrations ofCPA or mixtures of several CPAs and an extremely highcooling rate (>2000°C/min) are used to vitrify oocytes.Such conditions preclude the formation of intracellularice crystals. The automated programmable freezers
that are commonly used for slow freezing protocolsare not required for vitrification and the actual timerequired for cooling the specimens is significantlydecreased. Despite these apparent advantages, thehigh concentration and potential toxicity of the CPAsused in vitrification protocols can cause severeosmotic shock to the oocytes and compromise theirpost-thaw survival and developmental potential.Because oocytes are extremely permeable to ethyleneglycol (EG), its use lessens the likelihood of osmoticshock when oocytes are diluted out of even veryconcentrated solutions. Therefore, EG has been usedsuccessfully to cryopreserve MII oocytes which havebeen used to produce term pregnancies (10,11).Furthermore, the question of long-term stability of the“glassy state” of the vitrified cells, which is prone tofracture, remains to be tested under normal workingconditions in the IVF laboratory (i.e. storage in liquidor vapour phase under conditions of routine accessto storage tanks).
Table 3. Applications of oocyte and ovarian freezing
• Improve the efficiency of IVF
• Alternative to embryo freezing
• Oocyte preservation for patients with ovarian hyperstimulationsyndrome
• Oocyte donation programme
• The treatment of congenital infertility disorders
• Prevent fertility loss through surgery
• Treatment of premature ovarian failure
Application, indications andcontraindications for oocyte freezing
Cryopreservation of unfertilized oocytes or ovariantissue is desirable to improve the efficiency of assistedreproduction as it offers the possibility of establishingan oocyte banking system. Stored oocytes couldpotentially be used for several purposes (Table 3).
Routine oocyte freezing would greatly benefitART as it would provide an ethically acceptablealternative to embryo freezing. The ovarian stimula-tion regimens routinely adopted for in vitro fertiliza-tion (IVF) remain relatively imprecise as the numberof preovulatory follicles that develop in response tothese treatments varies greatly between individuals.As it is preferable to collect all ova from all stimulated
Cryopreservation of oocytes and ovarian tissue 147
follicles, these procedures may result in the recoveryof large numbers of oocytes from a range of antralfollicle sizes at different stages of maturity. However,because of the lack of efficient procedures tocryopreserve these cells, the common clinical practicein many countries is to fertilize all the oocytes andselect only two or three of the best quality embryosfor immediate transfer. The majority of the remainingembryos are frozen for subsequent frozen embryotransfer cycles. Therefore, because of the hetero-geneity of the stimulated follicle population, there maybe a significant wastage of oocytes from a typical IVFstimulation cycle. The ability to store oocytes fromcontrolled ovarian stimulation would allow greaterflexibility in the treatment of the oocytes of differentmaturational stages and so maximize fertilization ratesand embryo quality. Furthermore, after a period ofquarantine, excess cryopreserved oocytes could bedonated to other infertile women, an alternative thatwould help to overcome the chronic shortage ofoocytes for donation.
While the efficient cryopreservation of fullygrown oocytes would improve the efficiency ofcurrent ART practice, oocyte freezing could also beused to conserve the fertility of young women whoare diagnosed with cancer and are too young to haveeither started or completed their families. For patientsof reproductive age, conventional IVF and embryofreezing is often not possible because the treatmentis both costly and lengthy and, where there is no malepartner, donor sperm is required. What is more, therequired ovarian hyperstimulation may be contra-indicated in the case of steroid-dependent cancers.More importantly, it is often dangerous to delaycancer therapy in order to induce follicular develop-ment and oocyte collection. Finally, this strategy isclearly not an option for prepubertal girls.
In contrast to the preservation of mature oocytes,ovarian tissue cryopreservation has the potential tobe used as a means to conserve the fertility of bothyoung adults and prepubertal girls. In addition, high-dose chemotherapy is now being used for anincreasing number of nonmalignant conditions, suchas autoimmune diseases and thalassaemias. Finally,ovarian tissue freezing may become a viable optionfor fertility conservation in young women with afamilial history of premature ovarian failure. Ovariantissue banking has the added potential of restoringovarian function and natural fertility in these groupsby autografting the frozen-thawed tissue at either anorthotopic or heterotopic site within the body (50).
The safety of mature oocyte cryopreservation
Studies using MII oocytes suggest that oocytesurvival after freezing and thawing can be affected bya number of factors. Among the morphological factors,the presence or absence of the cumulus granulosacells during the freezing process may have a directimpact on oocyte survival, post-thaw. Furthermore,sublethal damage to the cells post-thaw may wellaffect their developmental capabilities. Although notproven, it is thought that the cumulus cells offer someprotection against sudden osmotic changes andstresses induced by the rapid influx of the cryo-protective agents during the procedures of equilibra-tion and removal of CPA during the prefreeze and post-thaw periods (19).
Mature human oocytes show great heterogeneityin the distribution and organization of cytoplasmicorganelles which may influence the outcome ofcryopreservation procedures (Table 4). For example,during human oocyte maturation in vivo the corticalgranules move to the periphery and are distributedunder the oolemma. Following fertilization, thegranules are exocytosed and their contents alter thebiochemistry and sperm-binding characteristics of thezona pellucida which induces zona hardening andprovides the natural block to polyspermic fertilization.Premature zona hardening will undoubtedlycompromise normal fertilization and may impairimplantation of the embryo (51,52). In support of thishypothesis, human oocytes stored after slow coolinghave lower recorded fertilization rates after standardIVF and electron microscopy of these cells hasdemonstrated a reduction in the number of corticalgranules (53), suggesting that zona hardening hasoccurred in response to the freeze-thaw process.However, Gook et al. (52) found an abundance ofcortical granules in the cytoplasm of cryopreservedoocytes. Where there is any potential risk of zonahardening as a result of cryopreservation, it can bebypassed by micromanipulation techniques such asICSI and assisted hatching (54,55) .
MII oocytes are vulnerable to cryoinjury becausethe meiotic spindle on which the chromosomes havebecome aligned is acutely temperature sensitive.Transient cooling of human oocytes to 20ºC can causeirreversible disruption of the spindle apparatus whilerapid depolarization occurs when the temperature islowered to 0ºC (56,57). The appropriate organizationof spindle microtubules is essential for the correctalignment and segregation of chromosomes when the
148 HELEN M. PICT ON, ROGER G. GOSDEN, STANLEY P. LEIBO
spindle reassembles once the temperature returns tonormal. Oocyte freezing can therefore increase theincidence of aneuploidies after extrusion of thesecond polar body through nondisjunction of sisterchromatids. This disruption of the cytoskeletalarchitecture may also lead to abnormal cytokinesis,retention of the second polar body and alterations inthe organization and trafficking of molecules andorganelles (58) . While deleterious effects on thecytoskeleton resulting from chilling may be avoidedby cryopreservation of GV oocytes, the difficultiesassociated with IVM and extended culture appear tocounteract the potential benefits of freezing oocytesat this stage. Furthermore, chilling reduces thedevelopmental capability of GV oocytes, quite apartfrom damage to the meiotic spindle (59) . Conse-quently, few pregnancies have been achieved afterIVM of human oocytes (60,61) and even fewer afterthe initial attempts to cryopreserve full-sized GVoocytes (Table 1). At present, cryopreservation of GVoocytes offers little or no advantage over freeze-storage of MII oocytes.
In addition to the cytogenetic impact of cryo-preservation, there is an increased risk ofparthenogenetic activation of the oocytes afterthermal shock and exposure to CPAs. Althoughindividual reports differ in the extent of activationobserved (62), parthenogenetic activation appears tobe influenced by the type of CPA used and by the useof ICSI versus IVF to fertilize the oocytes post-thaw.Although the precise mechanism by which activationis initiated is unknown, recent evidence suggests thatCPA exposure promotes the passive influx of Ca2+
across the plasma membrane (63), possibly bystimulating the release of Ca2+ from storage sites inthe mitochondria and endoplasmic reticulum.Furthermore, calcium fluxes are known to activateintracellular phospholipases, proteases, ATPases andendonucleases, which may result in altered plasmamembrane integrity, denaturation of cystolic proteins,and chromosomal fragmentation, all of which can leadto irreversible cell injury and apoptosis.
The safety of primordial oocytecryopreservation
Primordial oocytes appear to be less vulnerable tocryoinjury than mature oocytes as they are smaller,lack a zona pellucida and cortical granules, and arerelatively metabolically quiescent and undifferentiated(Table 2). Additionally, primordial follicles areapparently more tolerant to insults such as immersionin CPA solutions and cooling to very low tempera-tures as their small size makes them less susceptibleto damage induced by water movements into and outof the cells during freezing and thawing. Finally,primordial oocytes have more time to repair sublethaldamage to organelles and other structures during theirprolonged growth phase after thawing.
Although storage of slices of ovarian cortex is anattractive alternative to mature oocyte freezing, thereare a number of technical problems associated withthe cryopreservation of ovarian tissues compared toisolated oocytes. Tissues respond very differently toice formation than cell suspensions. Cells in tissuesare usually closely packed, and they also have
Table 4. Factors associated with cooling and cryopreservation that contribute to cellular injury and death in biologicalsystems [reproduced with permission from (3)]
System Type/cause of damage
All Intracellular ice formation, extracellular ice formation, apoptosis, toxicity, calciumimbalance, free radicals, ATP levels, general metabolism, fertilization failure, cleavagefailure, pHi, parthenogenetic activation, cleavage
Membrane Rupture, leakage, fusion, microvilli, phase transition
Chromosomes Loss/gain, polyspermy, polygyny (failure to extrude polar body), tetraploidy
DNA Apoptosis, fusion, rearrangements
Cytoskeleton Microtubules dissolve, actin
Proteins/enzymes Dehydration, loss of function
Ultrastructure Microvilli, mitochondria, vesicles, cortical granules, zona pellucida
Zona pellucida Hardening, fracture
Lipids Free radicals?PHi: intracellular PH
Cryopreservation of oocytes and ovarian tissue 149
interacting connections with each other and withbasement membranes. Tissues have a three-dimensional structure and are traversed by finecapillaries or other blood vessels. Changes in extra-cellular ice surrounding the tissue during the freezingprocess, and recrystallization during warming of thetissue are both hazardous. In the hands of experiencedcryobiologists, morphological assessments of cryo-preserved human ovarian cortex at the light micro-scopy (64) and electron microscopy (22,65) levelshave confirmed that cellular damage in the tissue canbe minimal. However, the choice of an inappropriateCPA together with poor laboratory practice can leadto extensive cellular damage which will compromisetissue viability on thawing (22). The problems ofachieving adequate permeation of tissue fragmentswith CPA can be overcome either by preparation ofthin strips of tissue no more than 1–2 mm thick, whichprovides maximal surface area for solute penetration(28), or by dissociation of the tissue into follicles orisolated cells before freezing (66).
Although the cryopreservation protocols used forthe banking of human primordial oocytes have notbeen fully optimized, they are nonetheless effective.Using the slow freezing approach, high post-thawfollicle survival rates of 84% and 74% have beenrecorded for human primordial follicles stored using1.5 M ethylene glycol and DMSO, respectively,compared with survival rates of only 44% and 10%with 1.5 M propylene glycol and glycerol, respectively(27). It is therefore anticipated that far greatertechnical problems will be encountered when thestored tissue is thawed and used to restore fertility.On the basis of animal experiments, it is likely thatfertility restoration will be achieved by heterotopic ororthotopic autografting (24,25,40,50) once the highlevels of follicle loss associated with re-perfusioninjury have been reduced (67). Xenografting has alsobeen successfully used as a research tool to investi-gate the developmental potential of frozen-thawedhuman ovarian tissues (68).
While it may be possible to store ovarian tissuefor young cancer patients where there is any risk ofreintroducing malignant cells in the tissue graft (69),a far safer strategy is to culture the follicles to maturityin vitro (61). Following fertilization by IVF or ICSI,embryos which are free from contamination could betransferred back to the patient. Human follicle cultureis an emerging technology and encouraging new datasuggest that it may soon be possible to grow folliclesto antral stages after cryopreservation (61). Nonethe-
less, a considerable amount of research effort will beneeded in the future to confirm that primordial folliclecryopreservation, followed by extended culture, is asafe procedure and that it does not induce epigeneticalterations in the female gametes (70). If successful,cryopreservation followed by follicle culture mayeventually supersede cryostorage and grafting as astrategy to restore natural fertility, as this approachmakes more economic use of scarce follicles.
Finally, the freeze storage of isolated oocytes andovarian tissue is subject to the usual safety concernsof long-term banking of tissues in liquid nitrogen.Because of the known risks of viral transmission innitrogen storage tanks (71), it is preferable thatpatients should be screened for blood-borne viraldiseases prior to tissue storage. The possibility of thelong-term storage of ovarian tissues from paediatricpatients also raises the question of how long bankedovarian tissues and oocytes should be stored. In thecase of ovarian tissue storage for young cancerpatients, it is important to ensure that the patient (orguardian) consents to an upper time limit for storageand also to the disposal of tissue in the event of deathor mental incapacitation.
Conclusions
Oocyte cryopreservation strategies still require muchdevelopmental work to improve the survival rates anddevelopment potential of frozen-thawed oocytes. Thepotential ethical benefits, the convenience and lowercosts which will result from successful programmesof mature or immature oocyte freezing will surelystimulate continuing efforts to improve protocols andclinical practice as this approach may well transformART.
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48. Lane M et al. Containerless vitrification of mammalianoocytes and embryos—adapting a proven method forflash-cooling protein crystals to the cryopreservationof live cells. Nature Biotechnology, 1999, 17:1234–1236.
49. Martino A et al. Development into blastocysts ofbovine oocytes cryopreserved by ultra-rapid cooling.Biology of Reproduction, 1996, 54:1059–1069.
50. Nugent D et al . Transplantation in reproductivemedicine: previous experience, present knowledge andfuture prospects. Human Reproduction Update, 1997,3:267–280.
51. Trounson AO, Kirby C. Problems in the cryo-preservation of unfertilized eggs by slow cooling inDMSO. Fer tility and Sterility, 1989, 52:778–786.
52. Gook DA et al. Cryopreservation of mouse and humanoocytes using 1,2-propanediol and the configuration ofthe meiotic spindle. Human Reproduction , 1993, 8:1101–1109.
53. Al-Hasani S, Diedrich, K. Oocyte storage. In:Grudzinskas JG, Yovich JL, eds. Gametes—the oocyte.Cambridge, Cambridge University Press, 1995.
54. Kazem R et al . Cryopreservation of human oocytes andfertilisation by two techniques: in vitro fertilisation andintracytoplasmic sperm injection. Human Reproduction,1995, 10:2650–2654.
55. Nagy ZP et al. Pregnancy and birth after intracytoplas-mic sperm injection of in vitro matured germinal-vesicle stage oocytes: case report. Fertility and Sterility,1996, 65:1047–1050.
56. Pickering SJ et al. Transient cooling to room tempera-ture can cause irreversible disruption of the meiotic
spindle in the human oocyte. Fertility and Sterility ,1990, 54 :102–108.
57. Zenzes MT et al. Effects of chilling to 0 °C on themorphology of meiotic spindles in human metaphaseII oocytes. Fertility and Sterility, 2001, 75:769–777.
58. Vincent C, Johnson MH. Cooling, cryoprotectants andthe cytoskeleton of the mammalian oocyte. OxfordReviews of Reproductive Biology, 1992, 14:72–100.
59. Martino A et al . Effect of chilling bovine oocytes ontheir developmental competence. Molecular Reproduc-tion and Development , 1996, 45:503–512.
60. Trounson AO et al. In vitro maturation and fertilizationand developmental competence of oocytes recoveredfrom untreated polycystic ovarian patients. Fertility andSterility, 1994, 62:353–362.
61. Picton HM, Gosden RG. In vitro growth of humanprimordial follicles from frozen-banked ovarian tissue.Molecular and Cellular Endocrinology, 2000, 166:27–35.
62. Imoedehme DG, Sigue AB. Survival of human oocytescryopreserved with or without the cumulus in 1,2-propanediol. Journal of Assisted Reproduction andGenetics, 1992, 9:323–322.
63. Litkouhi B et al . Impact of cryoprotective agentexposure on intracellular calcium in mouse oocytes atmetaphase II. Cryo Letters, 1999, 20:353–362.
64. Gook DA et al. Effect of cooling and dehydration onthe histological appearance of human ovarian cortexfollowing cryopreservation in 1,2-propanediol. HumanReproduction, 1999, 14:2061–2068.
65. Kim SS et al. The future of human ovarian cryo-preservation and transplantation . Fertility and Sterility,2001, 75 :1049–1056.
66. Cox SL et al. Transplantation of cryopreserved fetalovarian tissue to adult recipients in mice. Journal ofReproduction and Fertility, 1996, 107 :315–322.
67. Nugent D et al . Protective effect of vitamin E onischaemia–reperfusion injury in ovarian grafts. Journalof Reproduction and Fer tility, 1998, 114:341–346.
68. Oktay K et al. Development of human primordialfollicles to antral stages in SCID/ hpg mice stimulatedwith follicle stimulating hormone. Human Reproduc-tion, 1998, 13:1133–1138.
69. Shaw J, Trounson AO. Ovarian banking for cancerpatients—oncological implications in the replacementof ovarian tissue. Human Reproduction, 1997, 12:403–405.
70. Young LE, Fairburn HR. Improving the safety ofembryo technologies: possible role of genomicimprinting. Theriogenology, 2000, 53:627–648.
71. Tedder RS et al . Hepatitis B transmission fromcontaminated cryopreservation tank. Lancet, 1995,346 :137–140.
152 STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
Cryopreservation of human spermatozoa
STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
Gamete source, manipulation and disposition
Introduction
Documented efforts to maintain the fertilizing capacityof mammalian spermatozoa for extended times havebeen made for at least 135 years. Having observedsurvival of human spermatozoa that had been cooledto –15ºC, in 1866, an Italian physician, P. Mantegazza,proposed the concept of a human sperm bank to storesemen specimens (as described by Bunge et al. (1)).Among somewhat more recent, yet still early, formalstudies of sperm cooling were those of Hammond (2)and Walton (3). In companion investigations of rabbitspermatozoa, they showed that the fertility ofspermatozoa collected from the vas deferens of bucksor from the vaginas of mated does could be extendedfor several days by cooling sperm samples to tempera-tures of 15ºC or below. Ejaculated spermatozoa werestill fertile after four days at 10ºC, and spermatozoacollected from the vas were fertile even after sevendays at that temperature, resulting in multiple littersof live young after artificial insemination (AI). In aseldom cited paper, Shettles (4) reported preservationof human spermatozoa after plunging thin-walledcapillaries of undiluted semen directly into alcoholcooled to –79°C with dry ice or into liquid nitrogen at–196ºC or into liquid helium at –269ºC. Although thesurvival of sperm motility was low and variedsignificantly among eight donors, Shettles observedthat motility continued for several hours after thawing.
He wondered whether such spermatozoa were stillcapable of fertilization. Soon after, Hoagland andPincus (5) reported preservation of human and rabbitspermatozoa by making films of semen on a bacteriol-ogical loop, and plunging the loops directly intoliquefied gases to achieve very high cooling rates.Again, the results were highly variable, but in a fewcases they observed motility rates of 60% afterthawing frozen samples of human semen. They alsoattempted to dehydrate the cells by plasmolysis byexposing spermatozoa to various sugars beforeattempting to freeze them. Several aspects of thesemethods first described 60 years ago for spermpreservation presaged methods now being used tocryopreserve mammalian oocytes and embryos byultrarapid cooling. These include use of a fine capillary,the “open-pulled straw” method of Vajta et al. (6) , andthe “cryoloop” method of Lane et al. (7).
Apart from these early attempts at sperm preserva-tion, the single observation most often credited withhaving resulted in a reliable method of cryopreserva-tion of cells was that of Polge, Smith and Parkes (8).They found that fowl spermatozoa, suspended in aglycerol–albumen solution, survived freezing to–79ºC. They then showed that bull spermatozoa werealso protected by glycerol against damage caused byfreezing to –79ºC (9). The birth of the first mammalresulting from AI of a female with frozen-thawedsemen was reported shortly thereafter (10). These
Cryopreservation of human spermatozoa 153
results prompted Sherman and Bunge (11) to studythe effects on survival of human spermatozoa ofvarious cryobiological factors, such as glycerolconcentration and cooling rate. Since then, althoughdifficult to document precise figures, it is reasonableto estimate that many tens of thousands of humanpregnancies have been produced by AI with cryo-preserved spermatozoa. Numerous publications havedescribed the methods, results and variables affectinghuman sperm freezing (12–15), as well as that ofsperm cryopreservation of nonhuman primates (16–20).
Clinical use of cryopreserved spermatozoa
The first human pregnancies and births resulted fromAI of four women with semen samples that had beenfrozen and stored in dry ice at –70°C for up to six weeks(1). Several years later, births resulting from AI withhuman spermatozoa frozen and stored for 5 monthsin liquid nitrogen were reported (21) . These successesled to the gradual clinical application of cryopreservedhuman spermatozoa and the establishment of humansperm banks in several countries. One of the firstadvocates of this approach to treating infertility byinsemination with frozen semen was Sherman (22),who summarized the development and implementationof the first human sperm banks. Other advocates ofsemen banking were David and Lansac (23) whodescribed the unique organization and managementprinciples of the sperm banks of CECOS (Centred’Etude et de Conservation du Sperme Humain) inFrance. This sperm bank still operates under theguidelines that all semen donations are givenvoluntarily and without payment to the donor. Atabout the same time, Trounson et al. (24) summarizedthe experience of multiple sperm banks in Australia,and recently, Critser (25) reviewed the current statusof semen banking in the USA.
One of the most important aspects of clinicalapplications of frozen spermatozoa is its efficacy
compared to that of fresh semen for AI. Nowadays,because of the risk of transmission of humanimmunodeficiency virus (HIV), it would be unethical,if not illegal, to attempt such comparisons using freshspermatozoa from large numbers of sperm donors. Inmost countries of the world today, semen samples arefrozen and quarantined for at least six months so thatthe health status of sperm donors can be testedretrospectively, i.e., at the time when donors actuallyejaculated their specimens. However, in the past,several retrospective and some prospective compari-sons were conducted. For example, Steinberger andSmith (26) compared conceptions and births resultingfrom a total of 107 inseminations with fresh or frozensemen. They found that, on average, it requiredsomewhat more cycles of insemination and spermconcentrations about 50% higher to induce pregnancywith frozen semen; nevertheless, 61% of 59 attemptswith frozen semen resulted in pregnancy compared to73% of 48 attempts with fresh semen.
Details of previous comparative studies of freshand frozen semen are varied, and methods used tocryopreserve the spermatozoa differ substantially.Nevertheless, it is useful to consider these databecause they provide important information thatwould now be difficult to obtain. In Table 1, the resultsobserved in five comparative studies are shown interms of the average probability of pregnancy afterAI with fresh or frozen semen. Consideration of thesedata illustrates the difficulty of evaluating theefficiency of methods to cryopreserve humanspermatozoa. Undoubtedly, the principal objective ofthese trials was to induce pregnancy in the insemina-ted patients, not necessarily to optimize freezingmethods.
In three of these comparisons [Richter et al. (27),DiMarzo et al. (30) and Subak et al. (31)], theprobability of pregnancy with fresh semen was twoto four times greater than with frozen semen. In theother two studies (Bordson et al. (28) Keel andWebster (29) ), however, there was no apparentdifference between fresh and frozen semen. But
TTTTTababababable 1.le 1.le 1.le 1.le 1. Average probability of pregnancy per treated cycle after artificial insemination with fresh or frozen semen
Richter et al. Bordson et al. DiMarzo et al. Keel and Webster Subak et al.1984 (27) 1986 (28) 1990 (30) 1989 (29) 1992 (31)
Fresh Frozen Fresh Frozen Fresh Frozen Fresh Frozen Fresh Frozen
Treated cycles 676 1200 165 165 3405 371 67 209 102 96
Pregnancy probability 18.9 5.0 11.5 10.3 10.5 5.7 5.8 4.8 20.6 9.4
154 STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
differences in the methods used may account for someof the apparent differences among the results. Forexample, in the Richter study, patients receiving freshsemen received the entire ejaculate, whereas thosereceiving frozen specimens received only semen thathad been diluted with cryoprotectant, so that the totalnumber of spermatozoa was less. In the Bordsonstudy, a minimum of 40 x 106 total motile spermatozoa,whether fresh or frozen, were inseminated; in somecases, two inseminations were used (28). In the Keel–Webster trial (29) , patients were inseminated with theuse of a cervical cap, with at least 20 million motilecryopreserved spermatozoa; many of those insemina-ted with fresh semen were treated twice per cycle. Inthe DiMarzo study (30), at least 30 million totalspermatozoa/ml with more than 50% motility were usedfor fresh samples, whereas the frozen samplescontained 20–40 million motile spermatozoa perinsemination. In the Subak study (31), about two-thirds of the patients were inseminated with the useof cervical caps, and the balance by intrauterineinsemination (IUI). A confounding aspect of this trialemerged retrospectively. On average, patientsinseminated with fresh semen who became pregnanthad received 250 million spermatozoa, whereas thoseinseminated with frozen semen had received less than50 million spermatozoa. Not surprisingly, in all of thesestudies, and as previously observed by Steinbergerand Smith (26), the higher the concentration of motilespermatozoa, the greater the likelihood of pregnancy.The overall efficiency in terms of probability of
pregnancy resulting from inseminations with frozensemen found by Richter et al. (27), DiMarzo et al. (30),and Keel and Webster (29) were similar and wereabout 5%. In the analyses by Bordson et al. (28) andSubak et al. (31), the likelihood of pregnancy wasabout 10%.
An even clearer picture of the difference betweenfresh and frozen semen emerges when the cumulativelikelihood of pregnancy is plotted as a function of thesequential number of patients’ menstrual cycles duringwhich inseminations were performed. Such data forfour of the comparisons cited above have been plottedin Figure 1. Despite some differences in the methodsused, the probabilities of pregnancy with both freshand cryopreserved semen observed by both Richteret al. (27) and by Subak et al. (31) were very similar.In contrast, the likelihood of pregnancy resulting fromAI with frozen semen in the study by Bordson et al.(28) was approximately equal to that observed withfresh semen by DiMarzo et al . (30).
Other clinical trials of cryopreserved semen havealso been described in the literature. For example,Mahadevan and Trounson (32) conducted a detailedand exhaustive study of the role of various cryo-protective additives (CPA) on human sperm survivalafter freezing and thawing. The CPAs includedglycerol, dimethyl sulfoxide and ethylene glycol, insome cases supplemented with sucrose, raffinose, orglycine. Having derived a complex defined mediumwithout egg yolk for human semen, they determinedmethods that yielded high sperm survival after
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Figure 1. The cumulative probability of pregnancy as a function of the number of successive treatment cycles during which women wereartificially inseminated with fresh or frozen human spermatozoa.
Cryopreservation of human spermatozoa 155
freezing, and then conducted a double-blind clinicaltrial to compare their optimized method with a standardone. Of 52 patient cycles treated with the optimizedmethod, 50% of the women became pregnant and 24children were born.
Another very important clinical trial was describedby Federation CECOS (33) for the accumulatedexperience of French semen banks over the 15-yearperiod from 1973 to 1987. Since the inception of theCECOS programme, more than 17 000 pregnancieswere produced during that period with the use of cryo-preserved semen, despite the fact that many of thewomen who were treated successfully had varioustypes of infertility problems. The overall mean successrate per cycle was 8%, and the theoretical success ratewas 48% after six treated cycles. These rates are quitesimilar to those shown in Table 1 and Figure 1 above.Although fewer than in the past, clinical investiga-tions of the use of frozen semen continue to bepublished. For example, Byrd et al. (34) compared theuse of two media for semen preservation and thenperformed IUI of 304 patient cycles. The likelihood ofpregnancy with the standard bicarbonate-bufferedsolution was 9.8% for 164 cycles, whereas it was 17.5%when HEPES-buffered solution was used in thetreatment of 160 cycles. In a recent study, Matilsky etal. (35) compared the use of two-day treatments forIUI with cryopreserved semen with those of one-daytreatments. Of 180 one-day cycles, the pregnancy rateper cycle was 5.0%, whereas with 222 two-day cycles,the pregnancy rate per cycle was 17.9%. Comparisonof these results with those shown above in Table 1and Figure1 reveal that the overall efficacy ofcryopreserved semen for AI can be significantlyinfluenced not only by methods used to freeze thesemen itself, but also by various clinical variables. Therole of such clinical variables in treating humaninfertility with cryopreserved semen have recentlybeen reviewed by Oehninger et al. (36).
Sperm cryopreservation as an adjunct toassisted reproduction
When weighing the current status of cryopreservationof spermatozoa, another important issue must also beconsidered. The ultimate function of a spermatozoonis to fertilize an oocyte. In the past, methods ofassisted reproduction achieved fertilization primarilyby AI. In 1978, in a landmark publication, Steptoe andEdwards (37) reported the birth of the first child
resulting from in vitro fertilization (IVF) of a humanoocyte. Since then, tens of thousands of children havebeen born as a result of IVF in its various forms andvariations (summarized, for example, in the textbookby Edwards and Brody (38)). Furthermore, humanspermatozoa collected from fertile donors have beenused for successful IVF of oocytes aspirated frominfertile patients (39). In this comparison of freshversus frozen semen, equivalent fertilization rates of>90% were achieved. Those same investigators alsofound that it was possible to use cryopreservedspermatozoa from subfertile men for IVF. For manyyears, it has been common practice in the cattleindustry to use cryopreserved spermatozoa for IVFof oocytes (40). Because so few motile spermatozoaare required to effect fertilization of multiple oocytesby IVF, this has become a routine procedure. In thecase of cryopreserved mouse spermatozoa used forIVF, it has been shown that, in principle, frozenspermatozoa from a single male mouse are sufficientto produce thousands of offspring (41).
Several years ago, Palermo et al. (42) derived aninnovative method of assisted fertilization, referred toas intracytoplasmic sperm injection (ICSI), to treathuman male-factor infertility. Since then, ICSI, in whicha single spermatozoon is isolated from an ejaculate andinjected directly into an oocyte, has been widely usedas an adjunct to assisted reproduction in the human(43,44). The same procedure has been used to a lesserextent in domestic species (45). Remarkably, whenICSI has been used with animals, live calves have evenbeen produced by injection of deliberately killedspermatozoa into bovine oocytes (46) . Recently,Wakayama et al. (47) also produced live mice by ICSIwith spermatozoa killed by freezing. Although theselatter observations might suggest that ICSI with deadspermatozoa obviates the necessity of improvingmethods to cryopreserve spermatozoa, there willcontinue to be a very important role for frozenspermatozoa to be used for AI and conventionalmethods of IVF.
The procedure of ICSI is so efficient that it hasbecome the treatment of choice to alleviate male factorinfertility. Full-term human pregnancies have beenproduced by ICSI of spermatozoa aspirated directlyfrom the epididymis (48), and also by ICSI with frozen-thawed epididymal spermatozoa (49). It has even beenpossible to produce pregnancies and human births bythe transfer of embryos produced by ICSI withspermatids (immature spermatozoa) (50) . Anotherpractical and imaginative approach to ICSI has been
156 STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
described by Cohen et al. (51) who froze single or smallnumbers of human spermatozoa deliberately injectedinto empty zonae pellucidae obtained from human,mice or hamster oocytes. The spermatozoa that werefrozen within the zonae to improve the efficiency oftheir recovery were used to fertilize oocytes success-fully. This same method has also been used tocryopreserve small numbers of testicular spermatozoato be used for fertilization by ICSI (52). In the pastfew years, numerous articles have been publisheddescribing various factors that influence the efficiencyof cryopreservation of human spermatozoa obtainedby microsurgical aspiration of the epididymides (53).Comparison of frozen-thawed spermatozoa collectedeither by ejaculation or by epididymal aspirationshowed that a significantly higher rate of fertilizationwas achieved with ejaculated spermatozoa (54).Somewhat higher rates of pregnancy per transfer(27%) and of births (22%) were achieved withcryopreserved ejaculated spermatozoa compared tothose resulting from epididymal spermatozoa (18%and 12%, respectively). Nevertheless, the efficiencyis high enough to have clinical utility. A largeretrospective analysis has recently been made ofresults of ICSI in which fresh or frozen epididymalspermatozoa were used to fertilize totals of 1821 or1255 oocytes, respectively (55). The rates of fertili-zation and cleavage of injected oocytes were notsignificantly different between the two groups. Mostimportantly, rates of pregnancies and births wereapproximately the same: the percentage delivery percycle with fresh spermatozoa was 17.9%, comparedto 20.5% with frozen spermatozoa. A variation on thissame approach has been described in which smallpieces of testicular tissue have been obtained by anopen biopsy procedure and frozen for later use in ICSI(56). Spermatozoa have been isolated from thawedtissue, injected into oocytes, with resultant births of29 children.
The variables of sperm cryopreservation
Hundreds of millions of cattle and hundreds ofthousands of children have been born as a result ofAI of females with frozen-thawed spermatozoa(12,15,57,58). Measured in those terms, the procedureof sperm cryopreservation seems extremely success-ful. However, that is only partially correct. On average,of all human and cattle spermatozoa, the two speciesfor which the most comprehensive data have been
collected, 50% of sperm cells are damaged or destroyedby freezing and thawing, limiting the overall efficiencyand efficacy of semen preservation (13,15,59) . Formost other species, usually fewer than 50% ofspermatozoa survive cryopreservation (60). Whatmakes sperm freezing even less efficient is the fact that,within a species, spermatozoa from different malesexhibit widely variable responses to the same freezingconditions. Such differences among males of freezingsensitivity of their sperm are widespread amongvarious species and have profound practical andfundamental implications. Examples of male-to-maledifferences have been described for spermatozoa ofdogs (61), horses (60), cattle (62,63), and rhesusmonkeys (64). The results are usually presented aspost-thaw motility or recovery relative to prefreezevalues for individual males of each species.
Analogous and significant male-to-male differencesin sperm sensitivity to cryopreservation amonghumans have been reported by Glaub et al. (65),Cohen et al. (66), Taylor et al. (67), Centola et al. (68),Kramer et al . (69); and Morris et al . (70) . Asmentioned above, significant differences in theresponse of spermatozoa from different men were firstnoted by Shettles (4), and also by Steinberger andSmith (26) . Analysis of prefreeze and post-thawmotility of spermatozoa from 315 men showed that thecoefficients of variance for repeated ejaculates frommultiple individuals was much larger than the variancefor multiple ejaculates of the same male (71).
A detailed comparison has been made of themotility characteristics of ejaculated spermatozoa fromseveral individuals before and after cryopreservation(72); the results of this study are presented in Figure2. In general, freezing caused a decrease in thepercentage of progressively motile spermatozoa fromall men. However, as can be seen from the results inthis figure, the extent of the decrease varied widelyamong donors. With only one exception, the coeffi-cients of variation for a given man were smaller thanthe coefficients of variation among the six men. Thus,these results show that the response of spermatozoawas consistent among different ejaculates from thesame individual, but that spermatozoa from differentmen responded differently. An important practicalconsequence of such differences in sperm freezingsensitivity may occur in the treatment of cancer. Formany human males facing the prospect of chemo-therapy or radiation therapy, the option of having theirsemen frozen for future use may be precluded if theyhappen to produce freezing-sensitive spermatozoa. In
Cryopreservation of human spermatozoa 157
short, sperm cryopreservation is an integral andessential procedure used routinely in animal andhuman reproduction. Yet, for no species, including thehuman, does a single freezing procedure workeffectively for spermatozoa of all males of that species.
The process of sperm freezing
That there are such significant male-to-male differ-ences in freezing sensitivity seems difficult tounderstand. Cryopreservation of spermatozoa byequilibrium cooling usually consists of the followingsteps: (i) cells in suspension are placed in a solutionof a cryoprotective agent (CPA); (ii) the cells are cooledto temperatures near 0ºC; (iii) they are then cooled tosubzero temperatures at a moderately low rate ofabout 5–10ºC/min to an intermediate subzerotemperature (about –75°C for spermatozoa) and thenplunged into liquid nitrogen at –196°C for storage; (iv)to restore their function, cryopreserved cells arewarmed and thawed and the CPA removed. Any oneor all of these steps may damage cells during the entiresequence of cryopreservation. Spermatozoa, inparticular, are especially sensitive to these fluctua-tions of temperature and of osmolalities of solutionsbecause of the delicate nature of the acrosome, thefunction of which is to disassemble during fusion ofthe spermatozoon with the oocyte. Nevertheless, itseems reasonable to assume that all cells of a giventype ought to respond similarly to the same conditionsof freezing and thawing. One might theorize that the
same procedure should be reliable and reproduciblefor spermatozoa of all males of a given species. Thatclearly is not the case.
To understand the responses of spermatozoa tocryopreservation, it is useful to briefly consider thebasic aspects of cell cryobiology, especially as theyapply to spermatozoa. These have been reviewed bymany authors (12,15,58,60,73). There have beeninnumerable studies of the very many factors thatinfluence the survival of human spermatozoa whenthey are frozen and thawed. An early exhaustiveanalysis was that of Freund and Wiederman (74) whofound that rates of dilution with cryoprotectivesolutions and of cooling from 25ºC to 5ºC beforesemen samples were frozen affected the ultimatemotility after thawing. Other notable studies ofcryopreserved human spermatozoa in which effectsof CPA concentrations, methods of freezing, presenceor absence of seminal plasma, suspending media,thawing rates, effect of hyaluronate in the freezingsolution, and post-thaw dilution methods are thoseof Serafini and Marrs (75), Critser et al. (76), Hammittet al. (77)), Centola et al. (68), Verheyen et al. (78),and Sbracia et al. (79).
When cells suspended in an aqueous solution arefrozen, the following concomitant physical andchemical changes occur: (i) the temperature isdecreased; (ii) ice forms so that liquid water is removedin the form of crystals; and (iii) dissolved solutesbecome more concentrated. Depending on the initialcomposition of the solution (electrolytes andnonelectrolytes, its pH, and macromolecular supple-ments), when the temperature decreases sufficiently,some of the dissolved solutes become so concentra-ted that they begin to crystallize or solidify. Thesechanges in solution osmolality cause the cells insuspension to respond osmotically. The capability ofa given type of cell to respond osmotically toincreasing solution osmolality at decreasing tempera-tures reflects the cell’s hydraulic conductivity (Lp: itspermeability to water) and the activation energy of thatpermeability (E a: the effect of temperature on waterpermeability). Decreasing temperature decreases therate at which cells can lose water.
Almost 40 years ago, a mathematical model wasderived by Mazur (80) which predicted the responseof cells as they were frozen. This model incorporatesthe various parameters described above; it predictsthat a cell’s Lp and Ea are the principal characteristicsthat determine the cooling rate at which a cell must becooled to remain in osmotic equilibrium with increas-
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158 STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
ing solute concentration resulting from increased iceformation at lower subzero temperatures. As aconsequence of these factors, one of the mostimportant variables of cell cryopreservation is the rateat which it is cooled to low subzero temperatures. Ithas been demonstrated, with spermatozoa fromseveral species, that sperm motility and other basiccharacteristics vary significantly with cooling rate andwarming rate [pig (81) , sheep (82) , cattle (83),summarized for other species by Leibo and Bradley(58)].
Examples of the important influence of cooling rateon survival of human spermatozoa are shown in Figure3, in which data of Henry et al. (84) are presented.Figure 3 shows that the post-thaw motility of humanspermatozoa frozen in 0.85 M glycerol varies signifi-cantly as a function of cooling rate and also ofwarming rate. As is true for other types of cells,survival is low at low cooling rates, increases to amaximum at the optimum rate, and then decreases withfurther increases in cooling rate.
The generally accepted interpretation of suchinverted V-shaped survival curves is that high coolingrates damage cells by intracellular ice formation. Rapidcooling means that cells have insufficient time todehydrate during cooling. Thus, they freeze intra-cellularly; intracellular ice damages the cells bydisrupting their intracellular architecture. What is lessclear is the mechanism responsible for damage at lowcooling rates. The usual explanation is that slowcooling damages cells by exposing them for extendedtimes during cooling to solutions the properties ofwhich have been altered by ice formation. This effect
is referred to as the “solution-effect” injury.But the data in Figure 3 illustrate one contradiction
of that explanation. Consider spermatozoa cooled at0.1ºC/min. These would have been exposed to alteredsolutions for several minutes during the initialcooling. If warmed rapidly, about 5% survive. But ifwarmed slowly, 18% survive, despite the fact that slowwarming would have increased the cells’ exposure toaltered solutions as they melted. This suggests thatthe usual explanation of solution-effect injury isinadequate to explain damage caused to spermatozoaby slow freezing.
Predicting freezing sensitivity
Do male-to-male differences in sperm freezingsensitivity reflect properties of membranes? Are theseproperties genetically determined? Several lines ofevidence suggest that characteristics of spermmembranes are genetically determined. For example,it was recently reported that spermatozoa from onehybrid and two inbred strains of mice differ both interms of sensitivity to osmotic shock and to freezing(85). Fresh spermatozoa from B6D2F1, 129/J andC57BL6J mice fertilize oocytes with the same effici-ency. However, after their spermatozoa are exposedto and diluted out of a CPA solution, or especially afterbeing frozen, there are significant differences amongthe three strains in the viability and fertilizing abilityof their spermatozoa. Nakagata and Takeshima (86)had previously reported analogous differences insperm freezing sensitivity among eight inbred strainsof mice. Sperm membranes may also be influenced bydifferences among males in their hormonal status andby the season of the year. If the answers to thequestions posed above are positive, this will suggestthat factors that influence freezing sensitivity ofspermatozoa from species other than mice, e.g. cattleor humans, may also be genetically determined.Several observations regarding differences inpermeability and hormones provide clues as topossible explanations of variable responses ofspermatozoa from different individuals to the sameprocedure.
Permeability differences
Cells of a given type collected from differentindividuals may have different membrane characteris-tics. For example, oocytes from different females ofoutbred ICR mice exhibit significant differences in
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40
Post
-Tha
wM
otili
ty(%
)
. 1
Slow Warm Rapid Warm
Figure 3. The post-thaw motility of frozen human spermatozoaafter being cooled at each of five rates and then warmed eitherslowly or rapidly. The data are those of Henry et al. (84) and usedwith permission of the copyright owners and the authors.
Cryopreservation of human spermatozoa 159
their water permeability characteristics (87). Incontrast, oocytes from different females of an F1hybrid strain consisting of genetically homogeneousmice (heterozygous only for the gene pairs by whichthe parent strains differ) do not show such differencesin the same permeability properties (88). Very recently,Phelps et al. (89) reported that permeability coeffici-ents of spermatozoa from outbred ICR mice differsignificantly from those of a hybrid strain (B6C3F1).Together, these data suggest that membranes of thesame cell type collected from different individuals ofa genetically heterogeneous species, e.g. outbredmice or humans or cattle, may have significantlydifferent properties. These latter observations byPhelps et al. could explain the observations describedabove of Songsasen and Leibo (85) and of Nakagataand Takeshima (86) that spermatozoa from differentstrains of inbred mice have different freezingsensitivities.
Therefore, it seems reasonable to hypothesize thatdifferent human males, or in fact different males of allmammalian species, may produce spermatozoa ofwhich the membranes may differ very significantly. Byanalogy, different males may have significantlydifferent levels of serum cholesterol, yet still becompletely healthy. If the membranes of spermatozoafrom different individuals differ, then permeabilitycharacteristics of their spermatozoa may also differ.In turn, such differences may be exhibited assignificant differences in chilling and/or freezingsensitivity of the spermatozoa. Support for thisconcept is found in recent observations of Giraud etal. (90) who measured the fluorescence anisotropyof spermatozoa from 20 men before and aftercryopreservation to determine the fluidity of spermmembranes. Anisotropy refers to the rotational motionof the membrane probe distributed throughout thehydrophobic core of the lipid bilayer of the cellmembrane. These authors found that fluorescenceanisotropy varied significantly among different men,and that sperm membranes of all 20 individuals wererendered less fluid by the entire process of cryopreser-vation. Recently, measurements of lipid dynamics inthe plasma membrane of human spermatozoa showedthat lipid diffusion in the acrosome and midpiece ofspermatozoa was reduced after cryopreservationcompared to that of fresh cells (91). Together, all ofthese observations suggest that a key to understand-ing variable responses of spermatozoa to freezing maybe found in further studies of sperm membranes,especially comparisons among different men.
Part of the explanation of these differences amongmales may be found in the composition of spermmembranes. The lipid composition of sperm membranesis unusual (92). They possess the same types of lipidsas other cell membranes (phospholipids, glycolipidsand sterols) but sperm membranes differ in the relativeproportions of these molecular species (93). Inparticular, a characteristic feature of sperm membranesis the extremely high proportion of ether-linked fattyacids instead of the more usual ester links. Many ofthe phospholipids contain a docosahexaenoic acid(DHA) side chain, which may result in increasedmembrane fluidity. This fatty acid has been identifiedas being specifically localized in the head membraneof rhesus spermatozoa (94). The potential instabilityresulting from DHA is thought to be counteracted bythe presence of sterols like cholesterol. Sperm plasmamembrane lipids exist in two phases, fluid and gel. Atphysiological temperatures, the two forms coexist butas the temperature is lowered, a phase transitionoccurs in favour of the gel form (92). As mentioned,this leads to a reduction in the fluidity of the membrane,which has been associated with lower sperm survivalduring cryopreservation (90).
During the past few years, several groups havebeen investigating permeability characteristics ofspermatozoa of various species so as to explain andto improve their survival after cryopreservation.Several of these studies have been summarized by Gaoet al. (15) and by Watson (13). Notable among theseare determinations of permeability of human spermato-zoa to CPAs and to water (95–97). These studies haveled to the derivation of methods to add and removeCPAs from human spermatozoa while preserving highsurvival of their motility and membrane integrity. Inmany respects, these very recent observations confirmearly studies by Richardson and Sadleir (98), andMahadevan and Trounson (32).
Hormone differences
Laboratory-housed macaque monkeys exhibit diurnalvariations in their plasma levels of testosterone (99),and males of different ages also have significantlydifferent concentrations of androgens (100). Further-more, androgen concentrations in rhesus males, eventhose maintained in a controlled laboratory environ-ment, vary significantly as a function of season as wellas among each other. Others have reported similarseasonal changes in plasma levels of varioushormones (e.g. testosterone, ACTH) in laboratory-
160 STANLEY P. LEIBO, HELEN M. PICTON, ROGER G. GOSDEN
housed monkeys (64,101–105) . Since hormonesaffect the structure of the cellular cytoskeleton, suchas the distribution and domains of intermediatefilament proteins in spermatozoa (106–108), endo-crinological differences among individuals mayinfluence susceptibility of their spermatozoa tochilling injury. Recently, seasonal and male-to-maledifferences in the concentration of the phospholipid,platelet-activating factor, have been found inspermatozoa of squirrel monkeys (109). It seemspossible that analogous differences in hormone levelsmay exist within and among human males.
Other factors influencing sperm banking
Genetic consequences
One important yet frequently overlooked question iswhether the entire process of cryopreservation mighthave genetic consequences. The literature issomewhat in disagreement on this point, in that somehave concluded that defective spermatozoa areeliminated by cryopreservation, because there seemedto be fewer spontaneous abortions and birth defectsafter inseminations with frozen semen (110) . Incontrast, an increased frequency of trisomic birthsafter AI with frozen semen has also been reported(111). A more recent analysis of 1960 sperm karyo-types has been conducted by a method that permitsdirect visualization of human sperm chromosomesafter heterologous fertilization of hamster oocytes.This analysis showed that there were no significantdifferences in the frequency of structural chromo-somal anomalies before or after sperm freezing, andthere was no evidence of an altered sex ratio causedby cryopreservation (112).
Possible cross-contamination during long-term storage of frozen semen specimens
It has now been firmly established that cryopreservedspecimens of animal spermatozoa, as well as embryos,can be stored for decades with no loss of function(113,114) . A recent practical study demonstrated thatplastic straws commonly used for freezing semenspecimens may leak their contents if the straws arenot sealed properly (115) . Because frozen specimensmay be stored for extended times, and because virusesand other microbes survive freezing in liquid nitrogenfor many decades, special attention must be paid to
avoid the possible transmission of infectious agentsduring extended storage. Some concern has beenexpressed about this potential for cross-contami-nation of samples with viruses, such as HIV andhepatitis B (116,117). A transparent straw fabricatedof an ionomeric resin that is designed to be heat-sealed, and does not crack or become brittle at lowsubzero temperatures is now available commercially.Use of this straw ought to reduce possible cross-contamination, although it does not lessen the needfor vigilance and careful attention to methods usedduring the processing and handling of human semenspecimens. An alternative that is being implementedin some sperm and embryo banks is to store cryo-preserved specimens in the vapour phase aboveboiling liquid nitrogen at about –180ºC. This willprevent cross-contamination between samples withinliquid nitrogen. However, this places the specimensin a somewhat more precarious situation, in that theymay be subjected to unintended and inadvertentwarming to temperatures above –130ºC, the glasstransition temperature of ice. Incipient damage to thecryopreserved cells caused by recrystallization mayresult, but it may not become evident until months oryears later when the sample is thawed. The problemis that such slight damage is cumulative; each incidentof warming above –130ºC will contribute to decreas-ing functional survival of cryopreserved cells.
Long-term stability of frozen specimens
Once it had been established that frozen semenretained its functional ability to fertilize oocytes, it wasthen of interest to determine the length of time thatspermatozoa could be safely stored. As mentionedabove, some of the first publications on clinical trialsspecifically noted the length of time that specimenshad been stored. There have been reports that frozenhuman semen decays with length of storage. Forexample, Freund and Wiederman (74) found that whensemen was stored at –76ºC to –85ºC, there was asignificant loss of sperm motility after 14–15 monthsand even more after 22–23 months. More surprisingly,Smith and Steinberger (118) reported that frozenhuman semen was stable for three years of storage,but not for longer times. Recently, two investigationshave demonstrated that animal gametes are functionaleven after several decades of storage in liquidnitrogen. For example, frozen bull spermatozoa thathad been stored for 37 years in liquid nitrogen werecapable of fertilizing oocytes that subsequently
Cryopreservation of human spermatozoa 161
developed into blastocysts (113). Cryopreserved ramsemen stored for 25 years was capable of inducingfull-term pregnancies in ewes (114) . Although thereare profound ethical and legal issues that arise fromthis possibility, at a biological level, there seems tobe no practical limit to the length of time that spermato-zoa remain “alive” in liquid nitrogen.
Conclusions
Cryopreserved semen was used to produce the firsthuman pregnancies almost 50 years ago. Tens ofthousands of children have been born as a result ofthis rather simple procedure of assisted reproduction.Despite this unequivocal evidence of success, theprocedure of human sperm freezing can hardly beconsidered optimum, and the fundamental mechanismsresponsible for damage to spermatozoa resulting fromexposure to CPAs, or from chilling, or from freezingitself remain unknown. It is not known why spermato-zoa from different men respond differently to the samefreezing procedure, so that semen specimens of somemen exhibit high survival of sperm function, whereasspecimens of others exhibit little or no survival.Regardless of functional survival, it is not known whyabout half of the sperm cells in ejaculates of most menare damaged or destroyed by freezing. Anotherextremely important aspect of sperm cryopreservationthat will continue to be investigated is the capabilityto screen sperm donors for hereditary, as well asinfectious, diseases (119) .
Nevertheless, at a practical level, the advent ofICSI and other methods of assisted fertilization haveeliminated many of the limitations of current proce-dures of sperm cryopreservation. The ability tocryopreserve individual spermatozoa, or evenspermatids, or testicular tissue, coupled withinnovative ways to use such germ cells to fertilizeoocytes has revolutionized the treatment of humaninfertility. It requires little foresight to predict that other,equally imaginative approaches to medically assistedreproduction will be derived in the future.
Among such approaches will almost certainly bethe application and use of spermatozoa retrievedeither after death or from patients in a persistentvegetative state. Live animals have been produced byIVF with spermatozoa recovered post mortem within24 hours (120) and up to 7 days (121). There havebeen reports of such unusual approaches to humanreproduction, and the ethics of such procedures have
been discussed (122,123) . Another innovativeapproach to sperm preservation is that of freeze-drying. This method is currently being investigatedwith mouse spermatozoa, and preliminary resultsindicate that live young can be produced by ICSI ofmouse oocytes with freeze-dried spermatozoa. Ifsuccessful, this method will have profound implica-tions both at a fundamental level, as well as at apractical one.
Finally, there is yet another rather recent innova-tion in assisted reproduction with which spermcryopreservation will play an increasingly importantrole. This procedure separates X- and Y-bearingspermatozoa, so that fertilization of oocytes can beperformed to yield either female or male offspring,respectively (124). The procedure has been usedsuccessfully with spermatozoa of several animalspecies, especially of domestic species, and has alsobeen applied to human spermatozoa (125,126). Oneimportant benefit of this method is that it offers thepossibility to prevent the conception of children whowill be born with or will develop sex-linked diseases.Efficient use of this procedure requires that “sexed”semen be cryopreserved. Altogether, it seems clearthat there will continue to be the necessity to studysperm cryobiology, so as to improve cryopreservationof human spermatozoa.
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106. Virtanen I et al. Distinct cytoskeletal domains revealedin sperm cells. Journal of Cell Biology and Toxicology,1984, 99:1083–1091.
107. Ochs D, Wolf DP, Ochs RL. Intermediate filamentproteins in human sperm heads. Experimental CellResearch, 1986, 167:495–504.
108. Marinova TT et al. Distribution of vimentin inabnormal human spermatozoa. Andrologia, 1996, 28:287–289.
109. Roudebush WE, Mathur RS. Presence of platelet-activating factor in squirrel monkey (Saimiriboliviensis) spermatozoa: seasonal differences.American Journal of Primatology, 1998, 45 :301–305.
110. Sanger WG, Schwartz MB, Housel G. The use of frozen-thawed semen for therapeutic insemination (donor).International Journal of Fertility, 1979, 24:267–269.
111. Federation CECOS, Mattei JF, Lemarec B. Geneticaspects of artificial insemination by donor (AID):indications, surveillance, and results. Clinical Genetics,1983, 23:132–138.
112. Martin RH et al. Effect of cryopreservation on thefrequency of chromosomal abnormalities and sex ratioin human sperm. Molecular Reproduction andDevelopment, 1991, 30:159–163.
113. Leibo SP, Semple ME, Kroetsch TG. In vitrofertilization of oocytes by 37-year-old cryopreserved
bovine spermatozoa. Theriogenology, 1994, 42:1257–1262.
114. Fogarty NM et al. The viability of transferred sheepembryos after long-term cryopreservation. Reproduc-tion, Fertility and Development, 2000, 12:31–37.
115. Russell P et al. The potential transmission of infectiousagents by semen packaging during storage for artificialinsemination. Animal Reproduction Science , 1997,47:337–342.
116. British Andrology Society. British Andrology Societyguidelines for the screening of semen donors for donorinsemination Human Reproduction, 1999, 14:1823–1826.
117. Clarke GN. Sperm cryopreservation: is there asignificant risk of cross-contamination? HumanReproduction, 1999, 14:2941–2943.
118. Smith KD, Steinberger E. Survival of spermatozoa ina human sperm bank. Effects of long-term storage inliquid nitrogen. Journal of the American MedicalAssociation , 1973, 223:774–777.
119. Bick D et al . Screening semen donors for hereditarydiseases. The Fairfax cryobank experience. Journal ofReproductive Medicine , 1998, 43:423–428.
120. Songsasen N, Tong J, Leibo SP. Birth of live micederived by in vitro fertilization with spermatozoaretrieved up to 24 hours after death. Journal ofExperimental Zoology, 1998, 280:189–196.
121. An TZ et al. Viable spermatozoa can be recovered fromrefrigerated mice up to 7 days after death. Cryobiology,1999, 38:27–34.
122. Rothman CM. Live sperm, dead bodies. Andrologia,1999, 20:456–457.
123. Strong C, Gingrich JR, Kutteh WH. Ethics ofpostmortem sperm retrieval. Human Reproduction,2000, 15:739–745.
124. Gledhill BL. Selection and separation of X- and Y-chromosome-bearing mammalian sperm. GameteResearch, 1988, 20:377–395.
125. Fugger EF et al. Births of normal daughters afterMicroSort sperm separation and intrauterine insemina-tion, in-vitro fertilization, or intracytoplasmic sperminjection. Human Reproduction, 1998, 13:2367–2370.
126. Vidal F et al. Efficiency of MicroSort flow cytometryfor producing sperm populations enriched in X- or Y-chromosome haplotypes: a blind trial assessed by doubleand triple colour fluorescent in-situ hybridization.Human Reproduction , 1998, 13:308–312.
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Gamete and embryo donation
CLAUDIA BORRERO
Gamete source, manipulation and disposition
Introduction
The ready availability of donor sperm and the ease ofartificial insemination have long enabled couples withrefractory male infertility to achieve successfulpregnancy. The development of in vitro fertilization(IVF) and related techniques has made oocyte andembryo donation another option for infertile couples.
Oocyte, spermatozoa and embryo donation areethically and legally accepted forms of assistedconception in many countries. These treatments arealso associated with the highest pregnancy and livebirth rates after IVF (1–5).
Sperm donation
Donor sperm have been used in the treatment of maleinfertility for more than one hundred years. It isrecognized that pregnancy rates using frozen semenare lower than those with fresh semen (6) but, becauseof the risk of acquired immunodeficiency syndrome(AIDS), the use of frozen sperm that has beenquarantined for six months is now accepted clinicalpractice.
Donors
Complete medical, social, sexual, family and genetic
histories must be taken at the time of the initialinterview and donors must have a physical examina-tion. Donors over the age of 40 years may be acceptedbut only with the agreement of the recipient’sphysician and the couple.
Prior to cryopreservation and post-thaw cryo-sensitivity testing, two semen analyses must beperformed using criteria established by the semenbank. Semen samples should be examined beforeproceeding with the evaluation of potential donors.The World Health Organization (7) suggests thefollowing for normal semen analysis values:
• Volume >2 ml
• Sperm concentration 20 million/ml or more
• Sperm motility >50% or more with forwardprogression, or 25% or morewith rapid progression within60 minutes of ejaculation
• Sperm morphology 15% or more normal forms
• White blood cells fewer than 1 million/ml
• Sperm mixed antiglobulin fewer than 10% spermatozoareaction (MAR) test with adherent particles
Kruger and co-workers have reported that spermmorphology is the best prognostic indicator forsubsequent successful fertilization with IVF (8). Manyclinics have adopted strict criteria for the assessment
Gamete and embryo donation 167
of sperm motility after thawing, which should begreater than 50% of the prethaw value (9).
The health and fertility of the donor must beunimpeachable, and there should be no family historyof genetic disease. Screening for thalassaemia inMediterranean races, Tay–Sachs heterozygosity indonors of Jewish origin, and sickle cell disease indonors of African origin should be performed.Potential donors who are at high risk for AIDS (malehomosexuals, bisexuals and intravenous drug users)should be excluded as well as individuals who havemultiple sexual partners. Similarly, those individualswith history of herpes, chronic hepatitis and venerealwarts should be excluded. There is no absolute methodof completely ensuring couples that infectious agentswill not be transmitted by donor insemination, butadequate screening should make that possibilityremote. Testing should be performed when the donoris first seen and at repeat donations for
• human immunodeficiency virus (HIV)• syphilis (RPR/TPHA): there is no need to repeat it
unless clinically indicated• hepatitis B and C antigens: and repeated six
monthly• hepatitis B antibodies• gonorrhoea: semen or urethral cultures where
indicated from the potential donor’s history• Chlamydia trachomatis• cytomegalovirus IgG and IgM: every 6 months.
Before the sample is released, donors should beretested. Only IgG-positive tests may be accepted.
Clinics must only use frozen semen that has beenquarantined until the donor has been retested for HIVafter six months and found to be seronegative; thenthe specimen can be released. Procedures for theprecise identification of all semen samples must beestablished to allow appropriate tracking (10).
Genetic screening is recommended for all potentialdonors. Furthermore, couples should be aware of thefact that in 4%–5% of pregnancies following donorinsemination, the child could be born with a congenitalanomaly but that this risk is comparable to rates seenin spontaneous pregnancies (11) .
In a sense, a woman chooses her own donor bychoosing her partner (12). Most women want a donorto resemble their partner as closely as possible. Theresemblance is generally restricted to hair and eyecolour, ethnic origin, height and blood type. Often, thereason behind this wish for resemblance is secrecy.
Considerable debate continues on the type ofgamete donors to be recruited and payment of fees orexpenses (13–17) . Traditionally, men donating spermhave been paid a nominal fee including reimbursementfor their direct and indirect expenses. Several studiesof sperm donors have shown clearly that the majorityof men who donate sperm are young single studentswho are motivated predominantly by payment (18–20) . In the UK, the Human Fertilisation and Embryol-ogy Authority has suggested that payment can begiven (14–21). Following examination of variousaspects of payment for donors, the Authority agreedthat donation should be something entered into freelyand voluntary and it was felt that any risk that thedecision to donate might be influenced by financialinducement was not desirable (14). This issue hasbeen widely debated (16,22,23). In the USA, men havealways been paid to provide gametes. It has beensuggested that donors should be paid inconvenienceallowances similar to payment made to healthvolunteers who take part in drug and treatment trials(23). The largest group from which sperm donors arerecruited in the USA are students. Lyall et al. (15)undertook a survey designed to solicit opinion onwhether sperm donors should be paid. They surveyed717 individuals in three groups: the general public,students (potential donors) and infertility patients(potential recipients). The majority of the potentialdonor group was in favour of paying sperm donors,as were infertile patients. In contrast, the general publicwas not. Although not in favour of paying spermdonors, the general public overwhelmingly approvedof the use of donated spermatozoa for the treatmentof infertile couples. If such payments are withdrawn,there is a possibility that the availability of donorsperm may decline. This raises an interesting questionfrom an ethical and social perspective: should spermdonors be paid?
Limiting donors
There is concern about limiting the use of donors soas to reduce the risk of consanguinity between theoffspring of recipients of the same donor. This is aproblem in small communities in which a very limitedsupply of donors is available. It is far less likely wherethere are large commercial sperm banks. It has beensuggested that in a population of 800 000, limiting asingle donor to no more than 25 pregnancies wouldavoid inadvertent consanguineous conception (9).However, only 20%–30% of the pregnancies produced
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through commercial donations are ever reported to thesperm banks (24).
Protocols
The accurate prediction of the time of ovulation iscritical to success in a donor insemination programme.Most ovulation prediction techniques are indirect forreasons of logistics, cost, and patient or programmeconvenience. Ovulation in the natural cycle can bemonitored by several means. Progressive folliculargrowth and ovulation can be assessed ultrasono-graphically. The luteinizing hormone (LH) surge isdetected via rapid radioimmunoassay of the urine orserum, as well as by a monoclonal antibody urinarytest. The latter technique has gained widespreadacceptance because of its reliability, availability, lowcost and patient convenience. Less precise methodsof timing of insemination in the natural cycle includereliance on basal body temperature or cervical mucuschanges.
Intrauterine insemination (IUI) has shown clearadvantages over vaginal or intracervical insemination(25–27). Since the fertilizable life span of the ovum isestimated to be only 12–24 hours, the timing of theinsemination procedure may critically influencesuccess rates. There is controversy as to the optimalnumber of inseminations per cycle. The majority ofpublished series have documented the efficacy of oneinsemination performed on the day after the LH surge(25,28,29). Nevertheless, Centola et al. (30), in aprospective trial, reported a fertility rate of 21% withtwo inseminations per cycle compared to only 6%when one insemination was performed. Theprocedures were performed on the day after thepositive test (one insemination) or on the day of theLH surge and the following day (two inseminations).
The routine use of clomiphene citrate or any otherovulation-inducing agent in conjunction with IUIshould be reserved only for women who havedocumented anovulation.
The success rate of donor insemination can bemeasured by both cycle fertility (pregnancy rate percycle) and cumulative conception rates (number ofpregnancies per insemination cycle). It has beensuggested that the fertility rate using frozen,compared to fresh, semen will ultimately be almost thesame, although the number of cycles required forconception with frozen specimens will be substantiallygreater (50% success rate within six months for frozensemen versus three months for fresh semen) (31,32).
Total cumulative success rates of 70%–80% have beenobserved with twelve months of insemination withfrozen sperm. A study of 21 597 pregnancies obtainedafter artificial insemination with donor semen wascarried out in France, from 1987 to 1994 (33). It wasconcluded that, after donor insemination, the sponta-neous abortion and tubal pregnancy rates, the birthweight and the prematurity rate were not different fromthat of the general population.
The presence of coexisting factors interfering withfemale fertility should be ruled out, such as endo-metriosis, tubal disease, and ovulatory disturbances.Fertility also decreases with age (34,35). Thisconsideration is an important part of the counsellingprocess for all women considering donor insemination.
Record management
The nearly universal practice of physicians usingdonor insemination has been to keep confidential theidentity of both donors and recipients. Records,including those pertaining to donor suitability, qualityassurance, and collection, processing, storage,medical and laboratory data, must be retained for atleast ten years after insemination (10). This allows fordonors and recipients to be tracked in the event of amedical problem in the donor or donor’s family beingdiscovered.
Psychological and social implications
Perhaps the most common question asked of thepractitioner is whether the couple should inform thechild of the donor insemination. It is prudent to advisethe couple to explore their own feelings thoroughlyand to arrive at a conclusion with which they will becomfortable. Counselling with a psychologist may behelpful in this regard. It may also prove to be helpfulin addressing many issues that are not immediatelyapparent to couples considering donor inseminationsuch as disclosure and secrecy of the donor’s identity.
Oocyte donation
Successful oocyte donation as a treatment forinfertility was first reported 17 years ago (36). Thepractice of oocyte donation differs greatly from centreto centre and from country to country. In thisprocedure, the donor undergoes superovulation, aswith conventional IVF. Oocyte retrieval is performed
Gamete and embryo donation 169
and the donor oocytes are inseminated in vitro withthe sperm of the partner of the recipient. The fertilizedova are either transferred to the hormonally synchro-nized recipient in the same cycle or cryopreserved fortransfer at a later date.
Oocyte donors
Oocyte donation involves two women: the donor andthe woman who wishes to be pregnant. In somefertility centres, recipient couples can choose betweentwo types of donation: a known donor, such as a sister,a relative or a friend, or anonymous donation by a paiddonor or infertile patient who volunteers to donate aproportion of their ova (“shared” egg donation).However, in other programmes, only anonymousdonation is offered to couples (37).
One of the major difficulties in establishing adonor oocyte programme is the limited availability ofdonor subjects. Although the number of potentialrecipients is continuously increasing, the shortage ofdonors is the limiting factor. Donor recruitment is adifficult endeavour, taking into account that aconsiderable number of potential donors may have acontraindication found on medical, genetic, orpsychological testing that prohibits donation.Furthermore, in some countries, recruitment of paiddonors is prohibited by law (38–40).
It has been recommended that anonymous donorsshould be less than 35 years of age. The drawback ofusing oocytes from older women is the increased riskof chromosomal abnormalities. Another potentialproblem is that older donors produce fewer oocytesthan younger women.
Ovum sharing raises several ethical and medicalconcerns. A “shared” ovum donation programme islimited by the number of ova available for donationand the oocyte quality, which depends largely on thedonor’s age and in the case of donation by an infertilewoman, her infertility etiology. Historically, shareddonation involved IVF patients willing to donate someof their oocytes to a recipient. In return, recipientspaid the cost of ova collection. However, others(41,42) believe that an ethical problem might arise incases where the recipient woman conceives and givebirth to a child, while the donor herself does notconceive. With the current low-dose protocols thatare now used for induction of ovulation, the ovum-sharing procedure with IVF patients does not providea sufficient number of extra oocytes for donation.Furthermore, IVF patients wish to maximize their
chances of pregnancy by using a significant numberof their own oocytes and by cryopreservation ofsupernumerary embryos for their own future use.
Most fertility centres do not allow donors to becompensated financially, except for a reasonablereimbursement of their expenses.
Extensive and careful psychological screening ofpotential donors is recommended (37,43,44). Further-more, donors need to understand the boundaries oftheir role and need to be fully capable and free fromany coercion in giving informed consent.
Screening of oocyte donors
Oocyte donors should have attained their legalmajority and preferably be between the ages of 21 and34 years. Proven fertility is desirable but not required.All prospective oocyte donors should be screened forgenetic and infectious diseases in order to minimizetransmission to the recipient or their offspring. Thehistory and physical evaluation should excludeinherited disorders, and the possibility of reproduc-tive dysfunction. The laboratory evaluation shouldinclude a blood count and blood type to identifypotential Rh incompatibility. The screen for infectiousdiseases should, at a minimum, includes
• HIV• syphilis (RPR/TPHA)• hepatitis B antigen• hepatitis B antibodies• hepatitis C• Chlamydia trachomatis
In selected cases, sickle-cell disease or thalassaemiashould be ruled out.
A number of controlled ovarian hyperstimulationprotocols have been developed; essentially all of theminclude administration of gonadotrophins (humanmenopausal gonadotrophin [hMG] or recombinantFSH) in conjunction with GnRH agonists. Usually, theGnRh agonist is administered as a daily dose,commencing in the midluteal phase of the donor’sprevious cycle. Ovarian suppression is usuallycompleted at the onset of menses, one week later. Abaseline ultrasonogram and estradiol level areobtained on the third day of the following cycle, toexclude ovarian cysts and to ensure that adequateovarian suppression has been obtained.
Gonadotrophin therapy is initiated and monitoredthroughout the cycle. Human chorionic gonado-
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trophin (hCG) is administered at a dose of 5000 or10 000 IU, once appropriate follicular and hormonalcriteria have been achieved. Ultrasound-guided,transvaginal oocyte recovery is performed withintravenous sedation and analgesia. After a pre-incubation interval of two to six hours, the donoroocyte is inseminated with the recipient’s partner’ssperm. The embryos that result are either cryo-preserved or transferred to the synchronized recipient48–72 hours after the retrieval.
It is important that both the recipient and thedonor should be adequately counselled and be awareof the psychological, legal and moral implications ofoocyte donation, before being accepted into theprogramme (40,41,45). The psychological evaluationis intended to uncover any risk factors that may rendera subject emotionally unsuitable for ovum donationand to ensure that there is no element of coercion inher decision to donate oocytes, particularly in the caseof known donors.
The nature of any risk of developing seriouscomplications following donation, whether they bepaid ovum sharers or volunteer donors, should be fullyexplained.
Recipients
Both the oocyte recipient and her partner should behealthy, and there should be no physical contraindica-tion to pregnancy. Information on donor oocytesuccess rates for the individual centre should be givento the couple.
Screening for infectious diseases in the patientand her partner generally include tests for HIV,hepatitis, Chlamydia trachomatis and syphilis. Themale partner should have a semen analysis with asperm wash and swim-up in order to rule out acoexisting male factor. Hysterosalpingography shouldbe performed (or previous films reviewed) to evaluateany uterine abnormalities.
Debate over limiting oocyte donation to youngerrecipients continues. Perhaps the most controversialapplication of oocyte donation has been its use incircumventing age-related infertility in patientsnearing or beyond the menopause. The number ofwomen between the ages of 35 and 50 years is steadilyincreasing. Also, many women are electing to delaychildbirth for personal, economic or professionalreasons. Fertility potential decreases with advancingmaternal age and it is expected that most older womenwill be unsuccessful in their effort to reproduce. The
introduction of oocyte donation to establish pregnancyin patients with age-related infertility has allowedmany older women a new opportunity of conceiving.However, there are concerns over the health of theolder mother and her fetus during pregnancy andworry as to whether older women have the stamina toraise a child to adulthood.
Protocols
By definition, ovarian and endometrial events aredissociated in donor oocyte IVF cycles. Effectivesynchronization of embryonic and endometrialdevelopment is therefore crucial to the success of anoocyte donation programme. In most fertility clinics,the recipients undergo one or more preparatory cyclesto measure endometrial response to exogenousestradiol and progesterone. Assessment of thepreparatory cycles include serum steroid levels,measurement of endometrial thickness with trans-vaginal ultrasound and an endometrial biopsy forhistological review (46).
Synchronization between the donor and recipientdepends on whether or not the recipient has intactovarian function. Although in a natural cycle (patientswith a normal ovarian function) frozen embryo transferis a straightforward procedure, fresh embryo transfer,on the other hand, is difficult to achieve and may notbe possible because of the problem of synchronizationof donor and recipient cycles. Recipients possessingendogenous ovarian function are usually treated withan exogenous hormonal regimen, after suppressionwith a GnRH agonist. A variety of steroid replacementregimens have been developed, all of which aredesigned to approximate the pattern of hormonesecretion occurring in the natural menstrual cycle.Estrogen may be administered orally or by transdermalpatches. Protocols have been developed employingestradiol valerate; micronized estradiol-17-b usingtransdermal patches (46–47). Endometrial prolifera-tion can be induced with fixed or increasing doses ofestrogens (48). This protocol has the advantages ofsimplicity and providing a larger window for implan-tation.
Progesterone replacement is initiated the daybefore or on the day of the donor’s oocyte retrievaland is usually given as an intramuscular injection ofprogesterone in an oil vehicle (48), vaginal supposi-tories (46) , micronized oral progesterone (49) or morerecently, via a vaginal ring drug-release system (50).
Pregnancy and live-birth rates following oocyte
Gamete and embryo donation 171
donation are excellent in comparison with thoseachieved after transfer of the patient’s own oocytes(3). The reported pregnancy rates per ovum recipientvary between 20% and 67% per embryo transfer (51–54).
The technique of oocyte and embryo donationmakes it possible for women to be gestational motherswell beyond the age of the normal reproductive lifespan. Thus, women in their forties, fifties or more maybecome mothers as a result of oocyte donation. Thisscenario raises the ethical question of the potentialhealth risk to the gestational mother of being pregnantbeyond the age where this would occur in nature. Therisk of pregnancy for women increases considerablywith increasing maternal age (55). Thorough medicalscreening is essential to minimize the obstetric risk inthe older group of patients. Maternal complicationsare also increased by multiple pregnancies (56);limiting the number of embryos to be transferred totwo could reduce this risk (3). These women shouldbe encouraged to seek preconceptual counselling andearly prenatal care, and should be counselledregarding potential obstetric complications.
Social implications
While biomedical advances in oocyte donation havepreoccupied most investigators, more recently,interest in the behavioural aspects of this procedurehas begun to be reflected in the literature. A numberof studies have examined the attitudes of oocytedonors and recipients (37,57–59). To obtaininformation concerning Latin American oocyterecipients’ thoughts and feelings about the donation,the Latin American Network of Assisted Reproduc-tion undertook a multicentre study (37). A follow-upquestionnaire was sent to 106 women who underwentoocyte donation between 1989 and 1997. Therecipients were asked about their age, education,marital status and their thoughts and feelings after thetreatment. In all, 81% of the recipients were Catholicsand 62% had higher education. Sixty per cent of thepatients who became pregnant and 64% of those whodid not achieve pregnancy stated that they would bewilling to repeat the treatment; 76% of the recipientsintended not to disclose the type of treatment,whereas 24% were undecided. Dominant reasons fornot disclosing were the fact that the child “is my child,no matter his/her origin”. Responders noted severalprimary concerns when asked to discuss the mostdifficult part of an oocyte donation cycle. One
recurrent early theme centred around the need togrieve the loss of the “dream child” that would neverbe born. Although only 37% of the recipients hadpsychological counselling, 67% of the women statedthe need for such support before and throughout thetreatment.
Embryo donation
Embryo donation is a well-established and successfulform of assisted conception treatment when bothpartners are infertile.
Embryo donors
The large majority of embryo donors are couples whohave completed their families through IVF and havehad the spare embryos cryopreserved. The age of thewoman at the time the oocyte was obtained for IVFshould be taken into account when considering theuse of donated embryos: they should be above theage of 18 and below 36 years.
The other source of donated embryos is by wayof separate oocyte and sperm donation.
Screening of embryo donors
The embryo donors must sign an informed consentdocument indicating their permission to use theirembryos for donation, relinquishing all rights to theembryo(s) and any child or children that may resultfrom the transfer of these embryos. They should bescreened for genetic and infectious diseases toprevent transmission of these to the recipient or theoffspring. If embryos have been created as part ofanother couples’ IVF treatment, the appropriaterecords should be reviewed in an anonymous andconfidential manner to assess previous laboratoryresults including tests for HIV and hepatitis B and Cantibodies. The recipient couple must be fully awareand informed about the results of these tests.
Screening of embryo recipients
Embryo recipients should be informed about thechances of pregnancy based on each programme’sexperience with the transfer of cryopreserved embryos.Recipient couples should also be made aware of thelimitations of genetic and infectious disease screeningand informed there can be no guarantee of a child
172 CLAUDIA BORRERO
being born free of birth defects or illness. Becauseembryo donation is a new procedure, all couplesshould be aware of the uncertainty about the long-term outcome from the psychological or developmentalstandpoint.
Couples who will receive embryo donation shouldbe fully evaluated, including medical history, physicalexamination and psychological counselling. Pelvicultrasound should be performed to assess uterine size,endometrial thickness and rule out pelvic pathologysuch as endometrial polyps, myomas or ovarian cysts.Other tests that may be required are
• HIV antibodies• hepatitis B and C antibodies• syphilis antibodies• blood typing• cervical cytology• rubella antibodies.
Protocols
The protocol for embryo transfer depends on whetherthe recipient has ovarian function or not. Recipientswithout ovarian function will have their embryostransferred in a hormone replacement cycle with anestrogen and progesterone preparation. Differentprotocols have been developed, all of which aredesigned to approximate the pattern of hormonesecretion occurring in the natural menstrual cycle.
Recipients with ovarian function may have theembryos transferred in a natural cycle. This is generallyrecommended for patients with normal, regularmenstrual cycles. Patients are asked to attend the clinicfrom Day 10 of the cycle, and from this point, folliculargrowth is monitored by serial ultrasound scanningand serum estradiol and LH estimations. Embryos arereplaced three or four days after the LH surge has beendetected. No luteal phase support is given in thesecycles.
Psychological counselling
Adequate counselling should be offered to all coupleswho will undergo embryo donation. The recipientwoman and her husband or partner should be awarethat they would be the legal parents of any child (60).The recipient couple should be given adequateinformation on the limitations and possible outcomeof treatment, the likelihood of pregnancy and live birth,the possible side-effects of any medication and the
risks of treatment, such as multiple pregnancy (61),the extent to which genetics and infectious screeningtests have been performed and the cost of treatment.
Disclosure
With ovum, sperm and embryo donation as nowpractised, the resulting children may never learn thatthey were conceived via gamete or embryo donation.If disclosure does occur, the children may want furtherinformation about their genetic origin. The decisionas to whether to tell such children of their originremains a private one for the parents.
Indications
Sperm donation
The American Society for Reproductive Medicine (9)indications for therapeutic donor insemination are
• the male partner has azoospermia;• the male partner has a known hereditary or genetic
disorder which cannot be overcome with pre-implantation genetic diagnosis (PGD);
• the male partner has uncorrectable ejaculatorydysfunction secondary to trauma, surgery, medica-tion or psychological abnormalities;
• the female partner is Rh-negative and severely Rh-isoimmunized, and the male partner is Rh-positive;
• in ART where a severe male factor has beendemonstrated, such as previous failure to fertilize,male immunological infertility and where ICSI isunacceptable to the couple;
• in females without male partners.
Oocyte donation
Oocyte donation has increased rapidly in popularitysince it was first described (47,62). Initially, the majorindication for oocyte donation was premature ovarianfailure, defined as hypergonadotrophic hypogonad-ism occurring before the age of 40 years. Oocytedonation has now become widespread throughoutthe world to treat a variety of reproductive disorders,such as incipient ovarian failure, recurrent IVF cyclefailure, and poor response to conventional ovarianhyperstimulation. Some of these problems are agerelated. In general, women over 43 years who wish to
Gamete and embryo donation 173
become pregnant are asked to consider oocytedonation because of the low success rates for treat-ment with their own oocytes (3) . Donor oocytetechnology may also be applied in cases of inheritedmaternal genetic abnormalities (e.g. balancedtranslocations, autosomal dominant or X-linkedrecessive disorders) to obviate the risk of transmis-sion to the offspring. These patients currentlycomprise a small proportion of candidates for donoroocyte IVF, and its indication is likely to wane withthe continued development of specific gene probesand refinement of PGD.
Embryo donation
At present, there are two ways in which embryos aremade available for donation. Unwanted additionalcryopreserved embryos can be designated fordonation by couples who have undergone IVF, andembryos can be created for the specific purpose ofdonation using donor sperm and donor ova.
There are three main indications for embryodonation:
• women with an infertile partner;• recurrent IVF failure;• carriers of genetic disease or chromosomal
abnormalities.
Risk–benefit analysis
In the past century, sociological changes haveresulted in an overall delay in the decision to becomepregnant. This fact, along with the increase oftherapeutic alternatives offered to infertile couples,such as oocyte and embryo donation and surrogatemotherhood, has resulted in a significant increase inthe number of patients of more advanced age wishingto become pregnant. Several groups have shown thatwomen in their late fifties and older can achievesuccessful pregnancy after oocyte donation and thatthe uterus of a menopausal women can respond tosteroid therapy and embryos can implant therein(1,2,63). However, it has been postulated that olderpatients are at greater risk of having complicationsduring their pregnancies (64). Concerns do exist withrespect to extending oocyte or embryo donation toolder women and are based not only upon the welfareof the child but also upon beliefs that pregnancypresents a high medical risk for the elderly mother and
her fetus (55,56,65). It has been shown that most ofthe complications in pregnancy associated with olderage are caused by age-related confounders such asmyomata, diabetes mellitus, hypertension andmultiparity (56). Postmenopausal women should beconsidered particularly at increased risk of vascularcomplications during pregnancy. This risk is likely toincrease progressively with the number of years thathave elapsed since the onset of menopause. Atpresent, establishing pregnancy in postmenopausalwomen is more an ethical than a medical issue, partlybecause the information that is available on pregnancyin postmenopausal women is insufficient to determinea reliable risk profile.
Advanced maternal age has been associated withadverse pregnancy outcomes such as increasedperinatal mortality, preterm delivery, low birth weightand small-for-gestational-age infants.
There are concerns about increasing the inadver-tent consanguinity brought about the use of the samesperm donor or shared oocyte donation. Becausesome parents may choose not to disclose to theirchildren their genetic origins, it is remotely possibleto have unknown consanguinity between individualsgenetically related to the same oocyte or sperm donor.The risk of potential unknown consanguinity is notabsent in gamete donation because donors may havetheir own children. This raises the responsibility offertility clinics to limit the number of donor attemptsfor donor safety. Couples should be counselled aboutthe rare possibility of unknown consanguinity, a riskthat can be lessened with disclosure of the identityof the donor.
In the early years of reproductive medicine, themajor focus of clinicians was the well-being of theinfertile couple and the development of successfultreatments was the first priority. It was in the early 1990sthat more questions were raised about the long-termeffects on the well-being of the children born as aresult of gamete or embryo donation.
There is still no consensus on the possibleassociation between ovarian stimulation and epithelialovarian cancer (66–68) , but it is clear that thistheoretical risk is a concern. Two important studieshave suggested an association between exposure tofertility drugs and an increased risk of ovarian cancer.A pooled analysis of three case–control studiesshowed an odds ratio (OR) of 2.8 (95% CI 1.3–6.1) forovarian cancer in infertile women treated with fertilitydrugs compared with women with no diagnosis ofinfertility or fertility drug treatment (69). In 1994,
174 CLAUDIA BORRERO
Rossing and colleagues using record linkage with apopulation-based cancer registry, identified anincrease prevalence of ovarian cancer (invasive orborderline malignant tumours) with a standardizedincidence rate of 2.5 (95% CI 1.3–4.5) in a cohort ofinfertile women compared with age-standardizedgeneral population rates. An increased relative risk(RR 11.1; 95%CI 1.5–82.3) was also found in women,with or without abnormalities, who had been treatedwith clomiphene citrate for more than one year,compared with infertile women who had not taken thedrug (66). For this reason, a limit on the total numberof donation cycles per donor should be set, to reduceexposure to ovarian stimulation. This is an issue ofimportance when assessing risk-exposure.
Conclusions
Gamete and embryo donation have been shown to besafe, cost-effective, and an overwhelmingly beneficialtreatment for thousands of infertile couples. Athorough understanding of the clinical science andcontemporary guidelines, as well as the legal andsocial implications of these procedures, is requiredthat these treatments are used safely and effectively.
There is no doubt that ART helps many infertilecouples to have children. But some of these tech-niques, such as sperm, oocyte and embryo donationhave also given rise to a wide variety of legal andethical issues (60).
Research on the consequences for childrengrowing up in these new family structures is in itsinfancy. For example, although keeping the method ofconception secret from young children conceived byoocyte or sperm donation does not appear to have anegative impact upon family relationship or on thechildren’s prepubertal development, it remains to beseen whether nondisclosure leads to difficulties asthese children grow up and move into adolescence.
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43. Kennard A et al. A program for matched, anonymousoocyte donation. Fertility and Sterility , 1989, 51:655–660.
44. Schover L et al . The psychological evaluation ofoocyte donors. Journal of Psychosomatic Obstetrics andGynaecology, 1990, 11 :299–309.
45. Lessor R. All in the family: social processes in ovarianegg donation between sisters. Sociological Health andIllness , 1993, 15:393–413.
46. Rozenwaks Z. Donor eggs: their application in modernreproductive technologies. Fertility and Sterility, 1987,47:895–909.
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67. Venn A et al. Breast and ovarian cancer incidence afterinfertility and in vitro fertilization. Lancet, 1995,346:995–1000.
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Embryo culture, assessment, selection and transfer
GAYLE M. JONES, FATIMA FIGUEIREDO, TIKI OSIANLIS, ADRIANNE K. POPE, LUK ROMBAUTS,TRACEY E. STEEVES, GEORGE THOUAS, ALAN O. TROUNSON
Embryo selection methods and criteria
Embryo morphology and growth rate
Preparation for mitotic division begins with twohaploid pronuclei duplicating their DNA, the twopronuclei then come together and syngamy occurs at20–34 hours after insemination followed by divisionat approximately 35.6 hours which results in theformation of two diploid blastomeres containingapproximately half the cytoplasm of the fertilizedoocyte (1). Mitotic division during the preimplanta-tion period results in a rapid increase in blastomerenumbers, as there is no cell growth phase prior tomitosis. This results in daughter cells that are smallerthan parent blastomeres, leading to a progressivereduction in individual blastomere volume. With theuse of co-culture methods and the advent of complexand sequential culture media, the embryo quality andgrowth rate have improved and there are variations inthe cell number and morphology of the embryodepending on the culture media and culture conditionsemployed.
Once the sperm has fertilized the oocyte, thecentriole and microtubules arising from the spermbring the male and female pronuclei into juxtaposition(2). Pronuclear alignment occurs 16–18 hours post-insemination and failure to do so is indicative of oneor more fertilization events failing to occur (3) .Nucleoli are visible within the respective pronucleiduring this period and are responsible for rRNA
synthesis, which resumes at fertilization (4,5). Thenucleoli or nuclear precursor bodies show variouspatterns of presentation which are suggestive of thechromosomal status and developmental inferiority ofthe embryo. Tesarik and Greco (6) examined thepronuclear morphogenesis in an attempt to determineembryo viability dependent on distribution andalignment of the nucleolar precursor bodies in therespective nuclei. Embryos resulting from certaindistribution patterns exhibited greater viability andlower rates of embryonic arrest. This group constitu-ted the “normal” pronuclear stage morphology, withthe remaining groups described as abnormal,attributed to asynchronous pronuclear development,which the authors believe is harmful to embryoviability. Pronuclear alignment in relation to the polarbody axis, positioning of the nucleoli, and cytoplasmicconsistency have also been shown to affect embryoviability. Sadowy et al. (7) suggested that sizevariation between the two pronuclei may indicatechromosomal anomalies. The authors showed anincrease in embryonic arrest in zygotes with pronucleithat differ by four microns from each other. A higherincidence of multinucleation and mosaicism was alsoobserved in zygotes with dysmorphic pronuclei.Recent evidence suggests that polarity in mammalianoocytes, including human oocytes, exists and can beevidenced in the distribution of surface structuresand molecules, cytoplasmic organelles, and RNA. The
178 GAYLE M. JONES et al.
animal pole of the oocyte may be estimated by thelocation of the first polar body, whereas afterfertilization, the second polar body marks the so-called embryonic pole (8). In human oocytes, there isa differential distribution of the molecules leptin andSTAT3 to the cortical region of the oocytes containingthe animal pole and subsequent mitotic divisionsproduce blastomeres with different allocations ofthese polarized molecules (9). Prior to syngamy,pronuclei can be observed to rotate within theooplasm, directing their axes towards the second polarbody (10). Theoretically, embryos that do not achievean optimal pronuclear orientation may exhibit cleavageanomalies that may be observed as poor morphology,uneven cleavage or fragmentation. Garello et al. (11)demonstrated that there is no relationship between themagnitude of the angle between the first and secondpolar body and subsequent embryo morphology,probably due to the fact that the first polar body iscapable of moving over an angle of 30° while thesecond polar body remains stationary. However, theseauthors provided some evidence in support of thehypothesis that the orientation of the pronucleirelative to the polar bodies relates to the subsequentmorphological grade of the embryo (11) . Although theabsolute magnitude of the angle between the pronucleiand polar bodies did not relate to embryo grade, theangle increased significantly with decreasing embryoquality.
Tripronuclear oocytes are usually formed bydispermic fertilization and, as a result of the formationof a tripolar spindle, the majority (62%) divide into 3cells with severely abnormal chromosome numbers(12). Some oocytes with a bipolar spindle (24%) formtriploid embryos and some (14%) regain a diploidkaryotype by expulsion of a set of chromosomes in anucleated fragment (12). As a consequence, it isrecommended that tripronuclear oocytes are discarded.
Monopronuclear oocytes may be diploid andsome will develop to a blastocyst and to term whentransferred to patients (13–15). As a result, it has beenrecommended that monopronuclear oocytes arerechecked for multiple pronuclei within a few hours(16) and cultured for biopsy to confirm diploidy or tothe blastocyst stage for transfer.
In normally fertilized oocytes, the two pronucleicome together, the chromosomes arrange themselvesalong a common spindle and syngamy occurs. Thecentrioles pull the chromatids apart, a furrow appearsbetween the two poles and the zygote cleaves into atwo-cell embryo at a mean of 35.6 hours post-
insemination (1,17). Evidence from the distributionof surface markers on the human oocyte and embryoconfirm observations in other mammalian embryosthat the first cell division is meridional, with the polarbodies marking one pole (reviewed in (18)), and thesecond cell division involves a meridional division forone blastomere and an equatorial division for theother (9). Early entry into the first cell division hasbeen used as an indicator of embryo viability.Selection of embryos for transfer on Day 2 from thecohort that had undergone early cleavage by 25 hourspostinsemination resulted in higher pregnancy rates(19,20). Sakkas et al . (20) postulated this increase inviability in early cleaving embryos was due to intrinsicfactors regulating cleavage within the oocyte orembryo rather than the timing of fertilization.
On Day 2, embryos are at the four-cell stage ofdevelopment by 45.5–45.7 hours postsperm insemina-tion, and three days after fertilization are at the eight-cell stage by 54.3–56.4 hours (1,17). The individualcells of the embryo may be asynchronous in their celldivision resulting in embryos with uneven cellnumbers. Between the four-cell and the eight-cellstage, the transition from maternal to embryonic geneexpression occurs; therefore, during the first 48 hoursafter sperm insemination the embryo primarily relieson maternal transcripts rather than its own activatedgenome (21).
A morphological criterion used to assess embryoquality throughout human embryology is embryonicfragmentation. Fragmentation is the extrusion of theplasma membrane and subjacent cytoplasm of anembryo into the extracellular region. Fragmentation isnot an in vitro phenomenon due to compromisedembryonic development but appears to be a naturaloccurrence in human embryos as it is evident in in vivogrown embryos (22). The intracellular mechanismscausing fragmentation are not fully known, althoughit has been speculated that the process may be causedby developmentally lethal defects or apoptotic events(23). Hoover et al. (24) examined blastomere size andembryo fragmentation as an indicator of embryoviability and pregnancy potential. The authors foundblastomere size influenced the developmentalpotential; however, no correlation was observed withcellular fragmentation. Contrary to this, Giorgetti et al.(25) suggested that the embryo developmentalpotential decreased significantly as the number ofcytoplasmic fragments increased. Furthermore,Antczak and Van Blerkom (9) suggested that theamount of fragmentation an embryo has is not the
Embryo culture, assessment, selection and transfer 179
determining factor; it is what is being extruded thatrelates to embryo viability. These authors showed thatseveral regulatory proteins are localized to polarizeddomains in the oocyte and are asymmetricallydistributed to individual cells during developmentalprogression. A decrease or elimination of thesenecessary proteins by fragmentation may then leadto blastomere apoptosis. Therefore, the size anddistribution of fragments may have different conse-quences for the developmental competence of theembryo as a whole (26). Small, scattered fragmentsmay be due to imperfect cytokinesis during successivedivisions and not specific anomalies, as may be thecase with greater localized fragmentation.
Embryo morphology has been associated withchromosomal abnormalities. Almeida and Bolton (27)showed that 63.4% of embryos that arrest between thepronucleate and the eight-cell stage are chromo-somally abnormal. Embryos exhibiting irregular-shaped blastomeres and severe fragmentation areconsidered poor quality embryos and show a higherincidence of chromosomal abnormalities (62%)compared to embryos of good quality (22.2%) (28).Fragmentation has been shown to be correlated tochromosomal mosaicism (29). Slow cleaving (two tosix cells on Day 3) and rapidly cleaving (nine or morecells on Day 3) embryos show a higher incidence ofchromosomal aneuploidy than those embryosshowing normal cleavage kinetics (seven to eight cellson Day 3) (30).
On Day 2 or Day 3 an embryo may exhibit blasto-meres with more than one nucleus. The incidence ofembryos containing multinucleated blastomeres is notuncommon. These embryos are not necessarilydegenerate and some are capable of DNA and RNAsynthesis (31) . However, Munne and Cohen (32)showed that 30.4% of arrested embryos were multi-nucleated. Kligman et al. (33) found that 74.5% ofmultinucleated embryos are chromosomally abnormalcompared to 32.3% of nonmultinucleated embryos.Multinucleated blastomeres have been speculated toresult from accelerated ovulation induction response(34) or cytokinetic failure (32) and are indicative ofpoor development.
During Day 3 postinsemination, the cytoplasm ofthe embryo may become granular and tiny pits appear(cytoplasmic pitting). There is an increase in cell–celladhesion early in the morning of Day 3 at the eight-cell stage and loss of definition between individualblastomeres of embryos that are likely to undergocompaction (35) . The blastomeres of the embryo
undergo a rearrangement process during compactionwith the establishment of cell–cell adhesions leadingto communication between blastomeres. Desai et al.(36) speculate that cytoplasmic pitting and increasedcell–cell adherence may be early markers ofcytoplasmic activity and potential for embryonicactivation, as embryos exhibiting these features weremore likely to proceed to the next stages of preimplan-tation development—the morula and blastocyststages.
The embryo is termed a morula approximately fourdays after fertilization when it has undergonecompaction, the formation of tight junctions and gapjunctions and polarization of the blastomeres,resulting in communication between blastomeres andsegregation of two cellular populations of inside andoutside cells (37).
Once a cavity forms within the morula it is termeda blastocyst (38). Cavitation involves the formationof the blastocoele, the fluid filled cavity necessary forblastocyst formation. Wiley (39) showed that Na+/K+
ATPase, located on the basolateral membrane, pumpssodium out of the cell and into the intercellular spacesand water passively follows, thereby forming theblastocoele cavity. As cavitation proceeds, the twopopulations of cells formed by polarization of theblastomeres during compaction become (i) thetrophectoderm that forms extraembryonic tissue; and(ii) the inner cell mass that forms the embryo lineage(39) .
In vitro blastocyst formation occurs between Day5 and 7 postinsemination (40,41). Blastocysts thatoccur on the respective days do not appearmorphologically different, although their growth ratediffers, nor do they have significant differences in hCGsecretions, the latter suggesting comparable maturetrophectodermal tissue (40). The blastocyst hasseveral different appearances depending on itsdevelopment (42,43). When a cavity is apparent andthe inner cell mass and trophectoderm are distinct, theembryo is termed an early blastocyst. The blastocystbegins to increase in size, termed expanding blasto-cyst, until it has fully expanded. The expansion of theblastocyst causes thinning of the zona pellucida. Thezona pellucida is an acellular glycoprotein coat thatsurrounds oocytes and embryos and is importantduring fertilization and early preimplantation develop-ment as it keeps the blastomeres of the embryostogether when there are no intercellular junctions. Thezona pellucida thins with the growing blastocyst untilit ruptures and the blastocyst begins to herniate
180 GAYLE M. JONES et al.
through the zona pellucida in a process calledhatching. This occurs on approximately Day 6 or 7.When the blastocyst fully escapes from the zonapellucida it is termed a hatched blastocyst.
A morula may become vacuolated and appear tobe cavitated. The vacuoles do not appear to be linedwith the trophectoderm or inner cell mass (40). Theseembryos do not hatch from the zona pellucida,degenerate with ongoing culture (Day 8 or 9) and havesignificantly less cells than true blastocysts (41).These embryos are termed vacuolated morulae andshould be distinguished from blastocysts.
Blastocysts can appear morphologically similarbut may contain significantly different cell numbers(38,41,44–47) and have a different ability to hatchfrom the zona pellucida (46). Blastocyst cell numbersmay be correlated with embryo viability. Hardy et al.(44) found expanded blastocysts on Days 5, 6 and 7had an average of 37.9, 40.3 and 80.6 trophectodermcells and 20.4, 41.9 and 45.6 inner cell mass cells,respectively, using a simple culture medium. Theauthors also observed that the total cell numbers werelower in morphologically abnormal blastocysts andblastocysts arising from abnormally fertilized zygotes.Van Blerkom (46) found that the stage-specificdifferentiation of the cells and, in particular, the innercell mass, may be a function of age of the embryo ratherthan the overall number of cells that constitute theembryo. The distribution of the cells between the innercell mass and trophectoderm also affects embryoviability (44).
Therefore, embryo morphology and growth rateare determinants of embryo quality. The overallembryo quality differs markedly and this variation isevident in embryos produced in vivo (48) . Patientsgenerally do produce a similar embryo quality fromcycle to cycle independent of maternal age. Embryoquality may be an inherent feature of the female andprobably depends in part on oocyte maturity (49).There is a decline in embryo quality in embryosgenerated from oocytes from ageing women. Jannyand Menezo (50) speculate that this may be due toincreased chromosomal abnormalities, the role ofmaternally inherited products from the oocyte, timeof genomic activation, and the temporal pattern of geneexpression during the initial embryo development.Munne et al. (51) have also shown that embryos thatappear morphologically normal contain chromosomalabnormalities and the frequency of these abnormalitiesincreases with maternal age.
Human embryo culture media and cultureconditions
Culture conditions for human embryos have evolvedover the past decade; significantly increasing theviability of in vitro fertilized embryos. Improvementsin culture media and the physical environment in whichembryos are cultured have resulted from an increasedunderstanding of both the physiology of the embryoand the environment of the oviduct and uterus.Conventional media for culture of human embryos toDay 2 or Day 3 postinsemination were simple mediasuch as T6 (52), HTF (53) and EBSS (54) containinga serum additive. Development to the blastocyststage, however, was limited (55,56) because thesesimple media lack important regulators of embryodevelopment. Co-culture of human embryos withvarious somatic cell monolayers with more complexmedia and serum additives was shown to supportdevelopment of embryos to the blastocyst stage (57–60).
Co-culture of human embryos with somatic cellshas been reported to improve blastocyst development,decrease fragmentation and/or improve pregnancyand implantation rates (57,61–63), particularly forpatients with repeated IVF failures (61,64,65).Somatic cells may benefit embryo development byproviding trophic factors and/or by modifyinginhibitory media components (66–68). There is notgeneral consensus, however, that co-culture systemsimprove pregnancy rates (46,60,69). Co-culture istime-consuming with an associated risk of pathogentransmission.
A greater understanding of both the physiologicalrequirements of the embryo as it develops from thezygote to the blastocyst stages in vitro [reviewed in(70,71)], and the composition of oviduct and uterinefluids (72–74) has led to the more recent developmentof stage-specific or “sequential” complex media forextended culture. The first of such media was G1/G2(75) which was recently modified, resulting inincreased pregnancy rates after blastocyst transfer(76,77). Currently, conditions employed for humanembryo culture have been largely based on studiesusing mouse, rabbit and hamster models. Due to therestricted use of human embryos for researchpurposes, there is a general lack of prospectiverandomized clinical trial data relating to the effects ofvariable culture conditions on embryo viability.
The most abundant chemical constituents of
Embryo culture, assessment, selection and transfer 181
culture media (next to water) include solubilized ions.Ionic components detected in oviduct and uterinefluids (72) are present in formulations of both simpleand complex media that support human embryocleavage and blastulation in vitro, yet vary markedlyin comparative concentration (78). Little evidenceexists as to the significance of single ions on thedevelopment of human embryos. Many reportsimplicate the presence and variable concentrations ofmost of the dissolved salts [e.g. potassium (79,80)]in regulation of mouse embryo growth. Only theputative inhibitory effects of inorganic phosphate ionshave been investigated clinically (81) with contradic-tory pregnancy results (82,83). The subtle, integratedeffects of ions may be better assessed with simulta-neous optimization of concentrations, e.g. KSOMmedium (84,85), which was recently reported toenhance human blastocyst formation (86).
Irrespective of concentration, ions should besolubilized in injection-quality, filter-purified andtoxicity-tested water (87) to minimize the risk ofbiological contamination and to perhaps improve long-term outcome (88). Together with purified water, ionicconstituents contribute largely to the osmolality of amedium (or osmotic pressure imparted by dissolvedparticles)—a testable physical parameter (89). Mediathat range from 250–290 mOsmols can satisfactorilysupport mammalian embryo development (90,91).Deviation from this range and especially above 300mOsmols (92,93) can induce deleterious changes incell volume and hydration resulting in the compensa-tory uptake of organic osmolytes (94,95).
Protein sources in culture medium, aside fromplaying a major role in preventing embryo adhesion,may also act as organic osmolytes and pH buffers(reviewed in (78)). Filtered, heat-inactivated maternalserum, a traditional additive with undefined, variablecomposition (96,97), was found to have no effect onin vitro fertilization (IVF) pregnancy rates whencompared to media without protein supplementation(98). Since then, several attempts have been made tocompare fractionated serum proteins to whole serawith equivocal results with respect to embryo qualityand development (99–108) . Presently, there areseveral risk factors associated with supplementationof culture media with patient serum such as potentialviral transmission (99) and the negative effects onembryo development of sera from various subgroupsof infertile women (109,110) . Other negative effectshave included impaired blastocyst development (55),possible trophectodermal (111) and mitochondrial
deterioration (112) and metabolic perturbations (113).More chemically defined alternatives to human serainclude purified albumin (99), recombinant serumalbumin (synthesized by bacteria) (114) and glyco-saminoglycan molecules (115).
Media with conventional ionic and proteinsupplements vary little in their composition of themain energy substrates pyruvate, glucose and lactatewhich regulate mammalian embryo metabolism in astage-specific manner (70). Glucose, however, hasbeen excluded from some media formulations (81,105) . Only a small number of studies of humanembryos exist that confirm the mammalian evidencesuggesting that pyruvate is a requirement to supportcleavage and blastulation (116,117). However, thereis a shift in preference from pyruvate to glucose withthe onset of embryo compaction (118,119). There islittle evidence on the effects of energy substrates andtheir concentrations in IVF culture media formulationson embryo viability. Sequential media were designedto vary in concentrations of carbohydrates to moreadequately reflect the difference in composition offluid components in the oviduct and uterus (120).
Amino acids are found in the fluids of the humanreproductive tract (72,73); however, there has beenminimal research on the effects of amino acids on thehuman embryo. Studies in other mammalian specieshave found amino acids to be important regulators ofembryo development [for review see (78)]. Glutamine(1 mM) was found to significantly increase develop-ment of human embryos to the morula and blastocyststages and increase energy metabolism (121) . Taurine(94) and glycine (95) have been shown to act asosmolytes and therefore may help to minimize thestress induced by osmotic fluctuations. Interestingly,isoleucine (0.2 mM) and phenylalanine (0.1 mM), bothconstituents of Eagle’s essential amino acids (122),were found to inhibit cleavage and implantation ofhuman embryos (123). Based on mouse and hamsterembryo studies, sequential media for human embryostypically contain glutamine, taurine and Eagle’snonessential amino acids for development from Day1 to Day 3 postinsemination, and glutamine and Eagle’sessential amino acids for culture to the blastocyststage (75).
Vitamins are key components of cellular meta-bolism and have been shown to have significanteffects on embryo quality during culture of rabbit,mouse and hamster embryos (124–126). Despite thepresence of B-group vitamins in recently developedsequential media for the development of human
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embryos from Day 3 to Day 5, there is no informationas to the effects of these vitamins on the humanembryo. Ascorbic acid (vitamin C) had no significanteffect on embryo development or morphology up toDay 2 or 3 postinsemination (127).
The addition of growth factors such as leukaemiainhibitory factor (LIF) (128) , epidermal growth factor(EGF) (129) and insulin-like growth factor-I (IGF-I)(130), and the cytokine granulocyte-macrophagecolony stimulating factor (GM-CSF) (131), has beenshown to increase development of human embryosto the blastocyst stage. Furthermore, IGF-I (130) andGM-CSF (131) stimulated development of the innercell mass. Thus, further studies are required todetermine whether growth factors and cytokines havea significant impact on embryo viability.
EDTA and transferrin have also been added tomany media for their potential function as chelatorsof metal ions. Careful consideration should be given,however, to the addition of EDTA to media forblastocyst development as EDTA has been shown toreduce glycolytic activity and thus inhibit blastocystdevelopment in the mouse (132).
Human embryos have typically been culturedindividually in large volumes of media (usually onemillilitre). Studies in the mouse have found thatembryo density has a significant effect on cleavagerate and blastocyst development (133,134), possiblydue to embryo-derived trophic factors. Culture ofhuman embryos in groups for up to 48 hours post-insemination was associated with an increased rateof cleavage (135,136); however, the effects onpregnancy rates have been variable (135–138).Rijnders and Jansen (139) reported that culture ofhuman embryos to the blastocyst stage in eitherreduced volumes of media and/or groups, had noeffect on pregnancy rates; however, the culture mediawas not sequential and the sample size was low.
Further improvements could be made to theformulation of media for human embryo culturethrough determination of the effects of individualmedium components on embryo development andviability. The physical conditions under whichembryos are cultured also have a significant impacton viability. The majority of culture systems for humanembryos use a bicarbonate/CO2 buffered medium tomaintain a physiological pH of 7.2–7.4. Embryos aretypically cultured in an incubator at a gas atmospherecontaining 5% CO2 (76,139,140). According to theHenderson-Hasselbalch equation, the combination of25 mM sodium bicarbonate in the culture medium and
a 5% CO2 gas atmosphere, results in a pH of 7.45 atsea level. Thus, it would be prudent to cultureembryos at a slightly elevated concentration of 6%CO2 (123) , which theoretically results in a pH of 7.37.The optimal concentration of CO2 for culture of humanembryos is yet to be determined. An N-2-hydroxy-ethylpiperazine-N´-2-ethanesulfonic acid (HEPES)buffered medium is often used to maintain a pH of 7.3–7.4 when embryos are exposed to atmospheric oxygentensions for an extended period of time. It is importantto consider, however, that exposure to atmosphericCO2 and a reduced concentration of HCO3
– may affectthe embryo’s ability to regulate its intracellular pH,specifically acidosis, via the HCO3
–/Cl – exchanger(141).
The oxygen tension in the reproductive tract ofmammalian species has been reported to be lower thanatmospheric O2, ranging between 1.5% and 8%(142,143). Recent evidence indicates a low pO2 in thehuman vaginal epithelium (144). Culture of mammalianembryos at low concentrations of O2 (5%–7%) isthought to minimize the formation of embryotoxicreactive oxygen species; however, studies on humanembryos are few. Culturing human embryos at areduced oxygen tension (5%) for up to 46 hoursfollowing insemination had no effect on cleavagerates or subsequent pregnancy rates (140). Cultureof frozen-thawed pronuclear stage embryos for fourdays at a reduced oxygen tension (5%) did not affectblastocyst development but did significantly increasetotal cell number compared to culture at 20% O2 (145).Thus, it may be prudent to culture human embryos ata reduced oxygen tension.
Further optimization of human embryo culturesystems is needed to gain a fuller understanding ofthe specific requirements of the human embryo forregulatory support.
Selection of embryos for transfer
One of the most difficult aspects of assisted reproduc-tive technology (ART) is the determination of whichembryos are most suitable for transfer into the uterus.Two factors requiring consideration include thechoice of embryos with the best developmentalcompetence and the risks of multiple pregnancyassociated with the number of embryos transferred.The development of technological advances such asmicromanipulation and a wealth of experience inembryo culturing techniques have resulted in an
Embryo culture, assessment, selection and transfer 183
increase in embryo implantation potential. Numerouscriteria have been suggested to optimize the selectionprocess. These include: the rate of embryo develop-ment; blastocyst development; pronuclei expressionand nucleoli orientation; ovarian/follicular vascular-ity; noninvasive assessment of metabolic products ofembryos during development; preimplantationgenetic diagnosis; and morphological assessment.Embryo scoring techniques have been developed toaid in evaluating the potential of embryo implantation.
Morphological assessment has been employed formany years as a tool in determining which embryosdisplay the greatest pregnancy potential (146) .Embryos are scored based on cell number, fragmenta-tion pattern and extent, cytoplasmic pitting, blasto-mere regularity, presence of vacuoles and blastomereexpansion (36,147–151).
Fragmentation is one of the most commonmorphological features used in assessing embryoquality. Grading systems have gauged embryo qualitybased on the percentage of fragmentation observedwithin the embryo. Low implantation rates have beenreported from embryos with 10%–50% fragmentationon Day 2 of development (25,152). Not all fragmenta-tion appears to be detrimental to embryo developmentbut the pattern of fragmentation has a profound effecton the embryo’s developmental potential. Largefragments formed at the two-cell to four-cell stageappear more detrimental due to the depletion ofessential organelles such as mitochondria, orstructures such as pinocytotic caveolae, involved inexogenous protein uptake (26). The presence of smallfragments does not appear to effect developmentalrates to the same degree as large fragments. Theformation of small fragments may representincomplete cytokinesis. Implantation rates are similarbetween embryos without fragmentation and thosewith moderate fragmentation. Antczak et al. (9)compared the relationship between blastomerefragmentation and the effect on the distribution ofregulatory proteins. The findings demonstrated thatcertain patterns of fragmentation might result in partialloss of certain regulatory proteins from specificblastomeres, resulting in compromised developmentif fragmentation occurs during the one-cell or two-cellstages. Correlation between fragmentation andapoptosis is not clear but fragmentation may be aninitiator of apoptosis if regulatory proteins are altered.
Embryo development rates were initially used inscoring for embryo’s developmental competency (17).Early cleavage of fertilized oocytes to the two-cell
stage is used for its prognostic value in determiningembryos for transfer (19). A study by Giorgetti et al.(25) involving single embryo transfers, concluded thatthe use of embryo scoring based on cleavage rate andmorphology was advantageous in maximizingpregnancy rates. One of the shortcomings of earlycleavage as a selection criterion relates to oocytematurity. Immature oocytes may fertilize later thanmature oocytes under standard IVF culture condi-tions. Oocytes selected for intracytoplasmic sperminjection (ICSI) are biased due to maturation status.Sakkas et al. (20) concluded that early cleavage ratewas not entirely influenced by timing of fertilizationbut is more likely influenced by intrinsic factors withinthe oocyte or embryo. The expression of humanleukocyte antigen G (HLA-G) has been demonstratedto correlate with mRNA expression and improvecleavage rates (153). Embryos that have undergoneearly cleavage may be less likely to experiencecritically low reserves of maternal mRNA prior toembryonic genome activation (154).
Cell stage at the time of transfer has become asignificant factor in determining which embryos havethe greatest potential for implantation. Embryonicgenome activation occurs between the four-cell andeight-cell stages of preimplantation development (21) .Delaying embryo transfer to Day 3 of developmentallows a selection of embryos undergoing embryonicactivation.
In an attempt to further refine selection criterionbased on morphology, zygote scoring of pronucleiwas investigated. Scott et al. (155) outlined scoringsystems based on the alignment of nucleoli at thejunction of the two pronuclei and the appearance ofthe cytoplasm. These systems have been refined overtime to encompass embryo morphology and develop-ment rates and now include nucleoli alignment,appearance of cytoplasm and the incidence ofblastomere multinucleation.
The scoring system, often classified as a “Z”rating, for zygote, records a number of crucial phasesof development. The first record of pronuclei align-ment or appearance of “touching” at 16–18 hourspostinsemination relates to activation of the oocyteby the introduction of the spermatozoon. The sperm-derived centriole and the microtubules arising from itare responsible for alignment of the pronuclei. If thisfails to occur, developmental potential is limited (29) .Pronuclei are often slightly different in size but largedifferences have been associated with chromosomaldefects such as aneuploidy (7). Another aspect of
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“Z” scoring relates to size, number and distributionof nucleoli. Nucleoli are the sites where pre-rRNA issynthesized. Following fertilization, rRNA synthesisresumes and the nucleoli reform and grow. It ispresumed that “Z” scoring allows observation of theresumption of rRNA synthesis (155). Zygotes withthree to seven even-sized nucleoli per nucleus appearto give rise to embryos with greater developmentalpotential. Pronuclei scoring used in association withembryo development and morphology may offer atechnique for determining which embryos wouldbenefit from prolonged in vitro culture (156–158),particularly as the score has been related to the abilityto continue development to the blastocyst stage (3).
Extended embryo culture to the blastocyst stagewas proposed as a possible solution to the risks ofmultiple pregnancy. Determination of which embryossurvive to the blastocyst phase was considered themost vital criterion for selection of embryos with thegreatest implantation potential. Blastocyst cultureaddresses the issue relating to endometrial asyn-chrony, uterine hostility associated with earlycleavage-stage embryos, and the assumption that allembryos have equal implantation potential. Selectionof blastocyst-stage embryos may allow for the transferof a single blastocyst.
Blastocyst culture has developed significantlyover the past few years but is still fraught with theinherent problem of zygote development potential(159). Only half of all zygotes have the potential todevelop to the blastocyst stage. Aneuploidy can beused as an explanation for approximately half of theembryos failing to develop to the blastocyst stage(160). Extended culture to the blastocyst stage doesnot eliminate those embryos displaying chromosomeabnormalities (160) as 40% of embryos displayingnormal morphological development to blastocyst areaneuploid.
Blastocyst development occurs between Day 5and 7 postinsemination. Menezo et al. (161) observedthat the transfer of embryos at the compacting morulastage resulted in poor pregnancy rates. This is thoughtto be associated with the fragile nature of the embryoat this phase of development. Pregnancies have beennoted from the transfer of blastocysts ranging fromDay 5 to Day 7 of development. Shoukir et al.(162)suggested that “good” quality blastocysts not onlydisplayed well expanded blastocoelic cavities andwell-defined inner cell masses but also had attainedthis stage by Day 5 or 6. A scoring system forblastocyst development was first described by Dokras
et al. (41) . This system uses three grades forblastocyst classification based on the timing ofcavitation, cavity formation and inner cell massdefinition and trophectoderm distinction. Scoringsystems have undergone further refinement and nowinclude blastocoele volume, zona thinning andblastocyst hatching (120). Scholtes et al. (163)suggested the success of blastocyst culture tech-niques depends primarily on the number of oocytesretrieved and not maternal age. Others have also notedthat there is a reduction in the number of blastocystsformed in cases of male infertility (42,164,165).
Assessment of embryo metabolism presentsanother potential technique for viable embryoselection. Gardner et al. (70) suggested that glucoseuptake and metabolism might be used to predict theembryos most suitable for transfer. The noninvasivemeasurement of glucose and pyruvate uptake byhuman embryos (166), the measurement of ATP andADP levels (167,168), the expression of EGF,transforming growth factor alpha and EGF receptor(169), extracellular matrix protein production (170),the role of pregnancy-specific b -1 glycoprotein(86,171), production of human chorionic gonado-trophin (hCG) and HLA-G and pregnancy-specificb -1 glycoprotein (86), and expression of IGF (172)have all been suggested as having potential value inpredicting those embryos with high implantationcompetency. Jones (159) concludes that pregnancy;specific b -1 glycoprotein appears to be the bio-chemical factor with the greatest potential to act as aprognostic indicator of blastocyst viability. The useof biochemical factors as predictive markers in embryoselection is limited to those techniques that usenoninvasive assessments or measurements. Furtherinvestigation of such markers is required. Follicularvascularity has also been suggested as another toolin determining follicles containing oocytes withgreater developmental potential. Nargund et al. (173)concluded that a statistical correlation does existbetween follicular peak systolic velocity, the abilityto retrieve an oocyte and morphological development.Van Blerkom et al. (174) suggested an associationbetween intrafollicular oxygen content and peri-follicular vascularity, which may provide a usefulindicator in oocyte developmental potential. Defectsin chromosomal number, spindle organization andcytoplasmic structure have been observed in embryosdeveloping from oocytes retrieved from hypoxicfollicles. Colour Doppler imaging has been used as apredictive tool in analysing which preovulatory
Embryo culture, assessment, selection and transfer 185
follicles may contain oocytes with the potential todevelop to normal embryos (175,176). The predictivevalue of perifollicular blood flow on embryo develop-ment remains to be determined but it may offeradditional information useful in predicting embryoswith high implantation potential.
Embryonic developmental failures have beenassociated with cleavage arrest and chromosomalabnormalities. Aneuploidy is commonly associatedwith embryo arrest (51) . Preimplantation geneticdiagnosis offers another useful technique to eliminatechromosomally abnormal embryos with little to nodevelopmental potential prior to transfer. Sexselection of embryos for couples with sex-linkedgenetic disorders offers the possibility of eliminatingcarrier embryos prior to transfer.
Numerous embryo scoring systems have beendesigned to assist in determining which embryos havethe greatest developmental potential. Regardless ofthe many criteria proposed to aid in the selectionprocess, no single criterion has been identified whichoffers a significant benefit over the others. Themajority of embryo selection systems are based on acombination of criteria, including morphology,cleavage rate and embryonic genome activation. Theuse of blastocyst culture, first suggested as the mostuseful embryo selection process, does not take intoconsideration reduced oocyte numbers and embryoproduction due to maternal age and ovulatory defects.Nor does it overcome the problem of identifyingembryos with potential genetic abnormalities.Racowsky et al. (177) suggested an embryo selectionprocess which compensated for maternal age andetiology. This selection process incorporates thenumber of eight-cell embryos available for transfer onDay 3 postinsemination. Patients with greater thanthree morphologically “good” embryos are encouragedto undergo Day 5 (blastocyst) embryo transfer. Thisprocess not only attempts to address endometrialasynchrony but also to reduce the risks of multiplepregnancy due to the transfer of fewer embryos.
Preimplantation genetic diagnosis (PGD) isbecoming a useful adjunct in embryo selection withthe development of additional DNA probes, parti-cularly in cases of advanced maternal age. DNAfingerprinting may prove to be a significant tool infinally assessing which of the simple selection criteriaare beneficial. The current practice of transferringmultiple embryos precludes the identification of whichembryo is responsible for the pregnancy and DNAfingerprinting may provide conclusive evidence as to
which embryo is responsible for each live birth.Although a long-term assessment technique, even-tually embryologists may be able to quantify ,retrospectively, the criteria that are essential indetermining the “best” embryos for transfer.
Despite all the advances in determining embryodevelopmental competence, no consensus has beenreached on how many embryos to transfer. Multiplepregnancy rates remain high with recommendationsof three or more embryos for transfer, depending onmaternal age, still being promoted (178). One of thepotential benefits of refining embryo selection criteriais to reduce the number of embryos for transfer andthus the high multiple pregnancy rates.
Embryo transfer
The embryo transfer procedure should be consideredas important to the success of ART as embryo qualityand uterine receptivity. However, embryo transfer isperhaps the least understood link in the chain ofprocedures. Embryos from the one-cell stage (pro-nucleate embryos or zygotes) to the blastocyst stageof development may be transferred to either thefallopian tube or the uterus.
The fallopian tube can be cannulated from eitherthe fimbrial end (orthograde transfer) or the uterineend (retrograde transfer) (179). The surgical tech-niques of laparoscopy or laparotomy (orthogradetransfer), or the nonsurgical techniques of trans-cervical or transvaginal cannulation (retrogradetransfer) under ultrasound guidance, hysteroscopicguidance or by tactile sensation, can be used tocannulate the fallopian tube (180). Laparotomy is nolonger needed for tubal catheterization, as theprocedure can be performed successfully via laparo-scopy, using video guidance (180) . However ,laparoscopy usually requires the patient to have ageneral anaesthetic and the abdomen insufflated withCO2 (181) with attendant risks and side-effects. Forthese reasons, laparoscopic intrafallopian transfer hasbeen attempted with success under local anaesthesia,but has not received wide acceptance (181,182) .Laparoscopic transfer has fallen out of favour sincethe introduction of transvaginal ultrasound-guidedoocyte retrieval, which is usually performed with noanaesthesia, with or without light sedation. Cannula-tion of the fallopian tube via the cervix underultrasound guidance, hysteroscopic guidance or bytactile impression, without general anaesthesia has
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been performed with success for transcervical zygoteintrafallopian transfer (ZIFT), tubal embryo stagetransfer (TEST), tubal embryo transfer (TET).However, complications such as uterine anomalies, aretroverted uterus, or unsuspected tubal cornualobstruction may make it impossible to regularlycannulate the fallopian tube (183). Transcervicaltransfer to the uterus can then be undertaken but it ispossible the endometrium may have already beentraumatized during the initial attempts to cannulate thefallopian tube with a consequent reduction in thechance of implantation (184). There are also side-effects of the procedure including the possibility offlushing the embryos from the fallopian tube ifinjection flow rates are too high (185) , tubalperforation, vasovagal faintness and pelvic dis-comfort in some (less than 10%) patients (179).
Zygote or embryo transfer into the fallopian tubeis not possible in all patients, and in order to minimizethe risk of ectopic pregnancy, should only beperformed when the fallopian tube is patent and whenthe patient has had no previous history of pelvicinflammatory disease, ectopic pregnancy, or tubalsurgery (179,184,186). The fallopian tube transferprocedures include pronucleate stage transfer(PROST) in which pronucleate-stage embryos aretransferred to the fallopian tube, ZIFT in whichpronuclear to early cleavage-stage embryos aretransferred to the fallopian tube, and TET or TEST inwhich early cleavage-stage embryos are transferredto the fallopian tube.
PROST has been used for patients in whom theetiology of infertility is unexplained or due tomoderately severe male factor, antisperm antibodiesor endometriosis. Similarly, the techniques of ZIFT,TET and TEST have been used for patients with malefactor or immunological infertility and, in addition toconfirming successful fertilization, offer the furtherpossibility of eliminating those zygotes that fail toundergo the first cleavage divisions.
Until recently, one of the disadvantages oftransferring early zygotes was the inability to selectthe most viable zygotes from a large cohort fortransfer. However, high pregnancy and implantationrates have recently been reported for PROST whenzygotes are selected for transfer according to certainpronuclear morphological features (155). Early reportscomparing embryo transfer to the fallopian tube totransfer to the uterus reported significantly higherimplantation, pregnancy and birth rates when embryoswere transferred to the fallopian tube (187–190) .
However, others have reported no benefit whentransferring embryos to the fallopian tube instead ofthe uterus (191–196).
The majority of embryo transfers are currentlycarried out by nonsurgically cannulating the uterinecavity via the cervix (transcervical transfers).However, it is also possible to transfer embryos to theuterus using surgical techniques; ultrasound-guidedperurethral transvaginal embryo transfer (197) ; ortransmyometrial transfer (198,199). These methodshave been used for patients with nonpatent tubeswhen anatomical abnormalities of the uterus or severecervical stenosis would predict that cannulation of thecervical canal would be difficult or impossible (180).
Transmyometrial embryo transfer is widelypractised in Asia and pregnancy rates are reported tobe high (198). However, in a randomized prospectivetrial, no benefit could be demonstrated for trans-myometrial transfer over transcervical transfer andpregnancy rates were low (199). This difference maybe due to anatomical features of the cervix in orientalwomen. A more compressed cervical canal comparedto those from other races is frequently observed, butfurther studies need to be carried out to evaluate this(200).
Transcervical embryo transfer is a rapid and easytechnique, and does not require analgesics oranaesthetics (180) . Disadvantages include thetechnical difficulty encountered in patients withcervical stenosis (199), the risk of infection from theintroduction of microorganisms into the endometrialcavity (179), and release of prostaglandins that maycause myometrial contractions and loss of embryosinto the fallopian tube or vagina (179).
To perform an embryo transfer, preparation of thepatient is required. This includes positioning thepatient, introducing the speculum, cleaning the cervixand manipulating the uterus.
The dorsal lithotomy position is most commonlyused for embryo transfer, especially for patients withan axial or retroverted uterus, whereas for patientswith an anteverted uterus, the knee–chest position hasbeen recommended to eliminate expulsion of embryosfrom the uterus (201). However, there is no convincingevidence that patient position affects the outcome ofembryo transfer (202–204) and it is recommended tochoose a position most comfortable to both patientand clinician.
A bivalve speculum is then introduced gently intothe vagina to expose the cervix. Manoeuvring thespeculum can improve cervico-uterine alignment to
Embryo culture, assessment, selection and transfer 187
allow easier access by the catheter (200) . Furthermanipulation can be achieved by passive bladderdistension which has been reported to result insignificantly higher pregnancy rates than whenpatients have an empty bladder (205) and is arequirement if abdominal ultrasound monitoring ofcatheter placement is to be employed. The uterus canalso be straightened artificially by using a tenaculumor cervical suture; however, this may stimulate uterinejunctional zone contractions and lead to implantationfailure (206) or the transportation of the embryos intothe fallopian tube, increasing the risk of ectopicpregnancy (207). For patients with cervical stenosiswhere passage of the catheter is extremely difficult,cervical dilatation can be performed. It has beenrecommended that cervical dilatation be performed atthe time of embryo transfer (208) rather than at thetime of oocyte retrieval (209) as it does not appear toaffect pregnancy rates.
The vulva and vagina require no special prepara-tion but the cervix can be cleaned by swabbing,vigorous flushing, or aspiration to remove excessmucus and there is no clear consensus as to which isthe best method. Some favour complete aspiration ofcervical mucus (210) whereas others have demons-trated improved results when the cervix is vigorouslyflushed with culture medium to remove mucus (211).As yet, no controlled, randomized studies have beencarried out to evaluate the requirement of removingmucus prior to embryo transfer.
To gain a better understanding and knowledge ofeach patient’s anatomy, a “mock” embryo transfer canbe performed. A mock transfer can take place either ina cycle prior to the treatment cycle (201,212) or justprior to the real embryo transfer procedure (213).Performing a mock transfer offers many potentialadvantages: the most suitable catheter can be chosenfor each patient to facilitate atraumatic transfer; thedirection of the uterus can be assessed and the lengthof the uterus can be measured (213). The maindisadvantage of performing the mock transfer beforethe treatment cycle is that the uterus is mobile so it ispossible that the direction of the uterus may bedifferent on the day of the real embryo transfer (213).Mock embryo transfer has been shown to minimizethe problems associated with embryo transfer and toimprove pregnancy and implantation rates (212).
Medications such as anaesthesia, uterine relaxantsor prophylactic antibiotics and corticosteroids havebeen given during the embryo transfer procedure.General anaesthesia as a routine for embryo transfer
has not proven to significantly improve pregnancyrates (202) . However, general anaesthesia issometimes required if the embryo transfer procedureis extremely difficult. Care should be taken as to thechoice of anaesthetic agent used as it may affectresults (214). Tranquillizers such as diazepam havealso been used to reduce patient anxiety and promoteease of transfer (202,212) . However, it has becomecommon practice to withhold medication except in thecase of very difficult transfers. Instead, patientreassurance by staff members familiar to her, previousexperience with mock embryo transfer and a physicianperforming the procedure who is known to the patient,have appeared to be sufficient to achieve patientrelaxation and improve ease of procedure.
Prostaglandins may adversely affect outcomefollowing embryo transfer due to their action instimulating uterine contractions. Prostaglandininhibitors such as ibuprofen (215) or indomethacin(201) have been used to inhibit uterine contractionbut have not had any beneficial effect on pregnancyrate (202). Similarly, administration of the smoothmuscle relaxant, glyceryl trinitrate, has no affect onpregnancy rate (216).
Microbial contamination of the embryo transfercatheter tip is correlated with a significant reductionin pregnancy rate (217,218) . Prophylactic antibioticsadministered at the time of oocyte retrieval signifi-cantly reduce the incidence of positive microbialcultures from embryo transfer catheter tips 48 hoursafter antibiotic administration (219). However, nocontrolled, randomized studies have been undertakento investigate the effect on pregnancy rates. One ofthe many protective functions of the zona pellucidasurrounding the early cleavage-stage embryo is inreducing contact with microorganisms and immunecells. Zona-manipulated embryos when transferred tothe uterus, are potentially at risk of exposure to thesecells and for this reason, low-dose immunosuppres-sion with corticosteroids has been advocated (220).However, the effectiveness of this immunosuppressionand its effect on pregnancy outcome has not beeninvestigated in any systematic way.
There are over 50 different catheters availablecommercially for clinical embryo transfer and severalstudies have been undertaken to compare differentcatheters (221–227). Catheters are classifiedaccording to their tip, flexibility, presence of separateouter sheath, location of the distal port (end- or side-loading), degree of stiffness and malleability, memory,thickness and length. Catheters are generally manu-
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factured from nontoxic plastic materials but havedifferent sterilization processes that may affect therelative toxicity and handling procedures (200). Thereis little difference in concept and technology betweenembryo transfer catheters and so it is not surprisingthat there is no clear consensus as to the one catheterthat is superior. However, soft embryo transfercatheters are used most frequently as they producesuperior results (221,222) and are easy to use in allbut the most difficult transfers (222). The maincharacteristic required of a transfer catheter is theability to manoeuvre into the uterine cavity whilecausing no trauma to embryos and endometrium.
There is as yet no consensus as to the depth ofplacement of ET catheters within the uterus. However,contact between the catheter and the uterine fundusstimulates junctional zone contractions that may beresponsible for relocating intrauterine embryos, andso contribute to embryo transfer failure or ectopicgestation (228). High-frequency uterine contractionson the day of embryo transfer have been found todecrease clinical and ongoing pregnancy rates as wellas the implantation rate, possibly by expellingembryos from the uterine cavity (229). Others havereported that there is no relationship between the siteof embryo deposition in the uterus monitored byultrasound (measured as distance from fundus) andthe pregnancy outcome (230). However, all embryoswere deposited at least one to two millimetres from thefundus and no mention was made as to whether thefundus was touched by the catheter. Although thereis no agreement as to the exact depth of placement ofthe catheter within the uterus, there appears to begeneral agreement on the avoidance of touching theuterine fundus (231,232).
In order to assist more accurate catheter placementwithin uteri of various dimensions (233), ultrasound-guided embryo transfer has been developed insteadof relying on clinician “feel”. Studies comparingultrasound-guided embryo transfer to embryo transferby clinician “feel”. failed to demonstrate a significantimprovement in pregnancy and implantation rates(234,235), with the exception of a small subgroup ofpatients receiving a single embryo for transfer (234).However, tactile assessment of embryo transfercatheter placement has been demonstrated to beunreliable (236): in 17.4% of cases the guiding cannulawas inadvertently abutting the fundal endometrium;and in 7.4% of cases abutting the internal tubal ostia.More recent studies suggest that an improvement inboth the clinical pregnancy rate and the implantation
rate can be achieved if ultrasound-guided embryotransfer is used (221,237) . Ultrasound confirmationof the retention of the fluid droplet containing theembryos at the site of catheter placement results inimproved clinical pregnancy rates (221).
During ultrasound-guided embryo transfer,Woolcott and Stanger (236) identified that thetransfer catheter embedded within the endometriumin 24% of cases and deposition of the embryosbeneath the endometrium (intraendometrial transfers)occurred in 22% of cases. However, this appeared tohave no effect on pregnancy outcome. Intentionalintraendometrial embryo transfer has been carried outunder direct visualization using a CO2-pulsed flexiblehysteroscope (238) . A very low implantation rateresulted and it was concluded that the acidifyingeffect of the CO2 on the endometrial stroma might haveproduced a suboptimal environment for earlyembryonic development.
To minimize the potential for movement andexpulsion of embryos following embryo transfer, afibrin sealant, or biological glue, has been used toattach embryos to the endometrium at the site ofembryo deposition (239,240). In a prospective,randomized study, no significant difference in clinicalpregnancy rate or ongoing pregnancy rate, but asignificant reduction in ectopic pregnancies, wasfound (240). No follow-up studies have beenreported.
At the completion of transfer, the catheter shouldbe examined carefully by the embryologist for retainedembryos. Blood, mucus or uterine tissue may attachto the end of the catheter and impede egress of theembryos from the catheter. Blood on the outside ofthe catheter has been related to poorer results (241).Visser et al. (242) reported that failure to deliverembryos on the first attempt at embryo transferresulted in a decrease in pregnancy rate and suggestedthat retained embryos should be transferred one daylater. In contrast, no difference in the clinicalpregnancy rate was found in another study when allembryos were transferred in the first attempt comparedto when repeated attempts were necessary to transferall embryos (243).
Historically, bed rest for up to 24 hours followingembryo transfer has been advised. Bed rest began asa precautionary measure to try to improve implantationrates, even though there is a lack of evidence as to itsbenefit. Immediate mobilization of the patientfollowing embryo transfer does not, however, appearto have a detrimental effect on pregnancy outcome
Embryo culture, assessment, selection and transfer 189
(244–246). It has been shown by ultrasound thatstanding immediately after embryo transfer resultedin movement of embryo-associated air bubbles withinthe uterine cavity in only 6% of cases (247) .Furthermore, there was no evidence of movement ofembryo-associated air outside the uterine cavity andit would appear that standing shortly after transferplays no significant role in the final position oftransferred embryos.
It is difficult to know which embryo transferprotocol to follow to ensure the highest degree ofsuccess, as many of the technical aspects haveundergone very little scientific evaluation, if any. Infact, little evidence exists to support many of thechoices made in this aspect of ART. It is clear, however,that an easy, atraumatic transfer is important withfactors such as patient preparation, medication, mockembryo transfer, choice of catheter, transfer techniqueand bed rest optimized to provide improved outcomesand patient well-being.
Day of transfer
Embryos may be transferred to the patient on Day 1postinsemination at the zygote stage of development(PROST, ZIFT), on Day 2 as two-cell to four-cell earlycleavage-stage embryos (ZIFT, TEST, TET, ET), onDay 3 as six-cell to eight-cell early cleavage-stageembryos (ZIFT, TEST, TET, ET), on Day 4 as morulae(ET), or on Days 5 to 7 as blastocysts of variedmorphology (ET).
In the past 10 years, the majority of clinics haveopted to transfer embryos at the early cleavage stageof development to the uterus on Day 2 postinsemina-tion, despite the fact that, in vivo, the embryo wouldnot pass into the uterus until two to three days laterat the morula to blastocyst stage of development (22,248). Transfer of early cleavage-stage embryos hasbeen the preferred option as it allows confirmation offertilization and a limited assessment of developmentalpotential as the embryo undergoes its first fewcleavage divisions, while at the same time minimizingthe potential compromise to embryo viability posedby prolonged exposure to suboptimal in vitro cultureconditions. In fact, when in vitro culture conditionsare significantly compromised, embryo transfer at thezygote stage of development, rather than at the earlycleavage stage of development, results in much higherpregnancy rates (249).
Recent advances in the formulation of embryo
culture medium and culture conditions has seen a shiftin interest toward transfer of later-stage embryos,particularly blastocysts, as high pregnancy andimplantation rates have been reported despite the factthat fewer embryos are usually transferred (77,120,250–252). Transfer at the morula to blastocyst stageof development allows selection of embryos that havedemonstrated the potential for continued develop-ment under embryonic genomic control (21), althoughthese embryos may not necessarily have a normalchromosome complement (160).
More recently, morphological parameters havebeen established for embryos at the pronucleate orzygote stage of development that identifies embryoswith a high viability (3,6,19,20,155–158). It is difficultto determine which of the various options for day oftransfer will result in the highest success rates as veryfew controlled, randomized comparisons using similarpatient populations have been undertaken.
van Os et al. (253) were the first to demonstratethat embryo transfer could be delayed from Day 2 toDay 3 without any impact on subsequent pregnancyrates. In fact, they argued that a higher number ofviable pregnancies was established following transferof embryos on Day 3. In a later study, Dawson et al.(254) demonstrated that although the pregnancy rateis not different when embryos are transferred on Day2 or Day 3, the implantation rate is significantly higheron Day 3, indicating that selection of viable embryosis improved with a further day in culture. This wasfurther supported by the finding that fewer embryosmiscarried before six weeks of gestation when embryoswere transferred on Day 3 (254). A recent study, usingone of the newer culture medium formulations withoutglucose and phosphate, reported a significantimprovement in both pregnancy and implantationrates when embryos were transferred on Day 3 ratherthan on Day 2 (82). In contrast, Ertzeid et al. (255),in a prospective, randomized study, showed no benefiton the implantation rate or the live birth rate in delayingtransfer from Day 2 to Day 3.
Similarly, delaying embryo transfer until Day 4postinsemination results in similar implantation andpregnancy rates to those achieved following embryotransfer on Days 2 and 3 (256,257) . In addition,Huisman et al. (256) noted that delaying transfer toDay 4 provided the ability to identify embryos with avery high implantation potential. Transfer of cavitat-ing morula stages on Day 4 resulted in a 41% implanta-tion rate per embryo (256) . It was suggested thatdeferring embryo transfer for a few days may provide
190 GAYLE M. JONES et al.
the possibility of selecting fewer and better qualityembryos for transfer and therefore limit the incidenceof multiple pregnancy (256).
Initial attempts at extending culture to the blasto-cyst stage followed by embryo transfer on Day 5resulted in disappointingly low pregnancy andimplantation rates (56, 257). However, improvementsin the culture media and culture conditions for humanembryo development in the past few years haveresulted in the successful development of viableblastocysts (reviewed in (159) ). Scholtes andZeilmaker (258), in a prospective randomized trial,reported no significant difference in pregnancy andimplantation rates when embryo transfer wasperformed on either Day 3 or Day 5. However,deferring embryo transfer to Day 5 allowed theidentification of embryos with very high implantationpotential. Pregnancy and implantation rates werealmost double that recorded for Day 3 transfers whenexclusively cavitating embryos were transferred onDay 5. Gardner et al. (77) using culture mediaformulated to mimic physiological parameters reporteda significantly higher implantation rate when blasto-cysts were transferred on Day 5 compared to earlycleavage-stage embryo transfer on Day 3 (51% and30%, respectively). They further observed that theimplantation rate following blastocyst transfer was notaffected by the number of blastocysts transferred,suggesting that high-order multiple pregnancies couldbe avoided by reducing the number of embryostransferred without a corresponding reduction in thepregnancy rate. Similarly, Milki et al. (252), usingsimilar patient populations demonstrated that theimplantation and pregnancy rates following blasto-cyst transfer on Day 5 was higher than followingtransfer on Day 3. In contrast, in prospective,randomized trials using an unselected population ofpatients, it has been reported that there is nodifference in pregnancy and implantation rates whena similar number of embryos are transferred on eitherDay 3, Day 4 or Day 5 (259,260). Coskun et al . (259)suggested that the superiority in selection of anyparticular embryo stage should be shown by compar-ing the result of transfer of the best single embryo atany stage in a randomized trial.
Blastocyst development occurs in vitro betweenDays 5 and 7 (40,41) . Although several studies havereported that the rate of development to blastocystaffects viability (162,261), others have suggested thatin some instances, blastocysts that form as late as Day7 may have some inherent viability as there is no
difference in cumulative hCG secretion by embryoswhich formed blastocysts from Days 5 to 7 (41,262)and transfer of Day 7 blastocysts occasionally resultsin pregnancies (161). The majority of programmestransfer blastocysts on Day 5 but some programmeshave elected to delay transfer to Day 6 to allow for afurther element of selection among a cohort ofblastocysts (42,76,263,264). Delaying transfers untila time when selection of fully expanded or hatchingblastocysts is possible, rather than automaticallytransferring blastocysts on Day 5, may increaseimplantation rates by providing a further element ofselection (42). Transfer of cryopreserved blastocystshas revealed that pregnancies can be achievedfollowing transfer of blastocysts on Days 5–9following the LH peak but no pregnancy resulted fromtransfer of blastocysts as early as Day 4 following theLH peak (162).
One of the advantages of deferring embryotransfer beyond Day 3 is the possibility of performingpreimplantation genetic diagnosis. Embryo biopsy isusually performed on Day 3 and successfulpregnancies have been established following transferof biopsied embryos on Day 4 which has allowed afull day for genetic analysis by polymerase chainreaction (PCR) (265) or by repeated cycles offluorescence in situ hybridization (FISH) (266). Thereis also a significant advantage to extending cultureto the blastocyst stage of development beforeperforming the biopsy. At this stage, more cells canbe biopsied from the extraembryonic trophectodermfor more complex and accurate preimplantationgenetic analysis (262,267,268). Preliminary researchresults on the recovery rate of biopsied humanblastocysts are promising (262,268) but as yet theprocedure has not been performed clinically.
One of the disadvantages of deferring embryotransfer to Day 5 or beyond is that the embryo transfermay be cancelled if no blastocysts develop in vitro.Certainly, for some groups of patients, transfer on Day5 may not be the best option. It has been reported thatsperm quality can affect the number of blastocystsdeveloping in vitro (42,164,165) . In addition, severalstudies have reported a maternal age-related declinein the number of embryos developing to blastocystsin vitro (50,269,270). This finding may be due to theprogressive reduction in the number of oocytesretrieved with advancing maternal age (50), as thenumber of oocytes retrieved is correlated to thenumber of blastocysts that develop in vitro (42). Anincrease in the number of oocytes retrieved can
Embryo culture, assessment, selection and transfer 191
ameliorate the negative affect of maternal age (163).Racowsky et al. (177) suggested that the number ofeight-cell embryos on Day 3 should be used as thedeterminant for the day of transfer as this has beencorrelated to the number of blastocysts developingin vitro (42). For patients with three of more eight-cell embryos on Day 3, transfer on Day 5 results in ahigh ongoing pregnancy rate with a significantreduction in the incidence of high-order multiplepregnancies (177). Poor prognosis patients with noeight-cell embryos on Day 3 do not benefit fromdeferring embryo transfer from Day 3 to Day 5 (33%and 0% pregnancy rate, respectively) (177). It hasbeen hypothesized that the uterus is apparently ableto “rescue” some of the suboptimal, slower cleavingembryos and that extending the culture time to Day 5for these suboptimal embryos, even in optimizedculture systems, reduces their viability (177,271) .
In conclusion, the introduction in recent years ofmore subjective selection criteria that are better ableto predict viability has resulted in reports of highimplantation rates following transfer of embryos fromthe zygote to the blastocyst stage of development.Although blastocyst transfer has not always resultedin an improvement in pregnancy and implantation ratesin the wider population of infertile patients, it appearsto be the most likely choice if the number of embryostransferred is to be reduced to one to eliminate multiplepregnancies. As there is a relationship between zygotemorphology and embryo morphology at later stages(3), a combination of subjective assessmentsthroughout development may further improve thechances of selecting the single most viable blastocystfrom the cohort and improve the implantation rate andthe number of healthy offspring born as a result ofassisted reproduction procedures.
Endometrial suitability for embryo transfer
Embryo implantation is the result of the successfulinteraction between the embryo and the endometrium(272). Increasing evidence indicates that steroid-induced molecules acting as paracrine modulators arenecessary for embryo–uterine interactions. Success-ful implantation, therefore, is determined both by thequality of the embryo and the receptiveness of theendometrium.
To further improve pregnancy rates, it is clear thatART would benefit substantially from being able todetermine the exact timing of endometrial receptivity
(the implantation window). It is generally believed thatthis window of opportunity occurs between Days 18and 24 of the normal menstrual cycle (273). However,this window may not be absolute and considerableinterindividual variability may exist. Hence, the needto determine for each patient whether the endometriumis adequately prepared at the time of embryo transfer.
Currently available technology for the assessmentof the endometrium prior to embryo transfer can bedivided into microscopic assessment of endometrialbiopsies and imaging techniques.
Microscopic assessment of endometrialbiopsies
The major disadvantages of endometrial biopsies aretheir invasiveness, their negative impact on theintegrity of the endometrium and their interferencewith the implantation process itself. These techniquesshould only be used in unstimulated cycles prior toART. However, the extent to which assessmentsperformed in a natural cycle are predictive of thequality of the endometrium in a subsequent stimulatedcycle has not yet been studied. In addition, theliterature is unclear about the intraindividual variationfrom cycle to cycle. Some uncertainty also exists asto whether one biopsy per cycle is sufficient for theassessment of receptivity.
Histological dating used in the assessment ofmorphological markers has shown that the timing ofbiopsy, the methods used for chronological standard-ization, and the extent of discrepancy required todefine an endometrial biopsy as being “out of phase”remains unsettled (274). A high inter- and intra-observer variation has further limited the clinical utilityof traditional dating techniques.
The formation of pinopods, which are sponge-likesmooth membrane projections that arise from theentire surface of endometrial cells lining the uterinecavity, has been related to the presumed time ofblastocyst implantation (275). They are detected byelectron microscopy, making it a cumbersome andexpensive technique for use in a clinical setting.Conventional light microscopy has been shown to bean unreliable technique for the detection of pinopods(276).
There is a large body of evidence suggesting thatnumerous factors are involved in human implantation.The expanding group of potentially important factorsincludes mucins, integrins, trophinin/tastin, EGF, HB-EGF, amphiregulin, CSF-1, LIF, IL-1b , calcitonin, HOXa-
192 GAYLE M. JONES et al.
10 and COX-2. Most of these biomarkers are typicallyexpressed around the time of the implantation window.However, most of these putative markers of uterinereceptivity have no proven clinical relevance to date.The expression of bstudied extensively. These molecules are consideredlikely to correlate to uterine receptivity. While patternsof integrin expression cannot be used to accuratelydate the endometrium (274), they may reveal sub-groups of endometrial dysfunction in patients in theabsence of morphological abnormalities identified atthe light microscopic level (277–279). Although thisinformation may be useful when advising the patientabout the cause of her infertility, there are no objectivedata to show that integrin expression patterns actuallypredict endometrial receptivity.
Imaging techniques (ultrasound and magneticresonance imaging)
Because of their noninvasive nature, imagingtechniques are ideally suited to assess the endo-metrium immediately prior to embryo transfer. Incontrast to magnetic resonance imaging (MRI),ultrasonography is a much cheaper and more widelyavailable imaging technique. However, the spatialresolution (degree of detail) of MRI is superior to thatof ultrasonography.
Conflicting results have been reported regardingthe correlation between the thickness of the endo-metrium and pregnancy rates following ART (280–289). Measurement of endometrial thickness, or evenendometrial volume, with three-dimensional ultra-sound techniques does not yield better results (290).This may be explained by the fact that the thicknessof the endometrium has been shown to be moredependent on the time of exposure to estrogen ratherthan the dose of estrogen exposure (288). In addition,important interindividual variation in endometrialthickness on the day of hCG administration has beennoted.
The echogenicity of a tissue is a measure of itscapability to reflect ultrasound waves. Some studieshave shown that endometrial echogenicity in the latefollicular phase predicts ART outcome (280,283,288,291–293). Others, however, have failed to find arelation between endometrial echogenicity andimplantation rates (294, 295). This controversy maybe explained by operator-dependent variability, theuse of arbitrary and heterogeneous classifications,and the lack of control for confounding factors (e.g.
poor embryo quality and uterine cavity abnormalities)that influence the analysis of results. In an encourag-ing study, endometrial echogenicity on the day of hCGadministration was assessed objectively with acomputer-assisted module for the analysis of ultra-sound images in a selected subset of ART patients(289). In this study, echogenicity patterns werestrongly correlated with implantation rates. However,the diagnostic value in an unselected population ofpatients remains to be determined.
Endometrial blood flow may be used as a func-tional marker and since the development of powerDoppler sonography and, more recently, three-dimensional power Doppler sonography, it has becomepossible to evaluate the vessel density and perfusionin the endometrial and subendometrial layers in aquantitative way. Most studies so far have been rathersmall and conflicting results have frequently beenreported (296–301).
The junctional zone which is the myometrial layerjust underlying the endometrium, has recently beendescribed as a separate functional unit. One of thefunctional properties of this layer is that it producescontraction waves. Contractions can be directedtowards the uterine fundus, the cervix, or they can bechaotic or opposing. These contractions have beendemonstrated to be strong enough to displaceembryos in the uterine cavity (204). The direction andamplitude of these contraction waves are stimulatedby hormonal influences (302) and physical stimuli(e.g. difficult transfer) (204,206). One study wascontrolled for confounding variables and uterinecontractions were assessed objectively by acomputerized system (229). In the selected patientpopulation, high frequency contractions on the dayof embryo transfer were found to decrease implanta-tion and pregnancy rates. A negative correlationbetween uterine contraction frequency and serumprogesterone concentrations was also observed,illustrating the uterine relaxant properties ofprogesterone.
Ultrasonography clearly has a number of majoradvantages (low cost, wide availability, possibilitiesfor standardization using computer software), makingit the area with the greatest potential for clinicalapplication. However, to become generally accepted,any assessment will need to be rigorously tested forits diagnostic value. Although some tests have beenshown to be quite promising in selected subpopula-tions of patients, these same tests need to be re-evaluated in unselected patient populations. In these
Embryo culture, assessment, selection and transfer 193
evaluations, investigators will need to report oncommonly used parameters such as sensitivity,specificity, positive predictive value and negativepredictive value. In particular, receiver–operatorcurves should be provided with each test.
A further area of research will have to focus onhow the results of these endometrial assessments canassist the clinician in achieving better outcomes forthe patient. Some authors have suggested that freshembryo transfers may need to be delayed in the eventof an unfavourable assessment of endometrial recepti-vity. It seems unlikely that many patients will acceptthis decision and therefore research efforts shouldconcentrate on the development of medical interven-tions that may improve endometrial receptivity.
Luteal phase support
One area that has received a lot of attention is the needfor luteal phase support in downregulated cycles.Since the original articles of Smitz et al. (303) andWildt et al. (304) were published, the use of lutealsupport in downregulated ART cycles has beenaccepted as best medical practice. Various methodshave been described to support the luteal phase. Theuse of hCG injections has been abandoned in mostcentres in favour of progesterone. The long half-lifeof hCG and its direct stimulation of the ovarycontribute to the associated increased risk of ovarianhyperstimulation syndrome (OHSS) (305). Proges-terone can be administered in a variety of ways. Theintramuscular and vaginal routes are currently themost widely adopted. Orally administered proges-terone is rapidly metabolized in the gastrointestinaltract and its use has proved to be inferior (306). A lotof controversy still exists as to whether the vaginalroute results in better secretory endometrialtransformation. This controversy stems from the factthat vaginally administered progesterone results inadequate secretory endometrial transformation,despite serum progesterone values lower than thoseobserved after intramuscular administration, even ifthey are lower than those observed during the lutealphase of the natural cycle. This discrepancy isindicative of the first uterine-pass effect and thereforeof a better bioavailability of progesterone in the uterus(306).
Recent research has highlighted the detrimentaleffects of high estradiol levels on implantation(307,308). Implantation rates are lower in patientswho are high responders. The implantation and
pregnancy rates were correlated to the peak estradiolconcentration, regardless of the number of oocytescollected (309). The effect of estradiol was mediatedthrough endometrial receptivity as demonstrated in astudy involving oocyte donors. The implantation ratesin recipients of embryos derived from high responderswere similar to normal responders (309). It has beensuggested that stimulation protocols aimed at reduc-ing the follicular response may overcome the lowimplantation rates in high responders. Simon et al.(309) used the step-down protocol, originallyproposed by Fauser et al. (310), to successfullyimprove both the implantation and pregnancy ratesin high responders. This involved the administrationof 100 or 150 IU/day recombinant FSH starting on cycleDay 5 (311). From cycle Day 8 or later, cotreatmentwas begun with 0.25 mg/day GnRH antagonist. Noluteal support was provided. This pilot studydemonstrated that IVF is feasible with a minimalstimulation approach and that luteal support may notbe necessary.
This also raises the issue of whether the use ofthe short-acting gonadotrophin-releasing hormone(GnRH) antagonists is likely to change the need forluteal phase support. The pilot study of de Jong et al.(311) seems to suggest that luteal support is notnecessary following GnRH antagonist administrationin an IVF cycle. This finding is in direct contrast tothe results from another small study that concludedthat corpus luteum function may be impaired in cyclesstimulated with hMG and a GnRH antagonist (312).
Antiphospholipids
In a completely different area of research, mountingevidence suggests that inheritable thrombophilias,such as activated protein C resistance, Factor V Leidenmutation, or hyperhomocysteinaemia are associatedwith an increased risk of fetal loss and pre-eclampsia.Acquired thrombophilias, such as the antiphospho-lipid syndrome (APS), are also emerging as animportant cause of recurrent pregnancy loss. Thecommon pathogenic pathway is thought to be slowprogressive thrombosis and infarction in the placenta.For patients with APS who have a history of thrombo-sis or recurrent pregnancy losses, heparin plus low-dose aspirin appears to be the regimen of choice(313,314) . Interestingly, antiphospholipid antibodies(APA) have also been shown to interact with syn-cytiotrophoblast and cytotrophoblast layers andcould, therefore, theoretically affect implantation.
194 GAYLE M. JONES et al.
Several trials of treatment with heparin and aspirin inwomen with positive APA undergoing IVF have beencompleted. Although none of the studies wererandomized, prospective, blinded trials there does notappear to be a significant effect of heparin–aspirintreatment on implantation rate, pregnancy rate, orongoing pregnancy rate. Furthermore, it should bestressed that heparin–aspirin treatment may not bewithout complications. One maternal death has beenreported associated with heparin–aspirin treatment inIVF, due to a cerebral haemorrhage in a nine-weekpregnant woman carrying triplets (315) . Subcuta-neous heparin does not cross the placenta andtherefore has no adverse effects on the fetus, butpotential side-effects for the mother include bleeding,thrombocytopenia and osteoporosis.
Antibiotics
Recently, there has been growing interest in the effectof infectious agents on ART pregnancy rates. Theassumption is that women with specific vaginalpathogens may have an increased incidence ofendometritis, which would lead to a reduced implanta-tion rate. Although it is part of good clinical practiceto treat any clinically manifest genital tract infection,it is unclear whether screening for microorganismsshould be routine. One study assessed the impact ofindividual bacteria isolated from the vagina and thetip of the embryo transfer catheter on livebirth rates(316). It was found that different types of bacteriarecovered from the embryo transfer catheter hadvariable effects on live-birth rates. Prophylacticdoxycycline had little effect on the vaginal flora.
The issue of whether bacterial vaginosis, if presentat the time of oocyte recovery, adversely affectsfertilization and implantation has been investigatedmore closely. The prevalence of bacterial vaginosiswas much higher in infertile patients undergoing ARTtreatment than found by others in antenatal andgeneral gynaecological populations (317). In allstudies to date, no significant effect of bacterialvaginosis on fertilization and implantation rates hasbeen demonstrated (317–319). Therefore, routinescreening and treatment for bacterial vaginosis beforeART treatment would appear to be unwarranted.
Furthermore, antibiotic therapy may increase thelikelihood of inoculation of antibiotic-resistant patho-genic bacteria from the vagina into the embryo culturesystem during vaginal oocyte collection (320) .Whether screening and treatment of bacterial
vaginosis would result in a reduction in later complica-tions during pregnancy remains an open question(317).
In summary, ultrasound techniques seem to holdthe greatest promise of becoming clinically usefultools to assess endometrial receptivity. Most of theultrasound techniques still await proper validation inunselected patient populations. Further research isrequired to investigate how patients with a poorlyprepared endometrium should be managed clinically.
Impact on offspring
Since the birth of the first IVF baby in 1978, severalhundred thousand babies have been born worldwideas a result of assisted conception. Several interna-tional registers of births resulting from IVF have beenestablished to enable assessment of the health ofthese children and several analyses of the datarecorded in these registers have been published todate and are summarized in Table 1.
The majority of studies have demonstrated nomajor differences in outcomes for singleton preg-nancies except perhaps for an increased incidence ofpremature and low-birth-weight babies. However,these findings seem to be dependent more on patientcharacteristics than on the ART per se, as no majordifferences can be found for ART children comparedto the general population when patients are matchedfor parity, maternal age and year of delivery (321,322).
By far the greatest adverse impact on offspringborn as a result of ART is as a direct result of theincreased incidence of multiple pregnancy. The
Table 1. Summary of national registers of ART andoutcomes
Publication reference Register Years
(330,338,340,372–378) Australia and 1979–1997New Zealand
(321) Denmark 1994–1995
(332) Finland 1991–1993
(328,329) France 1986–1990
(327) Great Britain 1978–1987
(337) Israel 1982–1989
(323) Sweden 1982–1985
(339,379–387) USA and Canada 1988–1997
Embryo culture, assessment, selection and transfer 195
Swedish registry study showed a 20-fold increasedrisk of being born as a multiple birth baby for an ARTchild compared with the general population (323).The last world collaborative report on ART recordeda multiple birth rate of 29%, the majority of which weretwins (324). Multiple birth infants, regardless ofwhether they originate from ART or spontaneousconception, have an increased risk of preterm delivery,low birth weight, congenital malformations, fetal andinfant deaths and long-term morbidity and disabilityas survivors (325,326) . There is a fivefold increasein premature delivery of children resulting from ART(323). This can be explained in the main part by theincidence of multiple births but is also true forsingleton births (323,327–331).
There is also an increased incidence of low-birth-weight babies following ART compared to the generalpopulation, even when only singleton pregnanciesare considered(323,327–330,332) . More recently,with the increasing use of extended culture followedby blastocyst transfer, concerns have been expressedabout the potential for producing babies with highbirth weights similar to the “large offspring syndrome”reported following blastocyst transfer in domesticanimal species (333,334). However, human infantsconceived following blastocyst transfer are notsignificantly different in birth weight from infantsconceived spontaneously (335) or from infantsconceived following transfer of early cleavage-stageembryos (336). Perinatal and infant mortality is 1.7–3 times the national average (323,327–330,337) and,in some ART populations, is accounted for entirelyby the high percentage of multiple births (327,328) .
Children born as a result of ART have an increasedrisk of malformations compared with the generalpopulation; however, this risk can be partly explainedby the high proportion of multiple births in the ARTgroup (323). An increased incidence of neural tubedefects (anencephaly, hydrocephaly, spina bifida)(323,327,328,338), oesophageal atresia (323) andtransposition of the great vessels (338) has beenreported for ART infants. In the Swedish study, tenART infants (0.2%) had neural tube defects (anen-cephaly and spina bifida) compared with the expectednumber of three to four. Seven of these ten infants andsix of seven ART infants with hydrocephalus werefrom sets of twins (323). Similarly, in the Australianstudy, three of six infants born with spina bifida andtwo of four infants born with transposition of the greatvessels were from multiple births (338). Other studieshave reported no increase in congenital malformations
in large numbers of ART children, despite a very highincidence of multiple pregnancy (339).
Multiple pregnancies are also associated withincreased infant and childhood morbidity such ascerebral palsy and mental retardation, due primarilyto the increased incidence of prematurity and lowbirth weight (325,326) . The Swedish study failed toidentify any increase in the incidence of cancer inchildren resulting from ART (323) which is in contrastto a previous report indicating a possible increase inneuroectodermal tumours (340). Most follow-upstudies of children born as a result of ART have notbeen running for long enough to assess the risks oflong-term handicap.
A follow-up study of singleton infants conceivedby ART to first-time mothers for the first yearfollowing birth has shown no difference in mental,motor, speech and social development compared to amatched control from the general population (341).Similarly , the mental development of childrenconceived by ART at the age of 12 months was normaland not different from matched controls (342) .However, children of multiple births score lower onaverage, both on physical and mental scales (342).Brandes and co-workers (342) concluded that whenan ART pregnancy is carried to term, yielding anapparently healthy infant, the infant can be expectedto develop and thrive similarly to non-ART-conceivedpeers. Similarly, Wennerholm and co-workers (331)concluded that if the neonatal period is uncomplicated,subsequent growth and development of childrenconceived by ART will be normal. In studies of olderchildren, no independent ART effect has been foundfor growth and physical outcome (when matched forplurality and weeks of gestation) (343) or forcognitive, behavioural and social development (344) .
In very large studies, the sex ratio for birthsresulting from ART does not differ significantly fromthe national ratios (327,328), although it has beensuggested that sex selection may be inadvertentlyperformed in ART programmes by selecting for thefaster cleaving embryos (345). It has, however, beenreported that the sex ratio for births resulting fromblastocyst transfer, when the fastest cleaving embryosare selected for transfer, favours males and representsa significant shift in the sex ratio for births resultingfrom spontaneous conceptions (335).
The high incidence of multiple births followingassisted conception is largely due to the practice oftransferring multiple embryos. This practice has arisenfrom the data indicating that at least for the first three
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to four early cleavage-stage embryos transferred,there is a positive correlation between the number ofembryos transferred and the pregnancy rate (346).However, progress in the past decade has seen theintroduction of improved culture media, cultureconditions and selection criteria for embryo transferand the corresponding implantation rates haveincreased dramatically. The improvement in implanta-tion rates allows, for the first time, the considerationof reducing the number of embryos for transfer to two(152,250,347–356), and possibly even one (120,149,151,357,358), to eliminate the risks associatedwith multiple pregnancy whilst still maintaining highpregnancy rates.
However, reducing the number of embryos fortransfer will not entirely eliminate multiple pregnancies.Monozygotic twinning (identical twins formed fromthe one embryo) has been reported to be higherfollowing assisted reproduction (359,360) than in thegeneral population. Monozygous twins, and inparticular monozygous, monochorionic twins(identical twins which share the same chorion), addsignificantly to the risks associated with multiplepregnancy and to the poorer health and survival ofoffspring. The incidence of monozygotic twinning hasbeen reported to be very high in the subgroup of ARTpatients whose embryos have been zona manipulated,either for assisted fertilization (SUZI or ICSI) orassisted hatching (creating a small hole in the zonaby mechanical, chemical or laser methods) (361–364). Others, however , have reported that thefrequency of monozygotic twinning is not differentfor patients whose embryos have been zona manipula-ted and those that remain zona intact (365). Theincidence of monozygotic twinning has also beenreported to be very high following blastocyst transfer(366,367) .
Although the exact mechanism of monozygotictwin formation in ART is unknown, it has been ascribedto ovulation induction (368), ART culture conditions(359), zona architecture or micromanipulation (364),or asynchrony between the uterus and embryo (369).The observation that the incidence of monozygotictwinning following ovulation induction is also higherthan that of the general population (368) suggests arole for hormonal manipulation rather than in vitroembryo culture conditions. Alterations in thehormonal milieu may lead to delays in oocyte or embryotransport and implantation at crucial developmentalmoments resulting in induction of twinning (360).Alternatively, exposure to high concentrations of
gonadotrophins may lead to zona hardening (370)resulting in impaired hatching at the blastocyst stageand retention of part of the embryo within the zona.This could result in two separate embryos forming ifthe inner cell mass is bisected (371). Exposure to invitro culture conditions rather than oviductal anduterine secretions containing lysins may similarlyresult in zona hardening and impaired hatching (359) .The higher incidence of monozygotic twinningobserved following transfer of embryos that haveundergone zona manipulation suggests an additionalrole for the architecture of the zona (364). Thedimensions of the artificial gap created during assistedfertilization or assisted hatching, particularly if small,may impose a physical restriction to the emergingembryo causing it to split (364). The size of theartificial gap, however, varies significantly accordingto the method of assisted hatching and according tothe degree of technical expertise of the embryologistperforming the procedure. This variation may help toexplain the discrepancy in the reported incidence ofmonozygotic twinning following assisted hatching(365). Zona trapping, however, cannot be the entireexplanation for the increased incidence of monozygo-tic twinning reported following blastocyst transfer, asthe incidence remains high despite transfer of blasto-cysts that have had the zona chemically removed priorto transfer (G.M. Jones and A.O. Trounson, personalcommunication). The findings of Meintjes et al. (369)that the incidence of monozygotic twinning followingblastocyst transfer and in patients using donoroocytes lends some support to the idea that mono-zygotic twinning arises due to some compromisedendometrial–embryo communication and subsequentasynchrony between the uterus and endometrium.
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342. Brandes JM et al. Growth and development of childrenconceived by in vitro fertilization. Pediatrics, 1992,90:424–429.
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345. Tarin JJ et al. Sex selection may be inadvertentlyperformed in in-vitro fertilization-embryo transferprogrammes. Human Reproduction, 1995, 10:2992–2998.
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347. Tasdemir M et al. Two instead of three embryo transferin in-vitro fertilization. Human Reproduction, 1995,10:2155–2158.
348. Toledo AA et al. Blastocyst transfer: a useful tool forreduction of high-order multiple gestations in a humanassisted reproduction program. American Journal ofObstetrics and Gynecology, 2000, 183:377–379.
349. Ludwig M et al. Experience with the elective transferof two embryos under the conditions of the Germanembryo protection law: results of a retrospective dataanalysis of 2573 transfer cycles. Human Reproduc-tion, 2000, 15:319–324.
350. Hu Y et al. Maximizing pregnancy rates and limitinghigher-order multiple conceptions by determining theoptimal number of embryos to transfer based onquality. Fertility and Sterility , 1998, 69:650–657.
351. Matson PL et al. The transfer of two embryos insteadof three to reduce the risk of multiple pregnancy: aretrospective analysis. Journal of Assisted Reproduc-tion and Genetics, 1999, 16:1–5.
352. Devreker F et al. Comparison of two elective transferpolicies of two embryos to reduce multiple pregnancieswithout impairing pregnancy rates. Human Reproduc-tion, 1999, 14:83–89.
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356. Templeton A, Morris JK. Reducing the risk of multiplebirths by transfer of two embryos after in vitrofertilization. New England Journal of Medicine, 1998,339 :573–577.
357. Strandell A, Bergh C, Lundin K. Selection of patientssuitable for one-embryo transfer may reduce the rateof multiple births by half without impairment ofoverall birth rates. Human Reproduction , 2000,15:2520–2525.
358. Vilska S et al. Elective transfer of one embryo resultsin an acceptable pregnancy rate and eliminates the riskof multiple birth. Human Reproduction , 1999,14:2392–2395.
359. Edwards RG, Mettler L, Walters DE. Identical twinsand in vitro fertilization. Journal of In Vitro Fertilityand Embryonic Transfer, 1986, 3 :114–117.
360. Wenstrom KD et al. Increased risk of monochorionictwinning associated with assisted reproduction. Fertilityand Sterility, 1993, 60:510–514.
361. Slotnick RN, Ortega JE. Monoamniotic twinning andzona manipulation: a survey of U.S. IVF centerscorrelating zona manipulation procedures and high-risktwinning frequency. Journal of Assisted Reproductionand Genetics, 1996, 13:381–385.
362. Hershlag A et al. Monozygotic twinning associated withmechanical assisted hatching. Fertility and Sterility,1999, 71 :144–146.
363. Schieve LA et al. Does assisted hatching pose a riskfor monozygotic twinning in pregnancies conceivedthrough in vitro fertilization? Fertility and Sterility,2000, 74 :288–294.
364. Alikani M et al. Monozygotic twinning in the humanis associated with the zona pellucida architecture.Human Reproduction , 1994, 9 :1318–1321.
365. Sills ES et al. Human zona pellucida micromanipulationand monozygotic twinning frequency after IVF. HumanReproduction, 2000, 15:890–895.
366. Rijnders PM, Van Os HC, Jansen CAM. Increasedincidence of monozygotic twinning following thetransfer of blastocysts in human IVF/ICSI. Fertility andSterility , 1998, 70:S15–S16.
367. Peramo B et al. Blastocyst transfer and monozygotictwinning. Fer tility and Sterility, 1999, 72:1116–1117.
368. Derom C et al. Increased monozygotic twinning rateafter ovulation induction. Lancet, 1987, 1 :1236–1238.
369. Meintjes M et al. Increased incidence of monozygotictwinning when transferring blastocysts: laboratory orclinical. Fer tilility and Sterility, 2000, 74:S74.
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372. IVF and GIFT pregnancies Australia and New Zealand1988. Sydney, National Perinatal Statistics Unit andFertility Society of Australia, 1990.
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378. Hurst T, Shafir E, Lancaster P. Assisted conceptionAustralia and New Zealand 1996. Report No. AssistedConception Series No. 3. Sydney, Australian Instituteof Health and Welfare National Perinatal StatisticsUnit, 1997.
379. Medical Research International, Society for AssistedReproductive Technology, American Fertility Society.In vitro fertilization-embryo transfer in the UnitedStates: 1988 results from the IVF-ET Registry.Fertility and Sterility, 1990, 53:13–20.
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210 LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
Preimplantation genetic diagnosis
LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
Embryo selection methods and criteria
Introduction
The potential transmission of genetic disorders to theoffspring has been a major problem for many coupleswhen contemplating pregnancy. The risk has beengreatly decreased by the evaluation of the familyhistory or the age of the mother, and the implementa-tion of prenatal diagnosis in those couples where therisk was increased compared to the general population.
An alternative approach that is available withassisted reproductive technology (ART) is pre-implantation genetic diagnosis (PGD) by which it ispossible to have the disorder screened before thecorresponding embryo is transferred to the uterus ofthe mother. The idea of PGD emerged in the early 1960swhen sexing of rabbit embryos at the blastocyst stagewas attempted (1). This happened even before theintroduction of in vitro fertilization (IVF) techniquesin human reproductive medicine (2). In the followingyears, the merging of these two techniques made PGDpossible as a new approach for the prevention ofgenetic disorders.
PGD can be applied in two different situations: itcan be offered to couples at risk of having children withsingle-gene disorders, such as cystic fibrosis orthalassaemias; or, it can be implemented for thescreening of chromosomal disorders, both numerical(i.e. aneuploidy) and structural (i.e. inversions ortranslocations).
The application of PGD is especially relevant inreproductive medicine as genetic factors can beassociated with infertility. In addition, the identifica-tion, after chromosomal analysis, of euploid embryosand their selective transfer has a positive effect on theclinical outcome observed in patients at risk ofdeveloping aneuploid embryos. This is probably dueto the fact that chromosomal abnormalities representone of the major causes of spontaneous abortionsand, possibly, implantation failures. Ovarian hyper-stimulation and IVF are necessary to generate in vitroseveral embryos in order to select those that are notaffected. One or two cells are generally available forgenetic analysis and they are removed from embryoson Day 3 of development, or from the trophectodermof an expanded blastocyst (the clinical use of blasto-cyst biopsy is still under investigation and thereforeit is not taken into consideration in this review).Alternatively, polar bodies can be excised fromoocytes and used to analyse disorders of maternalorigin. In any case, the diagnostic method must besensitive enough to deal with very low quantities ofDNA and sophisticated to the point of giving resultswith the highest reliability. The polymerase chainreaction (PCR) is the technique of choice for theidentification of single-gene defects. Special strategiesare used to avoid contamination from exogenous DNAand to check that both alleles are amplified during thereaction. The numerical analysis of interphase
Preimplantation genetic diagnosis 211
chromosomes is based on the use of specific fluore-scence-labelled DNA probes in the fluorescent in situhybridization (FISH) technique. The use of multipleprobes permits the simultaneous screening of severalchromosomes and can be completed by successiverounds of FISH using different probes.
The first clinical applications of PGD werereported in 1990 (3,4) with the first pregnanciesobtained following blastomere biopsy and sexdetermination by PCR in couples at risk of havingchildren with X-linked disorders (3) . Since then,hundreds of PGD cycles have been undertaken whichshow a growing interest in this approach even byfertile couples who agree to IVF in order to make PGDpossible. The list of diseases for which PGD has beenused is rapidly increasing. Theoretically, it can beperformed for any condition for which gene sequen-cing is available. This information is necessary todesign the primers needed for the selective amplifica-tion of the DNA region involved in the mutation.Similarly, FISH can be used for the screening ofaneuploidies and structural chromosomal defectssuch as translocations. The advantages are represent-ed by an increased implantation rate and a concomi-tant reduction in the incidence of spontaneousabortions due to the better viability of euploidembryos (5,6). Therefore, PGD for aneuploidy is notonly an alternative to the management of embryoabnormality leading to therapeutic termination of analready established pregnancy, but also a method tomaximize the efficacy of ART procedures.
Special emphasis during the past few years hasbeen given to maximizing the efficiency of single-cellanalysis. Strategies aimed at the identification andexclusion of sources for misdiagnosis during PCR orFISH have been designed. This has enabled the defini-tion of the best conditions and scoring criteria whichprovide the highest accuracy and reliability of PGD.
The state of the art of PGD was reported at themeeting of the International Working Group onPreimplantation Genetics during the 3rd InternationalSymposium on Preimplantation Genetics held inBologna in 2000 (7). More than 2500 cycles had beenperformed worldwide at that time, resulting inapproximately 600 clinical pregnancies (24%) and thebirth of nearly 500 children. Seven cases of discord-ance between PGD and the genotype/karyotype of thecorresponding fetus have been reported, establishingan accuracy rate of 98.2%. The follow-up of the first236 infants born after PGD revealed a total of 11malformations (4.7%). This incidence is comparable
to the malformation frequency observed in the generalpopulation (7,8). A comprehensive review of theresults obtained over 1318 PGD cycles has beenpublished by the ESHRE PGD consortium (8).
Identification of problems with thetechniques, protocols and methodology
Diagnostic methods in PGD are based on DNAtechnology. PCR is mostly used for the detection ofsingle-gene mutations related to monogenic disorders ,while FISH is used to screen for aneuploidy orstructural chromosomal abnormalities.
The methods used to retrieve, from oocytes orembryos, the material destined to undergo PGD arethe same, irrespective of the type of genetic analysisrequired. The biopsy procedure entails micromani-pulation. Special attention has to be paid to the correctand clear labelling of the dishes used for biopsy andculture to guarantee concordance between thebiopsied cell and the oocyte or embryo of origin.
As a general consideration, an accurate assess-ment of oocyte maturity and quality—the appearanceof pronuclei and polar bodies—and a morphologicalevaluation of embryo development are crucial for theappropriate selection of the material for genetic analysis(9,10) . Therefore, a careful and expert evaluation ateach stage of oocyte morphology and developmentis necessary to obtain the best results (11).
Polar body biopsy
The majority of oocytes retrieved after induction ofmultiple follicular growth are at the metaphase II stageindicated by the presence of the first polar body (PB1)which is generally extruded at 36–40 hours after hCGinjection. The PB1 is the byproduct of the first meioticdivision and contains the counterpart of the oocytechromosomes, which are diploid at this stage.Following fertilization, the number of chromosomesin the oocyte is reduced by half by extruding a 23-chromosome set in the second polar body (PB2).
Analysis of both polar bodies is necessary toobtain a genetic diagnosis. In the case of PGD forsingle-gene disorders, PB1 and PB2 must be removedsequentially and analysed separately to evaluate thepossible occurrence of crossover between homo-logous chromosomes during meiosis. For screeningof aneuploidy, both polar bodies can be removedsimultaneously; the interpretation of the results is
212 LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
based on the fact that PB1 is diploid and PB2 haploid(9).
PB1 biopsy
Removal of the PB1 is performed by micromanipula-tion of the oocyte approximately four hours afteroocyte retrieval. At this time, PB1 is usually detachedfrom the oolemma. The oocyte is secured by theholding pipette with the polar body at the six or twelveo’clock position. A slit is opened in the zona pellucidaby using a glass needle and the polar body aspiratedwith a thin, polished glass pipette. Within one hour,oocyte insemination is accomplished by intra-cytoplasmic sperm injection (ICSI) with the injectionneedle introduced through the breach already openedin the zona. ICSI is recommended, not only to decreasethe risk of sperm DNA contamination, but also toavoid the high incidence of polyspermy resulting fromthe opening made in the zona pellucida. PB1 biopsydoes not adversely affect either fertilization orcleavage. This approach could be especially advan-tageous in the case of female translocations detectedby FISH analysis with chromosome painting (12).
PB2 biopsy
The PB2 is removed by introducing the aspirationpipette through the slit previously made to remove thePB1. This step is delicate as connections may still existbetween PB2 and the oocyte membrane. Biopsiedoocytes are then returned to culture dishes andincubated until the time they need to be checked forcleavage.
PB1 and PB2 biopsy
The simultaneous removal of both polar bodiesinvolves the same technique as described in the caseof PB1 biopsy. This strategy reduces the time andpossible stress associated with the micromanipulationprocedure, and limits biopsies and genetic analysesto normally fertilized oocytes. Nevertheless, someconcerns still remain about the frequent degenerativechanges found in PB1 at the time of fertilizationcontrol.
In conclusion, polar body biopsy maintainsembryo integrity as only byproducts of meiosis areused for the genetic analysis of the oocyte. It is alsoan alternative in cases where PGD is unacceptable.However, paternally-derived defects and those
originating after fertilization or the first embryonicdivisions cannot be diagnosed.
Blastomere biopsy
The biopsy of one or two blastomeres is generallyperformed 62–64 hours after insemination. This timeconstraint is due to the fact that compaction starts atthis time. Cellular damage is very likely if the procedureis attempted when cell–cell interactions and junctionshave already begun to be established. Alternatively,embryos can be washed in a divalent cation-deficientmedium to disrupt cell adhesions and tight junctions(13). The biopsy procedure involves an opening inthe zona pellucida of approximately 20–25 µm diameter.Three different methods have been proposed.
Mechanical
A glass microneedle is used to make a series of slitsin the zona pellucida. In this way, a V-shaped triangularor square flap opening is created (9). This method istime-consuming and requires a very skilled operator.
Chemical
After loading acidic Tyrode’s solution (pH 2.35) in a12 mm diameter pipette, the blastomere selected forbiopsy is set at the three o’clock position. The outeredge of the blastomere is brought into focus and thepipette is quickly lowered in close proximity to theembryo. The acidic solution is blown towards the zonapellucida at a point corresponding to the blastomere’sposition, with both the blastomere and the tip of theacidic solution pipette kept in focus. When the breachis open, the excess of acidic solution in the mediumclose to the embryo is aspirated by using the sameacidic solution pipette. This is the most commonlyused method (8).
Contact laser
A nontouch microdrill is used to make an opening inthe zona pellucida and there is no need to remove theembryos from the culture medium (14). Although veryquick and precise, not enough data are available yetabout the safety of this method when used on humanoocytes and embryos to make its use more common.
When opening the zona pellucida, the position ofthe embryo is selected so that a nucleated blastomere
Preimplantation genetic diagnosis 213
is at the three o’clock position. The presence of anucleus is fundamental for DNA analysis. Unfortu-nately, nuclei are not always visible and, in this case,the selection of the blastomere is mainly based on itssize and cytoplasmic appearance to reduce the chanceof removing anucleated fragments. A 30–40 µmdiameter glass pipette is brought close to the openingin the zona pellucida. The outer edge of the blastomereand the tip of the blastomere aspiration pipette arekept in focus. Using very gentle aspiration, theblastomere is slowly brought into the pipette and thenreleased in the medium. Extreme care is required toavoid cell membrane rupture and damage to either thebiopsied cell or the surrounding blastomeres. Afterbiopsy, the embryo is carefully washed, put in freshmedium and incubated until the time of transfer. Thebiopsied cells are left in the micromanipulation dishat room temperature.
In conclusion, PGD using blastomeres is advan-tageous due to the possibility of screening disordersof both maternal and paternal origin, and thoseoriginating after fertilization. Although the mass of theembryo is reduced, no detrimental effects on embryoviability have been reported (15). In fact, data fromthe clinical outcome of biopsied embryos havedemonstrated that approximately one-fourth of theseembryos are able to implant (5). On the other hand,mosaicism, which seems to be a common characteristicin human embryos generated in vitro , may representa problem for genetic diagnosis performed at thecleavage stage. This complication will probably persistin the case of blastocyst biopsy as well (16,17).
Chromosomal analysis
The cells obtained by the biopsy procedures describedabove are put in hypotonic solution, fixed on a glassslide with methanol and glacial acetic acid, dehydratedin increasing concentrations of ethanol and incubatedwith the hybridization panel.
The process of fixation is critical for the finaldiagnosis. The most common problems are:
• loss of the cell during fixation. Constant observa-tion under the microscope is necessary duringfixation; the location of the fixed nucleus must bedefined by encircling with a diamond pen.
• residual cytoplasm. All cytoplasm must be dis-solved completely so that it does not interfere withthe interpretation of the fluorescent signals.Fixative must be added when the cell starts to
flatten out and before the complete drying of thehypotonic solution.
• reduced spreading of the chromatin. The correcttiming for adding the fixative is critical to obtain agood spreading of the chromatin. An inversecorrelation has been demonstrated between thediameter of the fixed nucleus and the occurrenceof overlapping signals (18).
• loss of micronuclei. Following rupture of thecytoplasmic membrane, the addition of more fixativecan frequently cause loss of micronuclei (andchromosomes) which is easily detected by a highincidence of false monosomies (19).
Following dehydration of the fixed nuclei, thefluorescence-labelled probes are added for multicolourFISH to take place. Attention must be paid to (i)adding the probe on the same side of the glass slidewhere the nuclei are fixed; (ii) avoiding any scratchesby not touching the surface of the glass slide next tothe fixed nuclei with the dispensing pipette; and (iii)avoiding the formation of air bubbles, especially whenthe coverslip is added.
A simultaneous denaturation of DNA probes andspecimen DNA is accomplished at temperatures of 68–73°C for three to five minutes (these conditions canvary depending upon the probe mixture used and theprotocols established in each laboratory). Re-annealing and formation of hybrids follow byincubation at 37°C for at least three hours in the caseof blastomeres, but a longer incubation is required forpolar bodies. At the end of the reaction, the excess ofprobe (either unbound or nonspecifically bound) isremoved by washing at high temperatures (71–73°C)in salt solution. Following counterstaining in antifadesolution, fluorescent signals are scored under 600times magnification with a fluorescence microscope.Criteria for the interpretation of the fluorescent signalshave been described (9,19) . Rehybridization of thesame biopsied cell with additional probes in asubsequent round of FISH is important as it expandsinformation on a larger number of chromosomes (20) .The capture of the fluorescent signals on a computer-ized image analysis system is of help not only forstorage but also for the interpretation and review ofthe detected signals.
The most common sources of error during thisprocedure are loss of micronuclei, signal overlapping,failed hybridization, inadequate scoring criteria for theinterpretation of split signals and mosaicism.
Special precautions have been established to
214 LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
reduce the technical errors associated with chromatinfixation, hybridization and interpretation of the correctsignals. Mosaicism still remains a potential source ofmisdiagnosis; however, the simultaneous analysis ofmultiple chromosomes is of great help for theidentification of complex abnormalities (21). The mostrecent report about the accuracy of FISH results onsinge cells gives a rate of 97% (7).
Genetic analysis for single-gene disorders
When the biopsy procedure is completed, theremoved cell is transferred under the stereoscope toa microcentrifuge tube containing lysis buffer. Lysisis then performed using one of the most commonlyused procedures such as proteinase K treatment orpotassium hydroxide plus dithiothreitol.
The main problem with PCR is the possibility ofexogenous DNA contamination whose main sourcesare of maternal (cumulus cell) or paternal (sperm cell)origin. Operators can also contribute exogenous DNA.Special precautions have to be followed in bothlaboratories since standard sterile conditions are notsufficient to prevent DNA contamination.
In the IVF laboratory• all disposable, medium and oil involved in the
culture and micromanipulation of PGD cases areprepared from unopened, sterile packages;
• sterile gloves, masks and gowns are used at allstages;
• micromanipulation tools are exposed to ultravioletradiation before use; and
• at the time of biopsy, only the two embryologistsinvolved in the procedure are allowed in thelaboratory to minimize the air currents associatedwith persons’ movements.
In the genetic laboratory• a special, completely equipped room should be
exclusively dedicated to PCR for PGD cases;• the access to the PCR laboratory is restricted during
the analysis and preparatory phases;• opening of the tubes containing specimen and
reagents is reduced to a minimum; and• all reagents are checked the day before use for
DNA contamination by running a control PCR todetect the possible presence of human DNA.
Besides the positive controls necessary for theinterpretation of the results, a series of negative
controls are also added during the reaction to verifythe presence of external DNA, including oocyte orembryo culture media. In addition, polymorphicmarkers are included as an additional method ofidentifying exogenous DNA.
Different methods are used to analyse the PCRproducts, heteroduplex formation and restrictiondigestion being the most common (22,23) . Analternative approach is represented by the fluore-scent-PCR (F-PCR) where fluorescence-labelledprimers are used. In this case, the amplificationproduct is analysed on a fluorescence detector thatis more sensitive compared to the standard gel system.F-PCR is especially valuable for the detection of pointmutations where direct sequencing of the PCRproduct is necessary (24).
The correct interpretation of PCR results can bedistorted by the possible occurrence of allelicpreferential amplification failure or ADO (allele drop-out). This phenomenon is not confined to single-cellPCR, but in this case, the consequences are moreserious and can lead to complete misdiagnosis. Somestrategies have been defined to make ADO recogni-zable. The most efficient entails the definition ofpolymorphic markers which are strongly linked to thegene under study (7). These markers are generallyrepresented by short tandem repeats (STRs; shortsequences where a 2–5 base pairs per repeat unitoccurs throughout the human genome) that are mainlylocated in intergenic regions. STRs are amplifiedsimultaneously with the gene to which they arestrongly linked in a multiplex PCR with the presenceof several primers in the amplification mixture. F-PCRis the technique of choice for the simultaneousamplification of the studied gene and the correspond-ing informative linked markers. If two or moreinformative markers are available for the mutationunder study, the great majority of ADOs are detectedleading to an accuracy rate of approximately 97%(9,25).
Indications and contraindications for PGD
The use of PGD necessarily involves ART techniquesand even fertile couples need to undergo all the stepsassociated with ART treatment, including inductionof multiple follicular growth, oocyte retrieval at 34–36hours after the injection of hCG and in vitro insemina-tion of the oocytes. As a general consideration,several embryos are required to identify those that are
Preimplantation genetic diagnosis 215
affected by the disorder under study. Therefore, a goodresponse to hyperstimulation is an important requisite,especially when considering that embryos aretransferred not only on the basis of their geneticanalysis but also on the basis of their morphology.This approach makes embryo selection stricter sincePGD results are included as an additional selectioncriterion. If the incidence of affected embryos ispredicted to be 25%, in the case of single-genedisorders according to Mendelian inheritance, thefrequency of chromosomal imbalance will reach higherpercentages in selected categories of patients (26).In these cases, the pregnancy rate has been demons-trated to be directly related to the number of oocytesgenerated and makes the quality of response tofollicular hyperstimulation a key factor for a successfulPGD cycle (27).
Some of the more advanced techniques in ARThave made a great contribution to the outcome of PGD.Improved efficiency has been achieved using ICSI asthe insemination technique, thus minimizing the riskof sperm DNA contamination. In addition, embryocryopreservation, especially when performed at thetwo-pronuclear stage, provides the possibility oftiming the embryo transfer.
The results reported in the past decade show thatPGD is becoming a valuable choice for couples at highreproductive risk. The list of diseases for which PGDcan be performed is rapidly increasing.
In the case of a diagnosis of aneuploidy, theparents’ peripheral blood karyotype is necessary toselect the probe panel for the appropriate chromo-somes. In patients of advanced maternal age, thisselection generally involves the chromosomes whoseaneuploidies are more common in spontaneousabortions and live births, namely chromosomes XY,13, 16, 18, 21 and 22. Additional probes can also beincluded to identify other chromosomes whose errorscould have an impact on implantation. The resultsobtained can give useful information about thecontribution of single chromosomes to successfulimplantation. It is theoretically possible that an-euploidies of these chromosomes which are notthought to have clinical relevance are so deleteriousthat implantation never occurs due to very early failureof embryo development.
When one or both parents carry an alteredkaryotype such as balanced translocations, theselection of probes must include those specific for theabnormality. In the case of reciprocal translocations,an appropriate combination of telomeric and centro-
meric probes specific for the condition under studymust be identified. Preliminary testing of the selectedprobes on the carriers’ lymphocytes is recommendedin order to verify the efficiency of the system.
PGD of single-gene disorders entails a longpreparatory phase beginning with an estimate of thediagnosed mutations in the couple’s lymphocytes. Allmonogenic disorders are, in principle, detectable byPGD, if the corresponding coding region has beensequenced and the mutation identified. This step isnecessary for the development of the most suitableprimers. The PCR assay has to be prepared for eachparticular situation, with special attention being paidto the inclusion of informative linked polymorphicmarkers (when available) which are aimed at signallingexogenous DNA contamination and the occurrenceof ADO. When the PCR protocol is complete and thePGD for the studied condition is considered feasible,all the reagents involved must be demonstrated to beDNA-free.
There are no contraindications to undertakingPGD except those that are associated with either theinduction of multiple follicular growth by ovarianhyperstimulation or the establishment of a pregnancy.All couples at high reproductive risk can consider PGDas an alternative to therapeutic abortion, irrespectiveof their fertility status, including, for example, fertilecarriers of single-gene disorders. Different considera-tions are needed for PGD of aneuploidy which is aimedat increasing the chances of implantation by avoidingthe transfer of embryos with aneuploidy or structuralchromosomal abnormalities. Carriers of reciprocaltranslocations are often fertile but they have a verypoor prognosis as unbalanced segregation occurs atvery high rates. The selection of embryos with anormal or balanced karyotype can alleviate the poorprognosis associated with this condition which ischaracterized by a high incidence of spontaneousabortions (12).
Eligibility of patients
The use of PGD has increased considerably over thepast decade. Analysis of the data collected hasallowed the identification of the patient categories inwhich PGD is indicated.
Chromosomal abnormalities
Numerical chromosomal abnormalities are associated
216 LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
with implantation failure and high rates of embryonicdeath. Aneuploidy derives mainly from nondisjunctionevents during gametogenesis and increases signifi-cantly with maternal age (28). Nondisjunction canalso occur after fertilization, leading to the formationof mosaic embryos where normal, monosomic, andtrisomic blastomeres may coexist in combination withmore complex abnormalities (29) . Most cases ofaneuploidy are associated with implantation failure orspontaneous abortion although some (trisomy 13, 18,21 and aneuploidy of sex chromosomes, for example)are able to develop to term. All chromosomal ab-normalities, even the more complex, have beendetected in the inner cell mass of human blastocysts(16,17). This finding confirms that morphologicalcriteria alone, including blastocyst development, arenot sufficient to ensure the selection of euploid andviable embryos.
As reported at the meeting of the InternationalWorking Group on Preimplantation Genetics, morethan 1500 cycles have been performed worldwideresulting in approximately 400 pregnancies (7). Thefollowing categories of patients have been studied:
Maternal age 36 years or more
According to the largest studies reported, thepercentage of chromosomally abnormal embryos isapproximately 65% when the maternal age is 36 or moreyears, with an incidence that increases proportion-ately with the woman’s age. A significant improvementin the clinical outcome after PGD has been shown interms of a higher implantation rate and a decreasedfrequency of spontaneous abortion (5,6) . This isespecially true for women up to the age of 42 yearswhose chances of pregnancy after PGD are the sameas those found in younger women (30) . At older ages,other factors probably contribute to a poorer successrate.
Couples with >3 IVF failures
The occurrence of unexplained, multiple IVF failuresin young patients is probably due to the combinedeffect of many factors. The frequency of chromosomalabnormalities exceeds 55% in this group of patients;however, the selection of those with euploid comple-ment does not improve the clinical prognosis, and thepregnancy rate after FISH is similar to that obtainedin a control group (5). Haploidy/polyploidy andcomplex abnormalities are the most frequent chromo-
somal alterations detected. This finding suggests thataltered mitotic divisions possibly related to centriolardefects represent the origin of these errors (31).Alternatively, other chromosomes besides thosescreened could have an important role in the viabilityof the embryos (26, 32).
Altered karyotype due to chromosomalmosaicism or balanced translocations
Frequent implantation failure and the high incidenceof abortion are significantly reduced by the transferof euploid embryos (5). In these categories of patients,the frequency of chromosomally abnormal embryosis 62%, with monosomy and trisomy contributing 46%of the abnormalities. Carriers of reciprocal, balancedtranslocations are particularly likely to developunbalanced embryos (approximately 80%). Providedthat an acceptable number of normal or balancedembryos are detected, a higher rate of implantationresults from FISH selected embryos (12).
Epididymal or testicular sperm aspirationwith >1 IVF failures
A very high percentage of chromosomally abnormalembryos (72%) is found in this group of patients (33) .The transfer of PGD-selected embryos results in a 25%clinical pregnancy rate with an implantation rate of18.8%. This clinical outcome is similar to that observedin patients with multiple IVF failures. However, thecauses of this poor prognosis are probably differentas suggested by the type of abnormalities observed,with 45% due to monosomy and trisomy and,interestingly, 8.6% of the abnormal embryos havinggonosomal aneuploidies. A significant involvementof the male counterpart in the etiology of thesealterations is a plausible possibility.
Recurrent abortions
Preliminary data on this condition show a high rate(68%) of chromosomally abnormal embryos (30).Although the preliminary results in terms of live-birthrate are promising, more data and a comparative studyare necessary to evaluate the proposed validity ofPGD for aneuploidy in this category of patients (34).
Single-gene disorders
Presently, about 750 PGD cycles for single-gene
Preimplantation genetic diagnosis 217
disorders have been performed worldwide withapproximately 150 pregnancies and more than 100healthy infants born (7). PGD for 26 disorders havebeen reported and are listed in Annex 1. The list isexpanding rapidly.
Especially innovative are the applications fordynamic mutations such as Fragile-X syndrome,Huntington disease and myotonic dystrophy, whichare associated with the expansion of a trinucleotideclass of repeats that are located within the coding anduntranslated regions of genes (35,36,37). The use ofmultiplex markers has notably increased the reliabilityof the diagnosis. New developments are under evalua-tion to reduce the risk of misdiagnosis, especially inthe case of noninformative or partially informativemutations. With these diseases, a special concernarises about the information given to the patients ifthey are not aware of their status (e.g. Huntingtondisease).
Genetic predisposition for late-onset disorders hasbeen reported as suitable for PGD (7). Carriers of thep35 tumour-suppressor gene mutation are at higherrisk of developing an inherited predisposition tocancer. PGD can be performed to select embryoswithout this mutation. Whether a genetic predisposi-tion to severe disorders can be a criterion that justifiesselective embryo transfer is open to discussion. PGDfor HLA matching permits a pregnancy to be plannedwhere the baby will be a potential donor for an affectedbrother or sister who needs bone marrow transplanta-tion. The genetic analysis selects among the healthyembryos those with a haplotype match for the affectedchild (7).
In conclusion, PGD of single-gene disorders is notonly a technique aimed at establishing a healthypregnancy, but also a general approach towards theprevention and therapy of genetic diseases.
Risk–benefit analysis
Oocyte and embryo biopsy are invasive procedures,and concerns have been expressed regarding thedevelopment and viability of the embryo after biopsyhas been performed. Experimental studies havedemonstrated that biopsy at the eight-cell stage hadno detrimental effects on further growth (15). Moreimportant, data from the clinical outcome of biopsiedembryos showed that approximately one-fourth ofthem are able to implant (5).
The diagnosis of genetic disorders based on a
single-cell analysis demands extremely sophisticatedtechnology and special precautions to maximize theaccuracy of the procedure. Special care has beendevoted to evaluate the efficiency of the technique.Considerable improvement has been achieved in theidentification of possible causes of misdiagnosis,including the definition of guidelines to be followedin ART laboratories when dealing with PGD cases (38).
In the case of PGD for aneuploidy, a control onthe quality of the results is carried out by repeatbiopsy of the nontransferred embryos and performingFISH on the blastomeres that are obtained (19,20,39) .The results demonstrate an in vitro efficiency rate of97% that is confirmed by the in vivo efficiency rate(97.8%). The in vivo efficiency rate is calculated bythe data derived from prenatal diagnosis of theestablished pregnancies or direct examination of theinfants at birth (7).
Similar rates have been reported for PGD of single-gene disorders (7,9). The use of special precautionsto avoid exogenous DNA contamination and ADOhas dramatically reduced the main causes of mis-diagnosis.
Only a few misdiagnoses have been reportedworldwide (seven were reported by the InternationalWorking Group on Preimplantation Genetics, 2001);this figure establishes PGD as a safe and reliableprocedure. Despite these results, conventional pre-natal diagnosis still needs to be recommended topatients to confirm the PGD results by amniocentesisor chorionic villus sampling.
More recently, PGD for aneuploidy has beenconsidered a powerful criterion for the selection ofviable embryos. In this case, the higher take-homebaby rate after PGD of aneuploidy (5,6) suggests thatthe cost of a successful treatment cycle with PGD isless expensive than the corresponding number ofconventional ART cycles that are needed for a livebirth.
On the other hand, the majority of fertile patientswho decide to undergo PGD either have strongobjections to therapeutic abortion after prenataldiagnosis or have previously experienced terminationof affected pregnancies. Unfortunately, the stressassociated with the procedure, the relatively lowpregnancy rates and the high financial cost are majorconcerns. This is especially true in those countriesthat have decided not to fund assisted reproductionincluding PGD, despite the advantages to manycouples wishing to conceive a healthy child. It hasalways been said that the prevention of genetic
218 LUCA GIANAROLI, M. CRISTINA MAGLI, ANNA P. FERRARETTI
diseases is much less expensive that the cost tosupport the technology needed to make the diagnosis.
Conclusions
After 10 years of PGD in reproductive medicine andthe performance of approximately 2500 cycles, themain conclusions are that PGD is a reliable procedurein preventing the birth of affected children and it canbe regarded as an alternative to therapeutic abortion.
PGD of aneuploidy is effective and results in a hightake-home baby rate when implemented in selectedcategories of patients. Despite the efficiency of thetechnique, conventional prenatal diagnosis is stillrecommended.
References
1. Gardner RL, Edwards RG. Control of the sex ratio atfull term in the rabbit by transferring sexed blastocysts.Nature (London), 1968, 218 :346–348.
2. Steptoe PC, Edwards RG. Birth after reimplantation ofa human embryo. Lancet, 1978, 2:366.
3. Handyside AH et al . Pregnancies from biopsied humanpreimplantation embryos sexed by Y-specific DNAamplification. Nature (London), 1990, 344:768–770.
4. Verlinsky Y et al. Analysis of the first polar body:preconception genetic diagnosis. Human Reproduction,1990, 5 :826–829.
5. Gianaroli L et al . Preimplantation diagnosis foraneuploidies in patients undergoing in vitro fertilisationwith a poor prognosis: identification of the categoriesfor which it should be proposed. Fer tility and Sterility,1999, 72:837–844.
6. Munné S et al. Positive outcome after preimplantationdiagnosis of human embryos. Human Reproduction,1999, 14:2191–2199.
7. International Working Group on PreimplantationGenetics. 10th Anniversary of Preimplantation GeneticDiagnosis. Journal of Assisted Reproduction andGenetics, 2001, 18:66–72.
8. ESHRE PGD Consortium Steering Committee. ESHREpreimplantation genetic diagnosis (PGD) consortium:data collection II (May 2000). Human Reproduction,2000, 15:2673–2683.
9. Verlinsky Y, Kuliev A. An atlas of preimplantationgenetic diagnosis. London, The Parthenon PublishingGroup, 2000.
10. Magli MC et al . Chromosomal abnormalities inembryos. Molecular and Cellular Endocrinology, 2001,183 :29–34.
11. Gianaroli L et al . Atlas of embryology. HumanReproduction, 2000, 15 (Suppl. 4), Oxford UniversityPress.
12. Munné S et al. Outcome of preimplantation geneticdiagnosis of translocations. Fer tility and Sterility, 2000,73:1209–1218.
13. Dumoulin JC et al. Effect of Ca2+/Mg2+-free mediumon the biopsy procedure for preimplantation geneticdiagnosis and further development of human embryos.Human Reproduction, 1998, 13:2880–2883.
14. Germond M et al. Improved fertilisation and implanta-tion rate after non-touch zona pellucida microdrillingof mouse oocytes with a 1.48 mm diode laser beam.Human Reproduction , 1996, 11 :1043–1048.
15. Hardy K et al. Human preimplantation development invitro is not adversely affected by biopsy at the 8-cellstage. Human Reproduction, 1990, 5:708–714.
16. Evsikov S, Verlinsky Y. Mosaicism in inner cell massof human blastocysts. Human Reproduction , 1998,13:3151–3155.
17. Magli MC et al . Chromosome mosaicism in day 3aneuploid embryos that develop to morphologicallynormal blastocysts in vitro. Human Reproduction,2000, 15:1781–1786.
18. Munné S et al. Reduction in signal overlap results inincreased FISH efficiency: implications for pre-implantation genetic diagnosis. Journal of AssistedReproduction and Genetics, 1996, 13:149–156.
19. Munné S et al. Scoring criteria for preimplantationgenetic diagnosis of numerical abnormalities forchromosomes X, Y, 13, 16, 18, and 21. MolecularHuman Reproduction, 1998, 4:863–870.
20. Gianaroli L et al . Advantages of day four embryotransfer in patients undergoing preimplantation geneticdiagnosis of aneuploidy. Journal of Assisted Reproduc-tion and Genetics, 1996, 16:170–175.
21. Delhanty JDA et al. Multicolour FISH detects frequentchromosomal mosaicism and chaotic division in normalpreimplantation embryos from fertile patients. HumanGenetics, 1997, 99:755–760.
22. Handyside AH et al. Birth of a normal girl after in vitrofertilisation and preimplantation diagnostic testing forcystic fibrosis. New England Journal of Medicine,1992, 327:905–910.
23. Kuliev A et al. Preimplantation diagnosis for thalasse-mias. Journal of Assisted Reproduction and Genetics,1998, 15:253–257.
24. Findlay I, Quirke P. Fluorescent polymerase chainreaction: Part I. A new method allowing geneticdiagnosis and DNA fingerprinting of single cells. HumanReproduction Update, 1996, 2:137–152.
25. Rechitsky S et al. Accuracy of preimplantation diagnosisof single-gene disorders by polar body analysis ofoocytes. Journal of Assisted Reproduction and Genetics,1999, 16:192–198.
26. Gianaroli L et al. Will preimplantation genetic diagnosisassist patients with a poor prognosis to achieve preg-nancy? Human Reproduction , 1997, 12:1762–1767.
27. Gianaroli L et al. Gonadal activity and chromosomalconstitution of in vitro generated embryos. Molecularand Cellular Endocrinology, 2000b, 161 :111–116.
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28. Munné S et al. Embryo morphology, developmentalrates, and maternal age are correlated with chromo-somal abnormalities. Fertility and Sterility , 1995, 64:382–391.
29. Delhanty JD, Handyside A. The origin of geneticdefects in the human and their detection in thepreimplantation embryo. Human Reproduction Update,1995, 1:201–215.
30. Gianaroli L et al. Aneuploidy detection in ART. 10thInternational Congress on Prenatal Diagnosis andTherapy, Barcelona, 19–21 June, 2000.
31. Sathanathan H et al . The sperm centriole: its inherit-ance, replication and perpetuation in early humanembryos. Human Reproduction , 1996, 11:345–356.
32. Bahçe M et al. PGD of aneuploidy: were we looking atthe wrong chromosomes? Journal of Assisted Repro-duction and Genetics, 1999, 16:176–181.
33. Gianaroli L et al. Preimplantation diagnosis afterassisted reproduction techniques for geneticallydetermined male infertility. Journal of EndocrinologicalInvestigation, 2000, 23:711–716.
34. Simon C et al. Increased chromosomal abnormalities
in human preimplantation embryos after in vitrofertilisation in patients with recurrent miscarriage.Reproduction Fertility and Development, 1998, 10:87–92.
35. Sermon K et al . Clinical application of preimplantationdiagnosis for myotonic dystrophy. Prenatal Diagnosis,1997, 17 :925–932.
36. Sermon K et al . Preimplantation diagnosis forHuntington’s disease (HD): clinical application andanalysis of the HD expansion in affected embryos.Prenatal Diagnosis , 1998, 18:1427–1436.
37. Sermon K et al. Preimplantation diagnosis for Fragile-X syndrome based on the detection of the non-expanded paternal and maternal CGG. PrenatalDiagnosis , 1999, 19:1223–1230.
38. Gianaroli L et al . Guidelines for good practice in IVFlaboratories. Human Reproduction, 2000, 15:2241–2246.
39. Magli MC et al . Incidence of chromosomal ab-normalities from a morphologically normal cohort ofembryos in poor prognosis patients. Journal of AssistedReproduction and Genetics, 1998, 15:297–301.
Annex 1. List of the single-gene disorders for which PGD has been reported
Cystic fibrosisThalassaemiaSickle-cell anaemiaHaemophilia A and BDuchenne muscular dystrophyX-linked hydrocephalusNeurofibromatosis I and IITay–Sachs diseaseLesch–Nyhan syndrome
Marfan syndromeRhesus incompatibilityRetinitis pigmentosaMultiple epiphyseal dysplasiaAlport diseaseAlpha1-antitrypsin deficiencyAchondroplasiaLong chain hydroxyacyl CoA dehydrogenase
deficiency
PhenylketonuriaEpidermolysis bullosaOrnithine transcarbamilase deficiencyFanconi anaemiaFamilial adenomatous polyposis coliEarly-onset alzheimer diseaseFragile-X syndromeHuntington diseaseMyotonic dystrophy
220 OZKAN OZTURK, ALLAN TEMPLETON
Multiple pregnancy in assisted reproduction techniques
OZKAN OZTURK, ALLAN TEMPLETON
Multiple pregnancies and multiple births
Introduction
The incidence of multiple pregnancy has increasedconsiderably over the past two decades due to ovarianstimulation during fertility treatments (1). Womenundergoing in vitro fertilization (IVF) treatment facea 20-fold increased risk of twins and 400-fold increasedrisk of higher-order pregnancies (2). This is relatedto the current practice of transferring multipleembryos into the uterus. The emphasis on pregnancyrates as a performance indicator has provided apowerful incentive for increasing the number ofembryos transferred after IVF. Such a policy, however,challenges safe practice, increases perinatal mortalityand morbidity (3–5) and imposes a steep financialburden on maternity and neonatal services (6). In thiscontext, the medical, social and economic conse-quences of multiple pregnancy have been the subjectof much recent debate.
Clinicians and couples are under considerablepressure to maximize pregnancy rates. However,multiple pregnancy is an inadvertent and unaccept-able consequence of these pressures. Althoughpotential parents generally feel that multiple pregnancyis not an optimal outcome, their acceptance level maybe high (7). In fact, one survey of infertility patientsdemonstrates that multiple pregnancy is desired, withonly half objecting to triplets and 20% deemingquadruplets acceptable (8). However, it has yet to be
assessed how well-informed infertility patients are asto the adverse medical, psychological, economic andsocial consequences of multiple gestation and whetherit is really fair to expect them to solve this dilemma.
The impact of assisted conception on populationdemographics was highlighted in the 1994 figures fromthe American Society for Reproductive Medicine andSociety for Assisted Reproductive Technology(ASRM/SART) Registry. It reported a 36% multiplepregnancy rate with 7% triplets or higher, constituting55% of all the children born from IVF and gameteintrafallopian transfer (GIFT) (9). From 1980 until 1997,the annual number of live-born babies from twingestation rose by 52% (from 68 399 to 104 137), whilethe number of high-order multiple gestations increasedby 404% (from 1377 to 6727) (10). Looking at the 71826 ART cycles performed in 1997 as a whole, includingthe GIFT and ZIFT procedures, 38% of all birthsfollowing nondonor treatments were multiple, with26% twins and 5% higher multiples (11). Similarly, themost recent data on 80 634 ART cycles performed in1998 show 38% multiple live births. Twins constitute32% of these deliveries, while triplets or more areresponsible for 6% (12). Interpretation of the figuresshould take the effect of fetal reduction (MPFR)practices into consideration. These statistics from theUSA underline the extent and the persistence of themultiple pregnancy problem in ART.
The most recent data from the UK on 35 363 IVF
Multiple pregnancy in assisted reproduction techniques 221
cycles in 1998, compiled and published by the HumanFertilisation and Embryology Authority (HFEA), alsoshow a high incidence of multiple births as a result ofART (13,14). Of individual babies born from all typesof IVF treatment, 47% come from multiple pregnancy,and this figure has remained unchanged during theperiod 1994–1999. For conventional IVF treatment,including frozen embryo transfers (ETs), the contri-bution of multiple live births to total live-birth eventsin 1998/1999 was 27%, which remains almost un-changed since 1991. The figure for fresh ICSItreatment was 27%, which also showed minimumfluctuations since 1993. Breakdown of this overallfigure provides a live-birth rate of 24% for twins and2.4% for triplets and greater. The historical data fromthis national database during the periods 1994–1995,1995–1996, 1996–1997, and 1997–1998 demonstrate afairly stable trend with 25%, 27%, 25% and 25% fortwins and 4%, 3%, 3% and 3% for triplets, respectively(15–18). Our own experience from Aberdeen reflectsa totally different picture. Triplet births have beentotally eliminated with a steady increase in thesingleton birth rates since 1997. This difference fromthe national average is the direct result of a two-embryo transfer policy implemented as the routine. Thesame trend on a larger scale is also evident in Belgiumand the Nordic countries, without any evidence of anoverall reduction in success rates (19).
The situation with respect to other treatments forinfertility is not very different. Gonadotrophinstimulation is now a major cause of multiple pregnancy,particularly in the category of high-order multiplepregnancies (20). Evans and his co-workers high-lighted this emerging trend of escalating multiplepregnancy numbers, not only in IVF settings but alsoin gonadotrophin stimulation, over an eight-yearperiod from 1986 to 1993. They further emphasized thatovulation induction was responsible for a higherpercentage of quintuplets and higher-order preg-nancies than ART and this was attributed to therelative lack of control over gonadotrophin stimula-tion. The first large study to stress this problem in thecontext of gonadotrophin-mediated superovulationwas conducted by Guzick and colleagues, who foundthat superovulation was associated with a 20%incidence of pregnancy with twins and nearly 10%incidence of higher-order multiple pregnancies (21).These figures were similar to those reported in thelarge retrospective study by Gleicher and colleagues(22), whose results can be subgrouped as 20% twins,5% triplets, 2.3% quadruplets, 1.1% quintuplets and
0.5% sextuplets. A recent review, which provided acomparative view with a wider perspective docu-mented that 50%–72% of quadruplet and greatermultiple pregnancies were related to ovulationinduction in comparison to 42% in assisted reproduc-tion and 6%–7% in spontaneous conceptions (23).
Maternal complications
Multiple pregnancy is associated with greater risksfor both mother and fetuses compared to singletonpregnancy. Morbidity and mortality rates areappreciably increased, an issue that is underestimatedby the lay public, who tend to see the overall processas “double the joy”. However, the maternal responseto multiple pregnancy comprises a series of dramaticchanges in all organ systems (24,25) . The alterationsare so marked that they would be consideredpathological in a nonpregnant woman. Despite thisremarkable adjustment, actual complications arecommon and it is not an overstatement to considermultiple pregnancy as a major pathology. Commonlyencountered maternal complications with multiplepregnancy are discussed in the following section.
Miscarriage
The exact risk of miscarriage in multiple pregnancy isdifficult to determine because of the incompletelydocumented phenomenon of the “vanishing twin”. Upto half the multiple pregnancies diagnosed via first-trimester ultrasound are known to deliver more thanone baby (26–28). This is explained by the loss ofviability and subsequent resorption of fetuses withminimal or mostly no evidence of existence at term (29).The resorption process of nonviable embryos isobserved mainly during the first seven weeks ofgestation and does not occur beyond the fourteenthweek (30).
Nevertheless, miscarriage, either threatened orinevitable, was reported as a common complication ofmultiple pregnancy (31). The risk is an exponentialfunction of the number of fetuses. First-trimesterbleeding rates of 12%, 53% and 80% were observedin twins, triplets and quadruplets, respectively(32,33), with a correspondingly high clinical mis-carriage rate of 30% and 42% in twin and tripletpregnancies, respectively (34).
222 OZKAN OZTURK, ALLAN TEMPLETON
Preterm labour and delivery
The incidence of preterm delivery and its clinicalseverity increases with the number of fetuses in utero.Although the background risk is known to be high inIVF pregnancies, mothers who conceive multiplepregnancy by means of IVF are at an even higher riskof morbidity (35). Preterm delivery before 37 weeks’gestation was reported in 44% of all twin pregnanciescompared with 6% in singleton pregnancies in aScottish twin study (36). A number of investigatorshave also reported similarly high rates for prematurelabour and delivery in multiple pregnancies: 41%–50%,92%, and 75%–95% for twins, triplets and quadrup-lets, respectively (31,32,34,37,38).
The maternal risks are mainly associated withprolonged hospitalization (a mean of 23±19 and 56±30days, respectively, during pregnancy for triplets andquadruplets) (32) and the use of tocolytic therapy. Inparticular, an increased risk of pulmonary oedema wasobserved with beta mimetic tocolysis and steroid usein multiple pregnancies. Intravenous ritodrineinfusion for longer than 24 hours and excessive fluidadministration appear to be the main risk factors forthe development of pulmonary oedema (39).
Premature rupture of membranes, which occursmore frequently in multiple pregnancy (20% of tripletpregnancies), not only triggers preterm labour but alsopredisposes mothers to high risk of intra-amnioticinfection (37,38) .
Anaemia
There are differences in the conventional definitionsof anaemia based on clinical symptoms, haemoglobinlevels, red cell indices or bone marrow investigations.However, it is generally accepted that the dilutionaleffect of the increased maternal plasma volume andthe higher fetal demands for nutritional precursorspredispose multiple pregnancy to a state of iron andfolate deficiency anaemia. This incidence in tripletpregnancies was found to be between 27% and 58%(33,37,38,40). Women with multiple pregnancy arealso vulnerable to acute blood loss, mostly secondaryto postpartum haemorrhage, and in need of sufficientiron and folate levels to combat the high haemopoieticdemands.
Hypertension
Pregnancy-induced hypertension and (pre) eclampsia
occurs more frequently in multiple pregnancies. Theclinical presentation is much earlier and more severein comparison to singleton pregnancies (31,33,41–43). The risk was reported to be fivefold and tenfoldhigher in primigravidae and multigravidae with twinpregnancy in comparison to a singleton pregnancy(44). Both monozygotic (45) and dizygotic (42)pregnancies were found to be at a greater risk ofdeveloping pregnancy-induced hypertension.
The reported incidences for pregnancy-inducedhypertension were 17% for twins, 20%–39% fortriplets, and 50%–67% for quadruplets, respectively(32,34,37,40). Malone et al. observed severe pre-eclampsia in 24%; haemolysis, elevated liver functiontests, and low platelets (HELLP) syndrome in 9%; andeclampsia in 2% of a study group, which comprisedtriplet pregnancies beyond 20 weeks’ gestation (38).
Polyhydramnios
Polyhydramnios may be suspected clinically in up to12% of multiple pregnancies (46) and is associatedwith an increased risk of preterm labour. The acuteform, which tends to present in the second trimester,is a complication of monozygous twin pregnancieswith an incidence of 1/20 000 births, or 1/200 twin births(47,48). It is caused by a feto-fetal transfusion leadingto anaemia in the donor and polycythemia in therecipient twin.
Maternal risks are mainly associated with severediscomfort and the complications of bed rest,tocolysis and recurrent amniocenteses. Rare compli-cations due to pressure effects are also reported.Obstructive acute renal failure in a patient at 34 weeks’gestation with a twin pregnancy complicated bypolyhydramnios was presented in a case study. Theauthors emphasized the potential risk of increaseduterine pressure on the ureters as a cause of signifi-cant obstructive renal failure during pregnancy (49).A further case of spontaneous rupture of the renalpelvis during a twin pregnancy was also published(50).
Antepartum and postpartum haemorrhage
Despite the greater surface area of the placental bedand the associated risks of placenta praevia, placentalabruption and vasa praevia, clinical evidence does notprovide support for an increased incidence ofantepartum haemorrhage (31,41). A study, whichanalysed the outcome of 26 sets of triplet and five sets
Multiple pregnancy in assisted reproduction techniques 223
of quadruplet pregnancies resulting from IVF, reportedan 8% and 0% incidence of third-trimester bleeding,respectively (32).
However, the incidence of postpartum haemor-rhage (PPH) is significantly higher due to over-distention of the uterus leading to atonia. The higherincidence of operative deliveries is also a possiblecause contributing to postpartum blood loss. Thereported figures for PPH range from 9% to 35%(37,38,40).
Risk of an operative delivery
The likelihood of an operative delivery, whethervaginal or abdominal, is significantly higher in multiplepregnancy, mostly due to medical and patient choice,as well as intrapartum complications of malpresenta-tion, cord accidents, incoordinate uterine action andfetal distress. Operative delivery is associated with anincreased maternal risk of genital trauma, pelvicinfection and haemorrhage (40). Multiple pregnanciesare more frequently delivered by caesarean sectioncompared with singleton pregnancies, either as anelective procedure or an emergency (31,51). Albrechtand Tomich reported a 100% caesarean section ratein their series of 57 triplet deliveries (40). Nadal andhis co-workers however, delivered 87% of tripletpregnancies by caesarean section (52), reflecting thedifferences in local practices. The total twin caesareansection rate, including caesarean section for thesecond twin, was published as 45% in 1995–1997 byWolff from Sweden, while caesarean section for thesecond twin was performed in 11% (53).
Prolonged antenatal hospitalization
The traditional management of preterm labour,hypertension, polyhydramnios, and fetal growthrestriction in multiple pregnancies often requiresprolonged hospital admission (31,54). A meanduration of 9, 25, and 56 days of hospitalization wasreported for twin, triplet and quadruplet pregnancies,respectively (32,55). Further to recognized complica-tions of prolonged hospital stays, such separationsfrom the family are often a stressful experience (56).
Postnatal problems
After the initial sense of achievement of parenthood,the rearing of children in these cases is stressful andfraught with practical difficulties (57) . Impaired
maternal bonding, social isolation, marital disharmonyand depressive illnesses are all common. Even fouryears after delivery, mothers of triplets report fatigue,emotional stress and difficult relationships with theirchildren (40,58) . Lack of adequate psychologicalsupport and financial help was a common themeamong families of quadruplets (54).
Given the increased perinatal mortality amongmultiple pregnancies, the problems of coping with theloss of babies may be an added burden in the postnatalperiod (59–61). A wide spectrum of postnatalcomplications in 55 triplet pregnancies was reviewedby Malone et al ., including endometritis in 24%,postpartum haemorrhage in 9%, pneumonia in 4%,urinary tract infection 4%, and diastasis of the rectusmuscles requiring surgery in 2% (38).
Increased symptoms of pregnancy
An increase in nausea and vomiting is common inmultiple pregnancy and may be associated with theincreased hormonal levels in such pregnancies (62),although the etiology is not fully established. Theextra weight of multiple pregnancy inflates certainsymptoms of pregnancy such as dyspepsia, gastro-esophageal reflux, constipation, chronic backache,breathlessness, varicose veins, lower extremity andvulvar oedema. Postpartum laxity of the abdominalwall and umbilical hernias may occur frequently.Malone and his co-workers reviewed a wide spectrumof antenatal problems in triplet pregnancies. Theyreported acute fatty liver of pregnancy in 7%,gestational diabetes in 7%, supraventricular tachy-arrhythmias in 4%, dermatoses in 4%, urinary tractinfection in 4%, and acute disc prolapse requiringsurgery in 2% of their study group (38) . Theprevalence of gestational diabetes is a function of thenumber of fetuses, and is reported in 3% of singletonpregnancies in comparison to 5%–8% in twins, 7% intriplets, and >10% in quadruplets. Seoud et al.,however, published the much higher figure of 39% fortriplets (34) . One investigator found a higherincidence of gestational diabetes in pregnanciesconceived after ovulation induction in comparison tospontaneous pregnancies (63).
Prevention
Multifetal pregnancy reduction
Rates of perinatal mortality and morbidity are higher
224 OZKAN OZTURK, ALLAN TEMPLETON
in twins than in singletons, and the adverse maternaloutcome rises with increasing number of multiples.Recognition of these unfavourable features of multiplepregnancy, both at the individual and societal level,has initiated the move towards the implementation ofpreventive measures against the creation of multiplegestations in ART.
Against this background, multifetal pregnancyreduction (MFPR) has been presented as an optionto improve the pregnancy outcome of patients tryingto carry a pregnancy to term. Although there aretechnical, moral, ethical and psychosocial concernsabout reducing the number of fetuses (64), thisprocedure is now a choice for women found to have ahigher-order multiple pregnancy.
The term “multifetal pregnancy reduction” ispreferred to selective reduction, as selective reduc-tion implies a procedure in which an anomalous fetusof a multiple pregnancy is terminated with the intentof allowing the patient to deliver healthy infant(s) atterm. Multifetal pregnancy reduction, however, is theelective reduction of fetuses to a smaller number inan attempt to reduce the incidence of prematuredelivery, which accounts for most of the morbidity andmortality associated with multiple pregnancy (65).The intention is to enable the pregnancies to continuewith the least harm and most benefits (66–68).
A regression analysis on 274 IVF pregnanciesshowed that at the eighth week ultrasound, each viablefetus could be expected to reduce the duration of thepregnancy by about 3.6 weeks, and each fetusreduced medically or spontaneously could beexpected to prolong the pregnancy by approximately3.0 weeks (69). In multiple gestations of four fetusesor more, the overall benefits of MFPR in increasingthe duration of the pregnancy are generally recogn-ized (67,70). However, for triplet pregnancies, theplace of MFPR is more controversial because ofadvances in obstetric and neonatal care. Lipitz et al.
found a greater rate of total fetal loss and prematurityin triplet gestations compared to triplet pregnanciesreduced to twins (71). Furthermore, after reduction,the outcome of triplets was found to be comparableto that for twin pregnancies (72). Likewise, Yuval etal. reported a significant reduction in prematurity andlow birth weight following MFPR of triplets to twins(73).
Data from the HFEA in 1999 highlight theprevailing trend in the UK towards the use of MFPR,particularly in triplet pregnancies (Table 1). A recenttrend to minimize the risk of multiple pregnanciesfurther was manifested as “MFPR to a single fetus”.Brambati et al. reported a significantly better outcomeof pregnancies reduced to singletons than of thosereduced to twins (74).
However, multifetal pregnancy reduction comesat a cost. Postprocedure pregnancy loss rates arereported as 8%–23%, depending on the startingnumber of fetuses, while the delivery of severelypremature fetuses vary from 9% to 23% (75). Theimportance of increasing technical experience on lowerrates of pregnancy loss has been emphasized by manyauthors (76–79). Analysis of 3513 MFPR proceduresat 11 centres in five countries highlighted this trendof improved outcomes in pregnancy losses and earlyprematurity with time and experience. They reporteda collaborative loss rate of 4.5% for triplets, 7.3% forquadruplets, and 15.4% for sextuplets or higher-ordermultiple pregnancies (80).
Selective reduction for fetal abnormality, which issimilar in technique to MFPR, was reported in alltrimesters with good outcomes for the surviving fetusin >90% of cases (81). Geva et al. as well as otherspublished high success rates with second-trimesterMFPR (82–85), although the first-trimester approachstill remained safer (5%–6% miscarriage rate in first-trimester versus 8%–16% in second-trimester MFPR).Differences in pregnancy loss following reduction at
Table 1. Multifetal pregnancy reduction (MFPR) in high order multiple pregnancies (UK)
Triplet Triplet pregnancy Triplet Quadruplet Quadruplet pregnancy Quadrupletpregnancy undergoing MFPR delivery pregnancy undergoing MFPR delivery
1992–1993 130 4 (3.0%) 85 0 0 (0%) 0
1993–1994 151 4 (2.6%) 115 3 0 (0%) 2
1994–1995 204 17 (8.3%) 130 2 1 (50%) 0
1995–1996 215 18 (8.3%) 152 6 2 (33%) 2
1996–1997 260 37 (14.2%) 160 2 0 (0%) 1
Ref.: Human Fertilisation and Embryology Authority (HFEA) data, (15)
Multiple pregnancy in assisted reproduction techniques 225
different gestational ages were attributed to varyingbackground risks of spontaneous miscarriage (86).Based on these favourable reports on second-trimester fetal reduction and the anticipation of highspontaneous resorption rates during the first tri-mester, it was recommended that MFPR should bedelayed until 12 weeks’ gestation in quadruplet orhigher multiple gestations. However, this was not feltto be necessary in twin and triplet gestations (87).
Similarly, a large multicentre study reporting theoutcome of 402 cases of selective termination inpregnancies with dizygotic multiples from fourcountries found a loss rate of 7% up to 24 weeks inwhich the final result was a singleton fetus and 13%in which the final result was twins. Loss rates rangingfrom 5% to 9% attributable to the reduction procedurewere not statistically different (81).
One of the new developments in this area is theuse of chorionic villus sampling before MFPR. Theaim is to minimize the risk of selecting a chromo-somally abnormal fetus to proceed with the pregnancy.It has been shown that multiple pregnancies are at ahigher risk of carrying at least one fetus affected byMendelian or chromosomal anomalies. The incidenceis a function of the order of multiples (74). De Catte,from his small series of 32 multiple pregnancies,concluded that prenatal cytogenetic diagnosis duringthe first trimester prior to fetal reduction is a feasible,accurate and safe procedure, where abnormalchromosomal results indicate the fetus(es) that shouldbe reduced (88).
With the intention of improving safety andefficacy, different techniques of MFPR have beenadvocated, including transcervical aspiration,
transabdominal intracardiac or intrathoracic injectionof air, potassium chloride or hypertonic saline, as wellas transvaginal intrafetal injections or mechanicaldestruction of the embryo (89). Transabdominal fetalreduction using simultaneous transvaginal ultrasono-graphic guidance for selective feticide was used tocombine the benefits of both the transabdominal andtransvaginal approaches (90). Transvaginal puncturein comparison to transcervical aspiration at eight toten weeks of pregnancy was found to have less earlycomplications (73). The reduction of a fetus overlyingthe internal os by the transvaginal puncture procedurewas reported with similar success rates as thetransabdominally performed puncture procedures forMFPR (91). In this study, the corrected pregnancyloss in 148 cases of MFPR was 11%.
Although MFPR is advocated as an effective andsafe option for women with high-order multiplepregnancies, its use may still result in the loss of allfetuses and may have adverse psychological conse-quences for the potential parents (92–94). Further,selective fetal reduction with the attendant ethical andlegal issues may be unacceptable to many couples andshould not be perceived or presented as a quick fix toa fundamental problem.
Number of embryos transferred
Against this background, the number of embryostransferred is of crucial importance. One logical stepforward is to determine the point at which transferringan additional embryo either does not increase oractually decreases the probability of a singletonpregnancy without substantially increasing the
Table 2. Factors affecting the results of in vitro fertilization (IVF)
Odds of a birth P value Odds of a multiple birth P value(95% CI) (95% CI)
Maternal age 0.9 (0.9–1.0) <0.001 0.97 (0.95–0.99) 0.013
Tubal f actor infertility (versus no tubal infertility) 0.7 (0.7–0.8) <0.001 0.8 (0.7–0.90) <0.001
Number of previous attempts at IVF (versus none)1–3 0.8 (0.8–0.9) <0.001 1.0 (0.9–1.1) 0.85>3 0.6 (0.5–0.7) <0.001 0.6 (0.4–0.8) <0.001
Duration of infertility (per additional year) 0.98 (0.98–0.99) <0.001 0.98 (0.97–0.99) 0.02
Previous live birth (versus none)Not IVF 1.1 (1.0–1.2) <0.001 Not included in modelIVF 1.6 (1.4–1.8) <0.001 Not included in model
Ref.: Templeton A, Morr is JK, (96)
226 OZKAN OZTURK, ALLAN TEMPLETON
overall birth rates (2). A number of other key determi-nants of success in IVF treatment, including maternalage, duration of infertility and numbers of previousIVF attempts also appear to affect the risk of multiplepregnancy (95,96). It is this association which framesthe current debate on minimizing the risks of multiplepregnancy without jeopardizing the likelihood of asingle, healthy birth.
Analysis of a large national database provided theanswer to this question (96). Recognition of the factthat the number of ova fertilized and the number ofembryos available for transfer was an important factorin determining the outcome led to the formulation of aguideline. Where more than four embryos wereavailable for transfer, the live birth rate was noteffected by transfer of two or three embryos, althoughthere was a significant reduction in the multiplepregnancy rate when two embryos were transferred.This was shown to be valid for all ages up to the ageof 40 years. In women 40 years of age with more thanfour embryos available for transfer, transferring three
rather than two embryos would lead to an increase inthe rate of multiple births from 23% to 27% with noobvious benefit in the overall pregnancy rate (96).
This recommendation has been criticized on thebasis that no allowance was made for the possibilityof varying embryo quality (97). The ability to selectsuitable embryos remains an important determinant inthe outcome of IVF treatment (96,98,99). However,given the limitations of current embryo gradingmethods, only a large randomized trial would ensurecomplete comparability among women with differentnumbers and quality of embryos transferred. Further-more, availability of four or more embryos suitable fortransfer inherently designates a higher level of ovarianreserve and a potential for better embryo quality.
A further retrospective analysis of data from 35554 IVF procedures reported to Centers for DiseaseControl and Prevention in the USA in 1996 hasaddressed this argument, reporting that embryoquality was not related to multiple birth risk but wasassociated with increased live-birth rates when fewer
Table 4. Number of single, twin and tr iplet births according to the number of ova fer tilized and embryos transferred
Number of live births
0 1 2 3 or more Total number of transfers
2 ova, 2 embryosNumber 3 918 434 82 2% of transfers 88 10 2 0 4 436% of births 84 16 0.4
>2 ova, 2 embryosNumber 8 297 1647 586 8% of transfers 79 16 6 0 10 538% of births 73 26 0.4
>2 ova, 3 embryosNumber 23171 3980 1755 356% of transfers 79 14 6 1 29 262% of births 65 29 6
Ref.: Templeton A, Morr is JK, (96)
Table 3. Number of embryos available and treatment outcome
Eggs Embryos Odds of a birth P value Odds of multiple P valuefertilized transferred (95% CI) births (95% CI)
2 2 0.5 (0.4–0.5) <0.001 0.5 (0.4–0.7) <0.0013–4 2 0.6 (0.5–0.7) <0.001 0.7 (0.6–0.9) 0.0083–4 3 0.7 (0.7–0.8) <0.001 1.3 (1.1–1.4) 0.008>4 2 1.01 (0.9–1.1) 1.0 (0.9–1.1)>4 3 1.0 (0.9–1.1) 0.78 1.6 (1.5–1.8) <0.001
Ref.: Templeton A, Morr is JK, (96)
Multiple pregnancy in assisted reproduction techniques 227
embryos were transferred (100). The authors conclu-ded that the risk of multiple pregnancy from IVFtreatment varied not only by the number of embryostransferred but also by maternal age. Among women<35 years of age, maximum live-birth rates wereachieved when two embryos were transferred.However, unlike the UK study (96), this retrospectivecohort analysis indicated an increased live-birth rate,although not statistically significant at the 0.05 level,among women >35 years of age if more than twoembryos were transferred, but with a highly signifi-cant increase in multiple birth rate from 12% to 29%.
Age is a well-documented prognostic factor inembryo quality (101) and treatment outcome (95).Although live-birth rates drop with advancing age, itseffect on multiple pregnancy rates is not strongenough to relax the recommendations on the numberof embryos transferred. In this context, the research-based data have challenged the perceived sense ofsecurity regarding the low multiple pregnancy risksof women in their 40s. It was reported that althoughhigh-order multiple pregnancy rates showed adecreasing trend with diminishing implantation rates,no statistically significant effect was actuallyobserved as maternal age increased (102) . Thisconclusion was verified by other authors (103).Where more than three embryos were transferred inpatients with a poorer prognosis for successful IVFtreatment based on maternal age of >36 years,previous unsuccessful IVF treatment and poor embryoquality, a significant trend toward higher multiplepregnancy rate still remained (102) . Likewise, in theiranalysis of 1116 IVF cycles resulting in 242 preg-nancies with 70 multiple gestations, Senoz et al.showed that both overall and multiple pregnancy rateswere inversely correlated with age, but this trenddisappeared when the data were adjusted for thenumber of embryos transferred (104). Preutthipan etal. also found no significant effect of age, including>35 years, on multiple pregnancy rates (105).
From the earlier studies by Staessen et al .(98,99,106) investigating the effect of the quality andthe number of embryos transferred compared tomultiple pregnancy risks following IVF/ICSI treatment,to the recent retrospective case–control study byLicciardi et al. (107), the same trend has emergedpersistently. Reducing the number of transferredembryos from three to two largely eliminates theoccurrence of triplet pregnancies without alteringoverall pregnancy rates. The British Fertility Societyand the Royal College of Obstetricians and Gynaecol-
ogists recommends units in the UK to limit themselvesto two embryos per transfer (108). Recently the HFEAhave also recommended that only two embryos betransferred.
However, as these studies have already high-lighted, such a policy still does not address the highprevalence of twin pregnancies, which are morefrequent than higher-order multiples and contributesubstantially to perinatal morbidity. Therefore, if theultimate goal of IVF is the birth of a single healthychild, the way ahead must lie with elective singleembryo transfer (eSET), with the promise of subse-quent transfer of frozen-thawed embryos (109).
Until recently, eSET was not really an option inclinical practice, for fear that overall success rateswould decline too far. This presumption has beenperpetuated mainly by the published results of singleembryo transfer where only one embryo was available.Because no opportunity for the selection of moresuitable embryos existed, the implantation potentialof the only available embryo was usually poor withclinical pregnancy rates of around 10%.
Pregnancy rates reported by the French NationalIVF Registry for 1986–1990 ranged from 9% to 12%for single embryo transfers and incrementallyincreased for the transfer of two, three and fourembryos with rates from 30% to 35% (110) . Aretrospective study by Giorgetti et al. on 957compulsory single embryo transfers showed thatimplantation rates varied from 4% to 16% per transferin accordance with the embryo quality (111). In theUK, according to 1997 HFEA figures, the pregnancyrate per cycle was 8% after single embryo transfer, 20%after transfer of two embryos, and 27% after transferof three embryos (3) . Data in the Danish National IVFRegistry for 1994–1995 also showed that for IVF andICSI the birth rates per single embryo transfer was13%, two embryos 25%, and three embryos 26% (112).
Likewise, a retrospective cohort study fromFinland reported a 20% pregnancy rate in 94 patientswhere only one embryo was available for transfer and30% where single embryo transfer was elected bychoosing the best quality embryo from those available.The cumulative pregnancy rate after frozen-thawedembryo transfers in the elective single embryotransfer group was 47% per oocyte retrieval. Bycomparison, the pregnancy rate for two embryotransfers was 30% per transfer and 24% of these weretwin pregnancies (113). Retrospective analysis of 2573consecutive transfer cycles following either IVF orICSI revealed that the ongoing clinical pregnancy
228 OZKAN OZTURK, ALLAN TEMPLETON
rates were 4%, 9% and 18%, respectively, for thegroups with nonelective transfer of one, two and threeembryos, compared with 22% with elective transfer ofeither two or three embryos. Therefore, if thetransferred embryos are the only embryos availablefor transfer, thus eliminating any opportunity forselection of embryos, the pregnancy rates are muchlower (114). This point was further communicated byCoetsier during the ESHRE Campus Course 2000 basedon their comparative data on elective and compulsorysingle versus double embryo transfers (115) .
Initially, elective transfer of a single embryo wasevaluated in the theoretical sense (116). If 733 singleembryo transfers had been done electively in a goodprognostic group, defined on the basis of age, numberof previous IVF cycles, number of embryos availablefor transfer, and quality of transferred embryos with apredetermined implantation rate of 26%, a decrease inthe overall clinical pregnancy rate from 30% to 26%per initiated cycle, including both fresh and frozen-thawed embryo replacements, would have beenbalanced by a reduction in the multiple pregnancy ratefrom 28% to 15%. Although the reduction in theoverall pregnancy rate would be entirely due to thereduction of multiple pregnancies, this could easilybe compensated with 15% extra treatment cycles, allwith a prospect of singleton gestation (116).
This hypothetical exercise has also concluded thatthe selection of a good prognostic group for singleembryo transfer should be made to keep an acceptablebalance between reduction in multiple gestation andoverall pregnancy rates. Although more treatmentsmight be needed to achieve a similar live-birth rateafter single embryo transfers compared with twoembryo transfers, the lower twin pregnancy rate of theformer approach would cause it to be more cost-effective than three embryo transfer (117).
The concept of eSET in IVF practice, albeit in thecontext of clinical research, is not new. Much earlierthan the current debate on two versus three embryotransfer, Frydman et al. questioned the place ofalternative policies for embryo transfer in IVFprogrammes in 1988 and concluded that when threeor fewer embryos were available following an IVFcycle, the deliberate limitation of fresh embryo transferto one embryo followed by one or more cycles offrozen-thawed embryo transfer is not detrimental tothe pregnancy rate and is less likely to be associatedwith multiple gestation (118) .
However, the first prospective randomized trialcomparing elective single embryo transfer with double
embryo transfer was not published until 1999 (119) .It was shown that by using single embryo transfer andstrict embryo selection criteria in a good prognosticgroup of women aged <34 years and in their first IVF/ICSI treatment, an ongoing pregnancy rate similar tonatural conception in fertile couples can be achieved.In this pioneering trial from Belgium, 26 single embryotransfers resulted in a 42% implantation rate, 38%ongoing pregnancy rate and one monozygotic twinpregnancy, whereas 27 double embryo transfersresulted in a 48% implantation rate, 74% ongoingpregnancy rate and six twin pregnancies. Further datafrom the Finnish group indicated that, when the extrapregnancies obtained from the subsequent frozenembryo replacements were added, the cumulativepregnancy rates per oocyte retrieval became 48% inelective single embryo transfers and 41% in doubleembryo transfers (120).
The authors of the initial randomized study fromBelgium later extended their research experience tocomprise a series of 779 IVF/ICSI cycles (121). Theirfindings from 111 single embryo transfers confirmedthe previous outcome with similar ongoing pregnancyrates of 32% in single, and 34% in nonsingle embryotransfers. Multiple pregnancy was virtually eliminatedin the previous group (<1% versus 37%). They alsoemphasized the importance of embryo selection inelective single embryo transfers as ongoing preg-nancy rates dropped from 36% to 13% when thetransferred embryo was not “top grade”.
The second prospective randomized trial address-ing the same issue was presented by Tapanainen etal. in the ESHRE Campus Course Report (115). Theyreported similar implantation rates both for electivesingle and two embryo transfers in their selectedstudy population (31% versus 30%, respectively),likewise the cumulative pregnancy rates after freshand cryopreserved embryo transfers were comparablein both groups (46% versus 53%, respectively).However, the price of this statistically nonsignificantdifference was a 36% twin delivery rate in the twoembryo transfer group as opposed to one twin deliveryin the single embryo transfer group (115) .
In the same workshop (115) , De Sutter andCoetsier from Belgium further demonstrated that evenafter correction for the possible confounding effectof embryo quality, elective single embryo transfersachieved the same clinical pregnancy rates as electivedouble embryo transfers, reflecting the importance ofendometrial receptivity: 42% versus 40%, respectively,in the excellent embryo group and 45% versus 43% in
Multiple pregnancy in assisted reproduction techniques 229
the good embryo group (115). This emphasized theprevious observation that increasing the number ofembryos for transfer to compensate for lower uterinereceptivity only leads to higher multiple pregnancyrates without effecting the overall chances of preg-nancy (109).
Blastocyst transfer has been proposed as apossible means of restricting multiple pregnancies byreplacing fewer but more competent embryos. How-ever, this is yet to be demonstrated in clinical trials.Unresolved issues, such as criteria for selection of themost viable blastocysts, the possibility of failure toproduce blastocysts in extended culture and thelikelihood of fewer embryos for cryopreservation,mitigate against routine introduction of this interven-tion at the present time (122). Furthermore, the paucityof published data on elective transfer of oneblastocyst hinders attempts to provide conclusiverecommendations.
Superovulation and intrauterine insemination
Unlike the case with IVF, strategies for the preventionof multiple pregnancies in superovulation (SO)treatments have not been defined. Evans and his co-workers evaluated 220 cases of triplets or higher-orderpregnancies over an eight-year period and concludedthat the number of cases with triplets and quadrupletsas compared with quintuplets or greater showed animprovement for ART but not for ovarian stimulation(20). In its published guidelines, the Royal Collegeof Obstetricians and Gynaecologists highlights theinherent risks of administering gonadotrophins andrecommends careful monitoring of stimulated cycles(123). Gleicher and others have, however, reportedthat current guidelines for monitoring may not beenough to control the rate of multiple pregnancy(21,22,124). In their large retrospective cohort studyof 3347 gonadotrophin-stimulated ovarian cycles,Gleicher et al. found that the peak serum estradiol
concentration and the total number of follicles wereindependent predictors of high-order multiplepregnancy (22). However, the number of follicles witha diameter of 16 mm or more were not correlated withthe risk of developing this complication. Since thetotal number of follicles is often difficult to determineby ultrasound, and since the number of large folliclesdid not have the predictive power to be clinicallyuseful, sonographic assessment of the ovarianstimulation was not found to be valuable in reducingthe risk of multiple pregnancy. Furthermore, peakserum estradiol concentrations (5084 pmol/L), whichwere much lower than their current cut-off point forcancellation (7342 pmol/L), were significantlyassociated with the occurrence of multiple pregnancy.Beyond this cut-off point, where the risk of high-ordermultiple pregnancy was significantly higher, theprobability of pregnancy also started to exceed thatof no pregnancy. Therefore, it becomes evident thatassociations between ultrasonographic and hormonalparameters of ovarian stimulation and the clinicaloutcome were not clear enough for clinical guidance.The authors suggested that given the limitation ofcurrent guidelines and limited scope for developingbetter ones, the options to minimize the risks ofmultiple pregnancy were either to choose a regimenwith milder ovarian stimulation or to consider IVF asa substitute. While the philosophy behind the firstoption would lead to natural cycle intrauterineinsemination (IUI) or even IVF without ovarianstimulation, the second option would require a culturechange among the clinicians and couples towards oneembryo transfer.
In the context of superovulation, preovulatoryvaginal ultrasound-guided aspiration of super-numerary follicles has also been advocated as aneffective strategy to control multiple pregnancy rates(125). However, critics would argue the place of thistechnique, which intends to rescue the SO/IUI cyclein the presence of multiple follicles, but refuses toconvert the treatment to IVF/ET, which could provide
Table 5. Pregnancy outcomes by the number of embryos transferred (including frozen embryo transfers)
System Live births (%) Multiple births (%) Stillbirths and neonatal deaths(per 1000 birth events)
One-embyo transfer 8.0 2.9 8.4Tw o-embryo tr ansfer 22.8 24.7 20.8
Three-embryo transfer 22.3 31.0 22.1
Ref.: Human Fertilisation and Embryology Authority (HFEA) data, (15)
230 OZKAN OZTURK, ALLAN TEMPLETON
a higher level of clinical control over the prevailingrisks of multiple pregnancy.
Conclusions
As multiple pregnancy imposes significant risks andseveral adverse outcomes on both maternal and fetalhealth, the most important concern in any ART mustbe a reduction in the risks of multiple birth at least tothe level of natural incidence. In the context of triplets,this can be achieved in most women by transferringno more than two embryos at one time. This will notreduce the live-birth rate but will reduce the numberof children born prematurely. The perinatal mortalityrate associated with IVF would then decrease (seeTables 5 and 6), as would the significant risk ofdisability in the survivors. Better allocation ofresources would minimize the inequity and a largerpopulation could benefit from easier access totreatment. Similarly, with the increasing recognition oftwin pregnancies as an adverse outcome, transfer ofa single embryo is a feasible option that virtuallyeliminates the possibility of twins without compromis-ing cumulative birth rates.
A move in emphasis from pregnancy rate per cycleto cumulative live births per patient as a measure ofperformance will challenge current practices but havea demonstrable effect on the health of children bornfrom assisted conception technology. The adoptionof such an approach will inevitably have an effect onthe way treatments are planned, financed and valued(126). This implies a paradigm shift in traditionalbeliefs, values and attitudes of patients and phys-icians alike.
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Outcome of multiple pregnancy following ART:the effect on the child
ORVAR FINNSTROEM
Multiple pregnancies and multiple births
Introduction
This report focuses on multiple pregnancies, especiallytwinning following assisted reproductive technology(ART) and, to a limited extent, following ovarianstimulation, and the effects on the child. Comparisonsare made with singletons and with twins or tripletsborn after spontaneous pregnancies. Since the firstchild was born after in vitro fertilization (IVF) in l978,the number of ART children has increased steadily.At present, in the Scandinavian countries, more than2% of all children are born after ART (all techniques)and approximately 40% of these are the result ofintracytoplasmic sperm injection (ICSI) (1). This highrate of ICSI treatment, as part of ART treatment, hasbeen achieved recently, thus few reports on the fetal,neonatal and subsequent effects of ART, specificallyaddress ICSI. At present, slightly more than 20% ofART pregnancies result, in multiple births.
Since the introduction of IVF, ART has beenaccompanied by an increased number of multiple birthsdue to the transfer of two or more embryos in themajority of cases. The incidence of twin births variesfrom 18% to 24% in large published national series andthe birth of triplets or quadruplets from 3.2% to 5.7%(1–6). At present, about 45% of all live-born childrenfollowing ART are twins. Recently, the first report fromthe European Society for Human Reproduction(ESHRE) was published, based on treatments that
started in 1997 in 18 European countries (7). Majordifferences were found regarding the proportion ofmultiple births and considerably higher figures thangiven above were reported from some countries.
Over the past two decades, multiple births,especially twins, have increased in many countries.In about a third of the cases, this increase is the resultof ART treatment and in another third the result ofovarian stimulation for non-ART purposes. Increasingmaternal age is the third probable explanation (8,9) .Between 1971 and 1997, multiple births of all ordersincreased in epidemic proportions in the USA, for thesame reasons (10). The proportion of multiple birthsamong infant deaths has increased accordingly (11) .Few centres or countries have programmes forreducing multiple births following ART, namely,reducing the number of embryos transferred. InSweden, the proportion of twins following ART hasbeen reduced slightly, from a peak value of 41% ofliveborn children in 1991 to 36% in 1997. Triplets andquadruplets have almost disappeared, following agradual change in professional policy according towhich only two embryos are transferred in the majorityof cases.
The rationale for trying to reduce multiple birthsafter ART is obvious: all types of neonatal complica-tions as well as their sequelae have been found to bemore common in children born as the result of multiplepregnancies. However, the literature that specifically
236 ORVAR FINNSTROEM
addresses the effect of ART on twins and tripletscompared to controls is limited.
Sources for the present review
Relevant literature up to 1998 was reviewed extensive-ly by a working group within the Swedish Council onTechnology Assessment in Health Care (12). Up to1998, 9000 references dealing with ART were availablein Medline, but only about 350 of these discussed theeffects on the child. The following six aspects wereevaluated in all papers: selection criteria in theexperimental group; quality of the control group;quality of measurements; completeness of material;sources of error; and strategy of analysis. The greatestemphasis was on population-based studies (nationaldata), and on hospital-based studies with controlgroups. However, the number of population-basedstudies was limited. Reports based on national dataare listed in Table 1. This Council report has beenpublished only in Swedish, but forms the basis for partof the present report. An overview of the literature waspublished by Buitendijk in 1999 (13).
A Task Force was set up in Sweden in l996 withmembers from the National Board of Health andWelfare, the Swedish Society for Obstetrics andGynaecology and the Swedish Paediatric Society (seeAppendix). This Task Force has been responsible forconducting a Swedish national study on the effectsof ART which has a number of unique characteristics.This is one of the largest studies so far where perinataldata following ART have been compared with nationaldata and where information on the neurological out-come in comparison with controls is available. The studygroup included all children born in Sweden after ART.
All individuals in Sweden have a unique identi-fication number used by health care providers. All
deliveries are reported to the Medical Birth Registryat the National Board of Health and Welfare which hasbeen in existence since 1973. This registry containsinformation collected during pregnancy, delivery andthe immediate postpartum period. Medical data on theoutcome of delivery and on neonates, such as birthweight, duration of pregnancy and diagnosis duringthe neonatal period are included. The quality of theregistry has been assessed and the dropout frequencyis low (14). Malformations, including minor ones, arereported both to the Medical Birth Registry and to theSwedish Registry of Congenital Malformations, whichstarted in 1965. All ART pregnancies from all 14 IVFclinics are also reported to the National Board ofHealth and Welfare, and a special ART register hasbeen built up.
Perinatal data
The obstetric outcome of ART babies born between1982 and 1995 (n=5856) was compared with all babiesborn in the general population during the same period,by using data from the Medical Birth Registry and theRegistry of Congenital Malformations. The incidenceof childhood cancer was investigated through theSwedish Cancer Registry. In some of the analyses,data were stratified for birth year, maternal age, parityand duration of infertility. The results have recentlybeen published (1). In this paper , information onchildren born in 1996–97 has been added (n=3179).Thus, in total 9111 children are included. Data oncongenital malformations for the whole cohort 1985–1997 has been published previously (15).
Follow-up study
For all children born between 1982 and 1995 after an
Table 1. High-ranked studies showing delivery outcome. Ranking according to the Swedish Council on TechnologyAssessment in Health Care report Swedish Council on Technology Assessment in HealthÊs high-ranked studies withdelivery outcome following ART
National studies Number of deliveries Time period Controls
Bergh et al. 1999 (1) 4517 1982–1995 1 488 053 (all deliveries in Sweden)Gissler et al. 1995 (6) 1015 1991–1993 National datavon Düring et al. 1995 (5) 782 1988–1991 236 635 (all deliveries in Norway)FIVNAT 1995 (4) 5371 1986–1990 National dataFriedler et al. 1992 (3) 1149 1982–1989 National dataMRC working party 1990 (2) 1267 1978–1987 National data
Outcome of multiple pregnancy following ART 237
ART pregnancy, two control children were selectedfrom the Medical Birth Registry, stratifying for sex,year of birth and birth hospital. To control for the highfrequency of twins, another set of control childrenwere chosen—all spontaneously conceived twins—two for each ART twin. There is no national registra-tion of disabled children in Sweden but a search wasmade for ART children and controls in the registriesof the regional rehabilitation centres where all childrenwith more than minor disabilities are registered. These26 centres cover the whole country and provide alldisabled children and adolescents with free medical,psychological, social and pedagogical care. Reporteddiagnoses were converted to ICD 10 codes andcategorized into 20 major groups. In case a child hadmore than one diagnosis, the most important of thesewas chosen. At the follow-up the age of the childrenvaried from 1.5 to 17 years.
In addition, the national register of blind childrenor children with severely reduced vision was searchedto find children with severe visual impairment.Reduced vision was defined as visual acuity of <0.3using both eyes, or severely reduced visual fields.The results of these follow-up investigation have beenpublished recently (16).
Review of the state of the art:results of ART studies
Unless stated otherwise, different ART techniques aregrouped together.
Delivery outcome
The evaluation is based on studies with some type ofcontrol material, either national registry data or studieswith matched controls.
Preterm birth and low birth weight
The percentage of children with a birth weight below2500 g varied between 21.3% (1) and 36.0% (4), whichis approximately seven times the national level in moststudies. For children with birth weight below 1500 g,this varied between 6.0% (1) and 9.7% (5), which isseven to ten times the national figure. The number ofchildren with a gestational age below 37 weeks rangedfrom 23.6% (1) to 29.3% (4), which is a six- tosevenfold increase. Details are shown in Table 2.Thus, the risk of preterm birth or low birth weight isincreased considerably after ART pregnancies. Alarge proportion of the increased preterm births andlow birth weights is explained by the high rate ofmultiple births although few studies have addressedthis aspect. The Swedish study showed that 11% ofART singletons and 47% of ART twins were bornbefore 37 weeks, a twofold and ninefold increase inrisk, respectively, compared with the whole popula-tion. ART twins and their controls did not differregarding the proportion of low birth weights orpreterm births.
Perinatal mortality
In all population-based studies, the perinatal mortality
Table 2. Percentage of multiple births, low-bir th-weight children, and preterm children following IVF in six national studies(12)
Reference group Multiple births Birth weight Preterm birth
Twins Triplets >3 <2500 g <1500 g <32 weeks <37 weeks
Bergh et al. (1) ART 24.0 3.0 0.2 21.3 6.1 6.7 23.6Controls 1.1 0.02 – 3.8 0.8 1.2 5.1
von Düring et al. (5) ART 24.3 5.7 25.9 9.7 29.6Controls 1.2 (all multiple births) 3.8 1.4 6.5
FIVNAT 1995 (4) ART 22.4 4.2 0.2 36.0 5.6 4.8 29.3Controls 2.3
Gissler et al. (6) ART 21.7 4.6 0.2 30.6 7.0 24.7Controls 1.1 3.9 0.8 5.0
Friedler et al. (3) ART 18.7 4.6 0.3 23.8 6.3 28.6Controls 6.4 0.7
MRC working party (2) ART 19.0 4.0 32.0 7.0 24Controls 1.0 (all multiple births) 7.0 1.0 6
238 ORVAR FINNSTROEM
has been reported to be higher after ART pregnancy,varying from two (1,2) to three (5) times the averagefigures. A number of hospital-based studies, as a rulebased on a considerably smaller number of cases, donot find an increased perinatal death rate afterconventional ART (17) or ART with cryopreservedembryos (18). Several studies find no increase or onlya slight increase in the perinatal death rate for ARTsingletons compared to controls (1,2,3), although afew do (19) . The perinatal mortality for singletons andtwins was 11.7 and 39.7 per thousand total births in alarge study in the UK (2), and 11.0 and 34.0 perthousand total births in the Swedish study. WhenART twins and control twins were compared, noincrease in the death rate was found (1,3,20).Oliviennes et al. compared perinatal mortality for ARTtwins, twins conceived after ovulation stimulation orspontaneously and found no differences (20) .However, recently Lambalk et al . (21) found asomewhat higher perinatal mortality in twins born afterassisted reproduction compared with natural twins.Roest et al. (22) specifically analysed the results fortriplets and found a higher perinatal mortality amongtriplets than twins, and Friedler et al. (23) found similarresults for triplets born after ART or ovulationstimulation. Although spontaneous triplets had ahigher survival rate, the number of spontaneoustriplets was small.
Thus the higher death rate among ART childrenis mainly, but not exclusively, dependent on the highnumber of multiple births.
Few studies give results for ICSI children comparedwith standard ART. No differences were found in twostudies of limited size regarding the number of twins,gestational age, birth weight and perinatal mortality(19,24). Similarly, few studies deal specifically withthe effects of cryopreservation. No harmful effectshave been discovered so far (13,18) .
Neonatal care
Preterm infants and twins, also full-term twins, havean increased neonatal morbidity and consume moreneonatal care than full-term singletons. Few authorsaddress this question with regard to ART. More ARTinfants, singletons or twins, had a hospital stayexceeding seven days compared with controls (17).Tallo and co-workers reported prolonged hospitalstay, increased need of oxygen and ventilatorysupport in ART children (25).
Congenital malformations
Several studies discuss the malformation ratios, withconflicting results. In a large French prospectivemulticentre study, the malformation incidence did notdiffer from that of the general population in Europe orFrance (4). However, the risk of neural defects wasincreased in comparison with French national data. AUK study of 1581 children born after IVF or gameteintrafallopian transfer (GIFT) did not show anincreased malformation rate, but again the risk ofcentral nervous system malformation was 2–3 timeshigher (2). A smaller but later study in the UK foundan increased risk both for minor and major malforma-tions (26). Finally, the Swedish study showed afrequency for any type of malformation of 5.4% in ARTchildren, versus 3.9% in the general population—a50% increase. The frequency was 4.7% amongsingletons and 6.3% among twins (Table 3).
The difference between ART children and controlsdisappeared when the following confounders weretaken into consideration: year of birth; maternal age;parity; multiple birth; and length of infertility. Bothmajor and minor malformations were more numerousin ART children which is mainly due to the largenumber of twins. The following specific majormalformations were significantly increased: neuraltube defects including anencephaly; alimentaryatresia; and omphalocele. During the later time period,1995–1997, the incidence of hypospadias was alsohigher (15). Regarding spina bifida, three out of sixwere from a set of twins; all six cases of anencephalywere twins; five out of seven cases of hydrocephaluswere in twins, pointing to the increased risk of thesecentral nervous system malformations in twins. ARTand control twins did not differ regarding thefrequency of malformations (1).
Bonduelle and co-workers from Belgium comparedICSI children with national malformation data inseveral studies. The number of chromosomal aberra-
Table 3. Congenital malformations in Swedish IVFchildren born between 1985 and 1997 (Odds ratios and95% confidence intervals for being recorded in theMedical Birth Registry) (15)
Per cent Odds ratio 95% CI
All children, n=9011 5.4 1.47 1.34–1.61Singletons, n=5316 4.7 1.25 1.07–1.46Multiple births, n=3795 6.3 1.08 0.93–1.25
Outcome of multiple pregnancy following ART 239
tions transferred from the father increased after ICSIperformed because of male infertility but the numberof major malformations did not increase (27).
Thus, it is very likely that there is an increased risk(but low in absolute numbers) of congenital malforma-tions after ART. This can partly, but not solely, beexplained by the high number of twins. Severe centralnervous system malformations have been seen to bemore common after ART in several studies, againprobably due to the high number of twins. Theobserved increased risk of intestinal atresia is notrestricted to twins. An increased risk for hypospadiasis probably related to male infertility and ICSItreatment (15), as well as the observed increase in therisk of chromosomal aberrations (27).
Childhood cancer
Very few studies have investigated the question ofchildhood cancers and ART. However, there are a fewreports from small databases, which point to anincreased risk of congenital and embryonal tumours(28,29). Two studies based on a large ART datasethave analysed the occurrence of malignancies (1,30)and neither of these found an increased risk. However,since the number of malignancies is so small, it isdifficult to draw conclusions at the present time.
Neurological sequelae
Limited information is available on neurologicalsequelae and most studies are based on small hospitaldatabases. A few well-controlled but small studieshave not detected a difference at 1 to 2 years of ageconcerning development or neurological sequelaebetween ART children and controls (31,32) and in oneof these studies, children born following cryo-preservation were compared with children born afterconventional ART or controls (32).
D’Souza et al. (26) examined a cohort of 278children (150 singletons, 100 twins, 24 triplets, fourquadruplets) after fresh embryo transfer and controlsat the age of four years. The percentages of mild andmoderate disabilities were 2.1 in ART children and 0.4in the controls and they were all from multiple births.
The Swedish follow-up study gave the followingsignificant differences: 1.8% of the ART children wereregistered at rehabilitation centres in comparison with1.1% of controls, and 2.3% of twins. Thus the ARTchildren had a 70% higher risk of being registered atthe rehabilitation centres for any reason. They also
had a fourfold risk of being investigated at the centresfor suspected developmental delay (0.39% versus0.09%) and an almost fourfold risk of having cerebralpalsy, (0.55% versus 0.15%) (Table 4).
For other disease groups there were no significantdifferences. There was a slightly increased risk forsingletons versus controls, even after excludingpreterm and growth-retarded infants. ART twins andcontrols did not differ, however. On the other hand,twins showed an almost fivefold increased risk ofhaving a cerebral palsy syndrome compared with thewhole control group. For singletons, the risk was morethan doubled, (Table 4). The number of triplets andquadruplets was small in this study. Nine triplets(2.7%) and one quadruplet (4.0%) were registered atthe rehabilitation centres. Keith et al. (10) state thattriplets have a threefold increased risk of handicap incomparison with singletons, and an almost sevenfoldincreased risk of having cerebral palsy, which is thesame magnitude as twins in other studies (11). Therewas higher risk of severe visual disturbances reportedin the ART group compared with the controls (16).
Cognitive development and behaviouraldeviations
Information available on this subject is limited, andvery little of it concerns children born after multiplebirths, therefore limited conclusions can be drawn.Many studies lack control groups. This subject isextensively reviewed in the chapter “Parenting and thepsychological development of the child in ARTfamilies” by S. Golombok in this volume.
In two studies, cognitive development has beencompared for ART and control children, although at ayoung age. No differences were noted (31,33) .Cederblad et al. examined 81 children at five to sevenyears of age comparing the cognitive test results withgeneral Swedish data and found no statistical
Table 4. Cerebral palsy in ART singletons and twins andtheir controls. (Odds ratios and 95% confidence intervals)(16)
Incidence Per cent OR (95% CI)
Controls – all 0.15
ART children – all 0.55 3.7 (2.0–6.6)
ART singletons/controls 0.37 2.8 (1.3–5.8)
ART twins/controls 0.70 0.9 (0.4–1.8)
240 ORVAR FINNSTROEM
difference (34). Behavioural problems were alsoassessed in this study and compared with normativedata. Sixteen per cent in the general population butnone of the ART children showed behaviour problems.Golombok et al. (35) compared ART children, childrenborn after donor insemination, adopted children andchildren born after natural conception at the age of 4to 6 years. There were about 115 children in each group.No differences between the groups were noted, butthe number of dropouts was high. Olivienne et al. (36)used questionnaires and telephone interviews withART parents of 370 children between six and ten yearsof age. School performance was “good” for 92% ofthe children. Controls were not included.
Cook et al. (37) compared parental stress and childbehaviour in families with twins conceived by IVFwith families having naturally conceived twins. Thechildren were, on average, five years old at follow-up.No differences were found in parental quality andchild behaviour. ART parents reported greater stressassociated with parenting in this small group offamilies.
Different ART techniques, protocols andmethodology
It has not been possible in this review to distinguishresults obtained with different techniques for ART andthe effect on the child, with one exception: malforma-tions following ICSI. Among studies on the effect ofART and hormonal stimulation for non-ART purposeson the child, few deal with results other than perinataloutcome. However, in this chapter I have attemptedto describe aspects of short-term and long-termoutcome based on the available studies. The bestinformation is gained from a few comparatively largepopulation-based studies.
Conclusions
The incidence of multiple births is still very highfollowing ART and hormonal stimulation for non-ARTand there is an increased risk of preterm birth followingART, mainly due to the high frequency of multiplebirths.
The perinatal death rate is doubled after ART,mainly due to an increased frequency of multiplebirths. ART twins do not seem to have a higher risk ofperinatal death than other twins. There is, however, a
moderately increased risk of congenital malformationsin general following ART, partly due to the increasednumber of twins. There is probably an increased riskof the following malformations: neural tube defects;intestinal atresia; and hypospadias (following ICSI).There is evidence supporting that ICSI probablyincreases the risk of chromosomal aberrationstransferred from the father when the technique is usedfor the treatment of poor semen quality
The risk of contracting a malignant disease doesnot seem to be higher in ART children but there is anincreased risk of neurological sequelae in ARTchildren. The magnitude of this increase dependsupon the proportion of twins and higher-order multiplebirths, since multiple birth per se leads to an increasedrisk. The results presented in this chapter are basedupon data with comparatively few twins and very fewhigher-order multiple births and therefore the numbersare small (16). Bearing this in mind, there is a fourfoldincrease in the number of children cared for inrehabilitation centres in Sweden and a fourfoldincrease in the number of children with cerebral palsyborn as a result of IVF in comparison with controls.There is a small increase in the risk for singleton IVFchildren versus controls, but not for IVF twins versustwin controls. However, twins born after IVF, ovarianstimulation without IVF, or spontaneously have a five-to sevenfold increased risk of cerebral palsy syndrome.
Cognitive development is probably not affectedin ART children and they may have fewer behaviouralproblems at school age than their controls.
Triplets and multiple pregnancies of higher ordershould no longer be acceptable following ART. Thereis no scientific evidence that the transfer of more thantwo embryos enhances the likelihood of pregnancy(38). Since the high frequency of twinning explainsmost of the increased risks following ART, animportant aim should be to reduce instances wheremore than one embryo is transferred. The estimatedcosts per successful pregnancy after transfer of oneembryo only are lower, even if more treatments cyclesare needed (39). Reducing the multiple gestationpregnancy rate should be a high priority for assistedreproductive programmes according to the ESHRECapri Workshop Group (40) and others (22).
References
1. Bergh T et al. Deliveries and children born after in-vitro fertilisation in Sweden 1982–95: a retrospectivecohort study. Lancet, 1999, 354:1579–1585.
Outcome of multiple pregnancy following ART 241
2. MRC Working Party. Births in Great Britain resultingfrom assisted conception 1978–87. British MedicalJournal, 1990, 300 :1229–1233.
3. Friedler S, Mashiach S, Laufer N. Births in Israelresulting from in-vitro fertilization/embryo transfer,1982–1989: National Registry of the Israeli Associationfor Fertility Research. Human Reproduction, 1992,7:1159–1163.
4. FIVNAT (French In vitro National). Pregnancies andbirths resulting from in vitro fertilization. Fertility andSterility, 1995, 64:746–756.
5. von Düring V et al. Pregnancies, births and infants afterin-vitro fertilization in Norway (Norwegian). Tidsskriftfor den Norske Laegeforening, 1995, 115:2054–2060.
6. Gissler M, Malin Silverio M, Hemminki E. In-vitrofertilization pregnancies and perinatal health in Finlandin 1991 to 1993. Human Reproduction , 1995, 10:1856–1861.
7 . Nygren KG, Nyboe Andersen A. Assisted reproductivetechnology in Europe l997. Results generated fromEuropean registers by ESHRE. Human Reproduction,2001, 16:284–291.
8. Levene MI, Wild J, Steer P . Higher multiple births andthe modern management of infertility in Britain. TheBritish Association of Perinatal Medicine. BritishJournal of Obsterics and Gynaecology, 1992, 99:607–613.
9. Kurinczuk JJ et al. Singleton and twin confinementassociated with infertility treatments. Australian andNew Zealand Journal of Obstetrics and Gynaecology,1995, 35:27–31.
10. Keith LG, Oleszczuk JJ, Keith DM. Multiple gestation:reflections on epidemiology, causes and consequences.International Journal of Fertility and Women’sMedicine, 2000, 45:206–214.
11. Westergaard T et al. Population based study of rates ofmultiple pregnancies in Denmark 1980–94. BritishMedical Journal, 1997, 314:775–779.
12. The Swedish Council on Technology Assessment inHealth Care. Children born after artificial conception(IVF) (Swedish). Stockholm, 2000.
13 . Buitendijk S. Children born after in vitro fertilization.An overview of the literature. International Journal ofTechnology Assessment in Health Care, 1999, 15:52–65.
14. Cnattingius S et al. A quality study of a medical birthregistry. Scandinavian Journal of Social Medicine,1990, 18:143–148.
15. Ericson A, Källén B. Congenital malformations ininfants born after IVF: a population-based study. HumanReproduction, 2001, 16:504–509.
16. Strömberg B et al. Neurological sequelae in children bornafter in-vitro fertilisation: a population based study.Lancet, 2002, 359:461–465.
17. Dhont M et al. Perinatal outcome of pregnancies afterassisted reproduction: a case control study. Journal ofAssisted Reproduction and Genetics, 1997, 14:575–580.
18. Wennerholm U-B et al. Obstetric and perinatal outcomeof children conceived from cryopreserved embryos.Human Reproduction , 1997, 12:1819–1825.
19. Dhont M et al. Perinatal outcome of pregnancies afterassisted reproduction: a case control study. AmericanJournal of Obstetrics and Gynecology, 1999, 181:688–695.
20. Oliviennes F et al. Perinatal outcome of twin preg-nancies obtained after in vitro fertilization: comparisonwith twin pregnancies obtained spontaneously or afterovarian stimulation. Fertility and Sterility, 1996, 66:105–109.
21. Lambalk CB, van Hoff M. Natural versus induced twinsand pregnancy outcome: a Dutch nationwide survey ofprimiparous dizygotic twin deliveries. Fertility andSterility, 2001, 75:731–736.
22. Roest J et al. A triplet pregnancy after in vitrofertilization is a procedure related complication thatshould be prevented by replacement of two embryosonly. Fertility and Sterility, 1997, 67:290–295.
23. Friedler S et al. Perinatal outcome of triplet pregnanciesfollowing assisted reproduction. Journal of AssistedReproduction and Genetics, 1994, 11 :459–462.
24. Bonduelle M et al. Comparative follow-up-study of 130children born after intracytoplasmic sperm injectionand 130 children born after in-vitro fertilization.Human Reproduction , 1995, 10:3327–3331.
25. Tallo CP et al. Maternal and neonatal morbidityassociated with in vitro fertilization. Journal ofPediatrics , 1995, 127:794–800.
26. D’Souza SW et al. Children conceived by in vitrofertilisation after fresh embryo transfer . Archives ofDisease in Childhood Fetal and Neonatal Edition , 1997,76:F70–F74.
27. Bonduelle M et al. Seven years of intracytoplasmicsperm injection and follow up of 1987 subsequentchildren. Human Reproduction, 1999, Suppl 1:243–264.
28. White L et al. Neuroectodermal tumours in childrenborn after assisted conception. Lancet , 1990, 336:1577.
29. Toren A et al. Two embryonal cancers after in vitrofertilization. Cancer, 1995, 76:2372–2374.
30. Bruinsma F et al. Incidence of cancer in children bornafter in-vitro fertilization. Human Reproduction, 2000,15:604–607.
31. Brandes JM et al. Growth and development of childrenconceived by in vitro fertilization. Pediatrics, 1992,90:424–429.
32. Wennerholm U-B et al. Postnatal growth and health inchildren born after cryopreservation as embryos.Lancet, 1998, 353 :1085–1090.
33. Ron-El R et al. Development of children born afterovarian super ovulation induced by long-acting gonado-tropin-releasing hormone agonist and menotropins, andby in vitro fertilization. Journal of Pediatrics, 1994,125 :734–737.
34. Cederblad M et al. Intelligence and behaviour in childrenborn after in-vitro fertilization treatment. HumanReproduction , 1996, 11 :2052–2057.
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35. Golombok S et al. The European study of assistedreproduction families: family functioning and childdevelopment. Human Reproduction , 1996, 11 :2324–2331.
36. Olivienne F et al. Follow-up of a cohort of 422 childrenaged 6 to 13 years conceived by in vitro fertilization.Fertility and S terility, 1997, 67:284–289.
37. Cook R, Bradley S, Golombok S. A preliminary studyof parental stress and child behaviour in families withtwins conceived by in-vitro fertilization. HumanReproduction, 1998, 13:3244–3246.
38. Tempelton A, Morris JK. Reducing the risk of multiplebirths by transfer of two embryos after in vitrofertilization. New England Journal of Medicine, 1998,339:573–577.
39. Wolner-Hansen P, Rydhström H. Cost-ef fectivenessanalysis of in-vitro fertilization: estimated costs persuccessful pregnancy after transfer of one or twoembryos. Human Reproduction , 1998, 13:88–94.
40. Multiple gestation pregnancy. The ESHRE CapriWorkshop Group. Human Reproduction , 2000,15:1856–1864.
Appendix
Task force on evaluation of in-vitro fertilization in Sweden members:National Board of Health and Welfare: Inga Berg, Anders Ericson, Ingrid ÅkessonSwedish Paediatric Association: Gisela Dahlquist. Orvar Finnström, Karin Stjernqvist, Bo StrömbergSwedish Association of Obstetrics and Gynaecology: Torbjörn Berg, Torbjörn Hillensjö, Karl-Gösta Nygren,
Ulla-Britt Wennerholm.
Multiple birth children and their families following ART
JANE DENTON, ELIZABETH BRYAN
Multiple pregnancies and multiple births
Introduction
Couples who have tried for many years to have onechild may think they would be fortunate if they hadtwo or even three at once—thereby creating an instantfamily. Their mental picture may well be of two or threehealthy, happy children. They rarely think of themedical risks to the children as well as to the motherherself. Even less do such couples consider thepractical, financial and emotional stresses that oftenresult from the demands of having two or morechildren of the same age.
Few parents who are told they may conceive twinsor triplets after infertility treatment will have any priorknowledge of what is entailed in the care andupbringing of multiple birth children. Professionalsthemselves, including infertility specialists, often failto recognize the problems and stresses because theymay have dealt with few such families.
In the UK, assisted conception clinics providingin vitro fertilization (IVF) services must be licensedby the Human Fertilisation and Embryology Authority(HFEA) and the Code of Practice (1) by which theymust abide, specifically requires information on therisks and implications of a multiple pregnancy to begiven before treatment is commenced.
Background
The incidence of twin births has been steadilyincreasing in all developed countries since the early1980s (2,3). The incidence of triplets has been risingmuch faster. In addition to the increase in the numberof multiple births, there has been an even greater risein the number of multiple birth children who survivedue to the considerable recent improvements inneonatal care. The increase in multiple births is knownto be largely due to the widespread use of ovulationinduction and multiple embryo transfer in thetreatment of subfertility. However, East Flanders inBelgium is the only region that has so far providedaccurate data on the origin of all multiple births (4)and has done so since 1964. In most countries, as inthe UK, accurate data on conception are only availablefor those multiple births that arise following IVF orgamete donation. A single year’s survey of triplets in1989 showed that approximately one-third werespontaneously conceived, one-third followedovulation induction alone and the remaining thirdarose from IVF or genetic intrafallopian transfer(GIFT) (5). More recent estimates suggest that alarger proportion of triplets arise from IVF than fromovulation induction. Such data have never beenavailable in relation to twins.
Treatment by IVF has had statutory regulation bythe HFEA in the UK since 1991. The HFEA Code of
244 JANE DENT ON, ELIZABETH BRYAN
Practice requires the number of embryos that can betransferred in one IVF cycle to be limited to three.Nevertheless, the high and increasing incidence ofmultiple births in the UK, as elsewhere, continues tocause concern. The multiple birth rates in the mostrecent HFEA Annual Report (6) showed 27.3% (3.3%triplets) following IVF, 6.4% with donor inseminationand 26.9% with micromanipulation. As long as threeor more embryos continue to be transferred, tripletswill occur—and even quads. Either may include amonozygotic (MZ) pair. The MZ twinning rate isprobably several times higher among pregnanciesinvolving ovulation induction (7) or micromanipula-tion (8).
Problems of multiple births
Whatever their hopes may be, no couple expects tohave twins even when they have a two or three embryotransfer. Some couples, of course, would welcome theidea but even among those couples who have beenwarned of the risks, the diagnosis of a multiplepregnancy frequently comes as something of a shock.Pretreatment preparation is often inadequate (9) . Aftera multiple pregnancy is diagnosed, there is frequentlya lack of information and advice, resulting in manycouples suffering unnecessary anxiety.
Many professionals, having had little or noexperience with twins themselves, are not sufficientlyaware of the special needs of families who have them.For a childless couple, the practical and emotionaldifficulties of caring for two or more babies at the sametime may be particularly difficult to imagine. A surveyby the British Fertility Society and CHILD, a UKpatient support group, found that 66% of respondentsfelt that twins would be an ideal outcome of IVFtreatment (10). Older women, in particular, may feelthat this is the only chance to have two children.Nevertheless, it has been shown that parents do nothave realistic expectations of how the birth of twinswill affect their family (11). Mothers are often un-realistically optimistic about the likely outcome. Manyare unprepared, for example, for the impact the birthof twins can have on the relationship with their partner.The father may be genuinely surprised by how verymuch his help is needed with the baby care and maynot understand how much the mother’s attention andemotions will now be focused on the children. Apreliminary study of couples who have twins followingIVF indicated that they may find parenting consider-
ably less rewarding than they had expected (12).Studies have shown that both parent satisfaction
and parenting skills with IVF singleborn children are,if anything, superior to that with spontaneouslyconceived children. Perhaps not surprisingly, as thesewere all much wanted children, unlike some in thegeneral population, but the situation may be differentwith twins. In a small study comparing families withIVF twins and spontaneously conceived twins, Cooket al. (12) found that parenting stress for both mothersand fathers was greater in the IVF group although thequality of parenting was equally good. Parentalsatisfaction, however, was less. This may well be dueto the inevitable failure to reach the high standardsof parenting they had set themselves and had for solong expected to achieve (13) . Colpin et al. found thatfirst-time mothers of one-year-old twins with a historyof infertility obtained significantly higher scores forparental competence and health and showed lowerpsychosocial well-being compared with naturallyconceiving first-time mothers (14) . Even withsingleborn children, IVF mothers have claimed to feelless competent than those who had conceivedspontaneously (15,16).
An alternative explanation for the higher stress inIVF parents of twins could be that more parents ofspontaneous twins had previous experience of parent-ing. Studies on larger numbers are urgently needed.
Pregnancy
Both would-be parents of twins and their professionalcarers need to be clear that a multiple pregnancy ismore likely to be associated with medical complica-tions such as pre-eclampsia, anaemia, polyhydramnios,preterm labour and a difficult delivery. In addition, themother is likely to suffer from tiredness, indigestionand general discomfort far earlier than with a singlebaby. The severity of the symptoms may mean thatthe mother has to stop work early, thereby using adisproportionate amount of her total maternity leaveallowance before the babies are born.
The fetus in a multiple pregnancy is also at greaterrisk from conception onwards.
Vanishing twin
The miscarriage rate is higher than in singletonpregnancies but more common still is the survival ofonly one twin and the loss of one fetus (or more)—the vanishing twin syndrome. Accurate figures for the
Multiple birth children and their families following ART 245
rate of this event are not available but recent first-trimester ultrasound studies suggest that over half oftwin pregnancies may end up as singleton births (17).The effects of these early intrauterine deaths on themother or the surviving twin are still not clear.
Multifetal reduction
As the number of higher multiple pregnancies hasescalated, so have the number of couples who feelthey should maximize the chances of having a healthybaby or twins by reducing the number of viablefetuses. A few sets of quintuplets and sextuplets, aswell as many triplets and quadruplets, have been bornhealthy and lived happily. Nevertheless, some couplesexpecting higher multiples with all the risks andproblems involved, see a real dilemma in which a fetalreduction will seem the least bad option. Fetalreduction is never an easy or uncontroversial solutionand carries its own risk of medical and emotionalcomplications (18).
The balance of risks and advantages will be seendifferently by each couple but for all there will be asense of responsibility and much anxiety. Notsurprisingly, partners themselves sometimes disagree.One or both may have deep religious objections. One,often the mother, may be distressed at the thought ofdisposing of a potential baby of hers whereas thefather may be equally distressed by the idea of havinga disabled child. Partners are almost bound to disagreeto some extent, at least. There may often be a need tocompromise as to what is best for them as individuals,as a couple and as a family. Both partners will need toweigh carefully and sensitively the arguments on bothsides.
For many couples the overriding aim will be thesafe birth of the one healthy child they originallysought. Their next biggest concern will be the healthand welfare of any surviving twins or other children.Parents’ concern about the physical, emotional andfinancial demands will vary greatly between couplesand will not necessarily correlate with their socio-economic status (19).
Even where the couple has decided to undergo areduction, they may well be distressed by theseemingly (and often actual) arbitrary choice as towhich fetus should live and which should die. Someparents will feel a lasting grief and guilt over the deathof one or more potentially healthy children. Neverthe-less, it appears that the great majority still feel thatthey had made the right decision (20).
As yet, no studies have been reported on the long-term psychological effects on parents and thesurviving children. This is partly due to it still being afairly recent procedure. However, it may also in partbe due to parents’ reluctance to discuss their feelings.In contrast to studies on perinatal bereavement, asubstantial number of parents decline to participatein follow-up studies, being reluctant to talk or writeabout their feelings and personal experience (19) .Several highly sensitive questions are of courseinvolved. Any survivor could feel their own survivalwas at the expense of a sibling. They could also seetheir parents as “murderers” or their own existence asarbitrary and their own individual value as thereforeimpaired. Another key question is whether the parentsshould ever tell the survivors about the fetal reductionor keep it as a life-long secret. In the short term, atleast, the surviving children appear to be developingnormally and the parents rarely appear to regret theirdecision.
The Multiple Births Foundation (MBF) publishesa leaflet for couples faced with the option of fetalreduction and can also give more individual adviceabout dilemmas that are bound to be difficult andpainful and to which there cannot be an ultimatelypainless resolution.
Perinatal mortality
Despite improvements in obstetric care, the risks to afetus remain significantly higher throughout a multiplepregnancy and the stillbirth rate for twins is aboutthree times that for singletons.
The perinatal mortality rate in twins is nearly fivetimes higher than that in singletons. In triplets, it isseven times higher. The main contributor to the highdeath toll and rates of disability in multiple births isprematurity and its complications. The neonatal mor-tality rate is about ten times that of singletons (21).
Parents who lose a twin or one or two of tripletsand still have a surviving multiple, face specialproblems (22). They have a constant reminder of thedead child in the surviving child—especially with MZtwins. Parents of multiple infants also lose what manyof them see as a proud status and their bereavementis often underestimated by other people who mayindeed tell them that they are fortunate to still have asurviving baby. These factors further inhibit thegrieving process which has already been delayed bytheir inevitable preoccupation with the survivingchild.
246 JANE DENT ON, ELIZABETH BRYAN
The loss of babies from a higher multiple set canbe particularly difficult. After many years of infertility,a mother may suddenly have three, four or more livebabies but then see one, two or more of them die soonafter birth or die one by one over what can be manypainful months. Alternatively, all the babies maymiscarry before they are viable. Despite these deaths,a couple who is left with one or two babies will receiveremarkably little sympathy about the death of theothers.
Some couples have to cope with their grief overthe death of one (or more) babies while also having toface the daily difficulties and emotional strain of caringfor a disabled child at the same time. In one set ofquads, conceived following GIFT, after 12 years of theparents trying for a baby, the babies were born 14weeks early. One died after six days. The second diedafter six months, having never left hospital. The thirdwas severely disabled and the fourth proved to be abright child but very small. The strain on the familywas inevitably enormous and the marriage brokedown after four years.
Neonatal problems
Preterm delivery and low birth weight are the maincauses of the increased morbidity and mortality in theneonatal period. The average duration of pregnancyis 37 weeks for twins, 33.5 for triplets and 31.5 forquads. Half of the quadruplets who are born weighless than 1500 g compared to a quarter of triplets, onein ten twins and one in a hundred singletons (23).
Costs
The price of multiple births can clearly be high forboth the parents and for the children themselves.However, a considerable price has also to be paid bythe health and social services for the extra burdenimposed by the multiple pregnancy and its outcome.In the early period, especially, both the mother andthe children are likely to consume far more resourcesthan the average mother or singleborn child.
The cost of obstetric care of a multiple pregnancyis inevitably high in terms of hospital stay, extrainvestigations and the likelihood of operativedelivery. It has been calculated that the costs of twin,triplet and quad pregnancies compared to single onesare 2.1, 4.5 and 7 times greater, respectively (24).
Preterm infants, as such, add a huge burden to theneonatal services through the inevitable technical,
pharmaceutical and staffing requirements. Further-more, high multiple births often use up most or all thelimited number of available neonatal intensive carecots. If the preterm delivery of triplets or quads isexpected in a hospital those cots must be kept freethereby preventing the admission of ill singletonbabies.
The average financial cost of neonatal care for atwin infant has been estimated to be 13 times that fora singleton, with a triplet costing 41 times and aquadruplet 77 times that of a singleborn infant. Thismeans that, for the neonatal care alone, the infantsfrom a quadruplet pregnancy cost 308 times more thanthat from a singleton pregnancy (25).
Inevitably the drain on the health servicescontinues. The babies are more likely to have specialneeds and these will require ongoing paediatric careand other therapies as well as special education. Anidea of the costs involved can be derived from studiesof low-birth-weight children in general. It was shownthat the health care, up to eight years, of a low-birth-weight (<2000 g) child costs, on average, five timesas much as that of a normal-birth-weight child. For adisabled low-birth-weight child the cost was 17 timesgreater. The total cost of health care and educationup to the age of eight for a low-birth-weight child whosurvived with a long-term disability was four timesthat of a low-birth-weight child with normal develop-ment and nine times that of a normal-birth-weightcontrol (26).
In the UK and some other countries, the twins andtriplets born following assisted reproductive tech-nology (ART) in private clinics operating on acommercial basis are as likely as any others to becomea practical and financial burden on the publicly fundedneonatal, paediatric, educational and social services.This situation is a legitimate area for public policydebate.
Separation
In addition to the cost, higher multiples pose seriouslogistical problems to the neonatal services. Risks arerun not only of needing to transfer several verypreterm infants but of distributing the infants to twoor more hospitals. This often leaves the mother in theoriginal hospital separated from all her babies and unfitto travel. One or more of the infants may die beforethe mother even touches them.
Multiple birth children and their families following ART 247
Zygosity determination
In the past it was usually assumed that infantsconceived following ovulation induction or multipleembryo transfer must be dizygotic (DZ). It is nowrecognized that although the majority of iatrogenicmultiple pregnancies will be DZ twins or trizygotictriplets, the chance of MZ twinning either in twins orwithin a triplet set is not only equal to but greater—probably about threefold—than would be expectedin the general population (7).
Development
Although the development of most multiple birthchildren is within the normal range, for both medicaland environmental reasons, these children do face ahigher risk of long-term disability and learningdifficulties. In addition to the risks associated with lowbirth weight and prematurity, the problems of havingto constantly share the attention of their mother canaffect their development, particularly in relation tolanguage (27,28). Twin children have also been foundto have less good concentration and a higher incidenceof attention deficit hyperactivity disorder (29).Furthermore, depression, more commonly seen inmothers of preschool twins than in mothers of single-tons, could be an additional factor (30) as maternalemotional well-being is known to influence develop-ment.
Disability
The parents of multiple birth children, by definition,face not only twice (or more) the risk of one of theirchildren having a disability, but there is also a muchincreased risk per child. This is because many formsof disability, particularly cerebral palsy, are much morecommon among twins. Those with a monochorionicplacenta, as occurs in two-thirds of MZ twins, will beat particular risk from intrauterine damage associatedwith a haemodynamic imbalance in their shared bloodcirculation (31). Prematurity and intrauterine growthretardation also increase the risks.
Population studies have shown a threefold tosevenfold higher incidence of cerebral palsy in twinscompared to singletons: it is over tenfold higher intriplets. Of course the chances of any particularmultiple pregnancy producing a disabled child is much
greater still (32).The care of a child with special needs always
brings challenges for parents: these are increased bythe difficulty of caring for other children of the sameage, but with very different needs (33). The parents,and often the child too, have a constant reminder inthe unaffected child of how they both might—indeedshould—have been. Moreover, the special status ofhaving or being a twin is effectively lost if the twinslook very different.
The healthy child may also suffer emotionaldisturbance. He or she may feel guilt about escapingthe affliction but at the same time may constantly feeljealous of the time and attention given to his or hertwin.
Siblings
A little recognized problem arising from the arrival ofmultiples is the effect on other children in the family,particularly on the single toddler who has been thecentre of the family until suddenly displaced by anattention-attracting pair or trio. It has been shown thata sibling is likely to be more disturbed by the arrivalof twins than of a single sibling and that behaviourproblems in the older child are more common (34).
Psychosocial stresses
It is only in the past decade that information aboutthe lives of families with triplets and higher-orderbirths has become available. This emerged primarilyfrom a series of linked surveys called the UnitedKingdom National Study of Triplets and Higher OrderBirths. The population-based project was undertakenby the Office of Population Censuses and Surveyswith the National Perinatal Epidemiology Unit and theChild Care and Development Group at CambridgeUniversity. The study covered medical and socialaspects, from the time of conception, of over threehundred families with higher-order birth children bornin 1980 and 1982–1985 (35).
The report demonstrated that the practicaldifficulties alone of looking after three babies at onceare huge, even when all are healthy. At the mostsimple level, no mother can carry three babies at atime. Only with the greatest difficulty can she feed ortransport them on her own. These plain facts produceall sorts of stresses and complications. Many mothers
248 JANE DENT ON, ELIZABETH BRYAN
cannot take their babies out of the home and so becomehousebound and isolated as a result.
The UK study repeatedly found that help forfamilies, both statutory and private, had beeninadequate in amount and often slow to arrive. Toooften the parents became ill and exhausted before helpwas provided. A mother simply cannot look after threebabies on her own—there are not enough hours inthe day. A study by the Australian Multiple BirthsAssociation showed that 197.5 hours per week wererequired to care for six-month-old triplets and to carryout the necessary household tasks—but there areonly 168 hours in a week (36).
It is sometimes assumed that families with tripletsbecome rich through commercial sponsorship. The UKstudy disproved this belief. Although 75% of familieswith triplets received some local or national presscoverage, few derived financial benefit from it. Onlywith sets of five or more healthy babies was substan-tial sponsorship forthcoming and for that the pricewas the loss of any remaining privacy.
Few people appreciate the very great financial costof triplets to the families compared with that of threesingle children. A new car and house may be neededurgently. Clothes and equipment have to be boughtat once for all three. They cannot be handed down.Unlike a family that grows gradually and can plan andsave, most of a triplet family’s expenditure has to beimmediate. Furthermore, an otherwise working motheris likely to take longer to get back to work and thefather may well be torn between working extra hoursand spending more time helping at home. A similar butless extreme financial situation is met by the parentsof twins.
Increasingly the clinicians providing treatment forinfertility are aware of the many medical and psycho-social disadvantages resulting from a twin conception,let alone that of a higher multiple. Nevertheless, itappears that the couples themselves are less able toperceive the problems. Several studies have shownthat the couples are now becoming aware of thechances and of the implications of a multiplepregnancy but, despite this knowledge, many are stillfully prepared to take the risk. Gleicher et al. (37)found that in the USA 67% of couples undergoinginfertility treatment would “love to have twins” andless than 10% would have been “upset to have twins”.Indeed 50% would not have been upset to conceivetriplets. Similarly, Murdoch (41) found that in the UK,69% considered that twins would be the ideal outcomeof their treatment.
Help
All the economically advanced countries are report-ing increasing numbers of children from higher-multiple births but assistance from public health andsocial services has generally been inadequate andvery patchy. It varies greatly in quantity and qualitybetween different countries and regions. For example,no help is automatically provided in the UK whereasin New Zealand and Belgium help is routinely offeredby the state. Regular practical help is needed bynearly all families during the early years as theextended family can only rarely provide the amountneeded and may well be daunted by the challenge. Insome cases, grandparents have become overwhelmedby the task and moved away (35).
Few, if any, countries give adequate financial andpractical help from statutory sources to multiple-birthfamilies. Many parents have to spend time and emo-tional energy striving to get any of the help they need.
Experiences of the Multiple BirthsFoundation
The MBF was established in the UK in 1988 as thefirst organization to offer professional support tofamilies with twins, triplets and more, as well asinformation, advice and training to the many medical,educational and social work staff concerned with theircare.
Initially the work focused largely on helpingfamilies, through Twins Clinics (and also special onesfor higher multiples), the Telephone Advisory Service,parent evening meetings and literature. The eveningmeetings focus on particular topics such as prenatalpreparation, language, behaviour, individuality andschooling. The Telephone Advisory Service providesbooked consultations at which information, adviceand support are given to parents. It is also given toadult twins, including those who have been bereaved.
One charitable organization can never itself meetthe needs of all families. It is anyway much moreappropriate for the family’s own professional care-givers to advise locally. Therefore, the MBF is nowconcentrating increasingly on the education ofprofessionals including doctors (infertility specialists,obstetricians, paediatricians and family doctors),nurses (midwives and community), social workers andteachers. It does this through a teaching programmeand by offering the services described, including the
Multiple birth children and their families following ART 249
Telephone Service, as models for others to follow.Future plans include working closely with
midwives and health visitors (community nurses) todevelop models of good practice that will be dissemi-nated nationally and internationally with the MBFacting as a specialist information and advice centre.
With financial assistance from the EuropeanUnion, a series of five Guidelines for professionalcaregivers have recently been completed for the careof multiple-birth families from before conceptionthrough adolescence (38).
Services provided worldwide
Most European countries as well as Australia, India,Indonesia, Japan, New Zealand, Nigeria, Sri Lanka,Republic of Korea, Russian Federation and the USAnow have some form of association for parents oftwins and for twins themselves which providesinformation and mutual support. A national organiza-tion will often act as an umbrella for the local groupsor clubs. In the UK the Twins and Multiple BirthsAssociation (TAMBA) also provides a TelephoneHelpline and a number of subgroups including onesfor bereaved families, for those with a twin with specialneeds, and those with “supertwins” (triplets andmore). Another group provides for parents whosechildren were conceived following treatment forinfertility. This latter group has links to infertility clinicsand members are available to talk with those consider-ing treatment which may result in multiple births. Theyalso produce a newsletter, keeping members in touchwith each other.
The financial and practical support provided formultiple-birth families from government sources variesgreatly from country to country and even within acountry.
Information for couples consideringtreatment for infertility
The Royal College of Obstetricians and Gynaecol-ogists (RCOG) Guidelines (39,40) and those of theBritish Fertility Society give detailed information onthe chances of a multiple pregnancy. The HFEA Codeof Practice requires information to be given about therisks associated with multiple pregnancy and thepossible practical financial and emotional impact of amultiple birth on the family and this should be
distinguished from counselling (1).The HFE Act stipulates that counselling must be
offered to all those seeking licensed treatments andunderstanding the implications of the proposed treat-ments is defined in the Code of Practice as part of thecounselling process. Counselling is strongly recom-mended but couples are not obliged to accept the offer.
Fetal reduction should be discussed in advancewith those whose treatment could result in the concep-tion of triplets or higher-order births.
Written information should always be provided aswell as an invitation to a further discussion. A leaflet“Multiple Pregnancy and Multiple Birth” specificallyto inform couples about the risks and implications ofa multiple pregnancy has been produced by the MBF(42). This is freely available in all infertility clinics andshould be promoted by any clinicians, includinggeneral practitioners, who are offering ovulation-inducing therapy.
A visit to a family with multiples can sometimesbe more enlightening for a couple than severalsessions with a counsellor! But, however careful andthorough the counselling, it can be difficult forcouples themselves to make a rational decision aboutthe number of embryos to be transferred, when theyare under emotional stress in their long and painfulquest for a baby. The decision should therefore be ajoint one between the clinician and the couple withthe final responsibility being taken by the clinician tominimize the risk of a higher multiple pregnancy.
Conclusion
For a childless couple the practical and emotionaldifficulties of caring for two or more babies at the sametime may be particularly difficult to imagine. Whatevertype of treatment is planned couples therefore needto be seen together, not only to be given factualinformation on the risks and implications of a multiplepregnancy, both medical and psychosocial, but toreceive counselling on the possible implications forthem as individuals and as a couple. This shouldinclude not only the problems associated with thepregnancy and of having a preterm and low-birth-weight infant, but also the likely psychosocial costsof parenting multiples.
References
1. The Human Fertilisation and Embryology Authority.
250 JANE DENT ON, ELIZABETH BRYAN
Code of practice, 5th ed. London, HFEA, 2001.2. Imaizumi Y. Trends of twinning rates in ten countries,
1972–1996. Acta Geneticae Medicae et Gemellologiae,1997, 46:209–218.
3. Kiely JL, Kiely M. Epidemiological trends in multiplebirths in the United States, 1971–1998. Twin Research,2001, 3:131–133.
4. Loos R et al . The East Flanders Prospective TwinSurvey (Belgium): a population-based register. TwinResearch, 1998, 1 :167–175.
5. Levene M et al. Higher multiple births and the modernmanagement of infertility in Britain. British Journalof Obstetrics and Gynaecology, 1992, 99:607–613.
6. Human Fertilisation and Embryology Authority. AnnualReport. London, HFEA, 2000.
7. Derom R, Derom C, Vlietinck R. The risk of mono-zygotic twinning. In: Blickstein I, Keith LG, eds.Iatrogenic multiple pregnancy. London, ParthenonPress, 2000:9–19.
8. Slotnick RN, Ortega JE. Monoamniotic twinning andzona manipulation: a survey of U.S. IVF centerscorrelating zona manipulation procedures and high-risktwinning frequency. Journal of Assisted Reproductionand Genetics, 1996, 13:381–385.
9. Spillman JR. A study of maternity provision in the UKin response to the needs of families who have a multiplebirth. Acta Geneticae Medicae et Gemellologiae, 1992,41:353–364.
10. Murdoch AP. How many embryos should be transferred?Human Reproduction, 1998, 13:2666–2669.
11. Hay DA et al. What information should the multiplebirth family receive before, during and after the birth?Acta Geneticae Medicae et Gemellologiae, 1990,39:259–269.
12. Cook R, Bradley S, Golombok S. A preliminary studyof parental stress and child behaviour in families withtwins conceived by in-vitro fertilisation. HumanReproduction, 1998, 13:3244–3246.
13. Mushin D, Spensley J, Barreda-Hansen M. Children ofIVF. Clinical Obstetrics and Gynecology, 1985, 12:865–876.
14. Colpin H et al. Parenting stress and psychosocial well-being among parents with twins conceived naturally orby reproduc-tive technology. Human Reproduction,1999, 14:3133–3137.
15. Gibson FL et al . Psychosocial adjustment, childbehaviour and quality of attachment relationship, at 1year post partum for mothers conceiving through IVF.American Society for Reproductive Medicine Conference,Boston, Mass, USA, 1996:2–6.
16. McMahon CA et al. Psychosocial adjustment and thequality of the mother-child relationship after IVFconception from pregnancy to four months postpartum:an observational study. American Society for Repro-ductive Medicine Conference, Boston, Mass, USA,1996:2–6
17. Pharoah POD et al. Epidemiology of the vanishing twin.Twin Research, 2001, 3:202.
18. Bryan E, Higgins R. Embryo reduction of a multiplepregnancy: an insoluble dilemma? In: Bryan E, HigginsR, eds. Infer tility. New choices, new dilemmas. London,Penguin, 1995:130–140.
19. Garel M et al. Psychological reactions after multifetalpregnancy reduction: a 2-year follow-up study. HumanReproduction, 1997, 12:17–22.
20. Schreiner-Engel et al . First-trimester multifetalpregnancy reduction: acute and persistent psychologicreactions. American Journal of Obstetrics andGynecology, 1995, 172:541–547.
21. Office of National Statistics Series DH3, No 32,London, 2000.
22. Bryan EM. Perinatal bereavement after the loss of atwin. In: Ward RH, Whittle M, eds. Multiple pregnancy.London, RCOG Press, 1995:186–195.
23. Macfarlane AJ et al. Early days. In: Botting BJ,Macfarlane AJ, Price FV, eds. Three, four and more; anational survey of triplet and higher order births.London, HMSO, 1990:80–98.
24. Mugford M, Henderson J. Resource implications ofmultiple births. In: Ward RH, Whittle M, eds. Multiplepregnancy. London, RCOG Press, 1995:334–345.
25. Papiernik E. Cost of multiple pregnancies. In: HarveyD, Bryan E, eds. The stress of multiple births. London,Multiple Births Foundation, 1991:22–34.
26. Stevenson RC et al. Cost of care for a geographicallydetermined population of low birthweight infants to age8–9 years. II. Children with disability. Archives ofDisease in Childhood, 1996, 74:118–121.
27. Hay DA et al. Speech and language development in pre-school twins. Acta Geneticae Medicae et Gemellologiae,1987, 36:213–223.
28. McMahon S, Dodd B. A comparison of the expressivecommunication skills of triplet, twin and singletonchildren. European Journal of Disorders of Communi-cation, 1997, 32:328–345.
29. Levy F et al. Twin sibling differences in parental reportsof ADHD speech, reading and behaviour problems.Journal of Child Psychology and Psychiatry and AlliedDisciplines, 1996, 37:569–578.
30. Thorpe K et al. Comparison of prevalence of depres-sion in mothers of twins and mothers of singletons.British Medical Journal, 1991, 302:875–878.
31. Cincotta RB, Fisk NM. Current thoughts on twin–twintransfusion syndrome. Clinical Obstetrics andGynecology, 1997, 40:290–302.
32. Petterson B, Stanley F, Henderson D. Cerebral palsy inmultiple births in Western Australia. American Journalof Medical Genetics, 1990, 37:346–351.
33. Bryan E. The disabled twin. In: Bryan E, ed. Twins andhigher multiple births. A guide to their nature andnurture. London, Edward Arnold, 1992:165–170.
34. Hay DA, McIndoe R, O’Brien PJ. The older sibling oftwins. Australian Journal of Early Childhod, 1998,13:25–28.
35. Botting BJ, Macfarlane AJ, Price FV, eds. Three fourand more. A study of triplets and higher order births.
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London, HMSO, 1990.36. Australian Multiple Births Association. Proposal
submitted to the Federal Government concerning ‘Actof Grace’ payments for triplet and quadruplet families.Australian Multiple Births Association, Coogee,Australia, 1984.
37. Gleicher N et al. The desire for multiple births in coupleswith infertility problems contradicts present practicepatterns. Human Reproduction, 1995, 10:1079–1084.
38. Bryan E, Denton J, Hallett F. Guidelines for profes-sionals: multiple births and their impact on families.London. Multiple Births Foundation. Facts aboutmultiple births (1997); Multiple pregnancy (1997);Bereavement (1997); The twin with special needs
(1999); Twins and triplets. The first five years andbeyond (2001).
39. Royal College of Obstetricians and Gynaecologists. Themanagement of infertility in secondary care. London,RCOG Press, 1998.
40. Royal College of Obstetricians and Gynaecologists. TheManagement of infertility in tertiary care . London,RCOG Press, 1998.
41. Murdoch A. Triplets and embryo transfer policy.Human Reproduction , 1997, 12:88–92.
42. Denton J . Multiple pregnancy and birth—for patientsconsidering treatment for infertility. London, MultipleBirths Foundation, 1997.
Section 4
Social and psychological issues in infertility and ART
Consumer perspectives
SANDRA DILL
Introduction
Most people take for granted their ability to have achild. Some choose not to but most of those who tryto have a child have no difficulty in achieving thatgoal. However, for between 13% and 24% of coupleswho would like to have a child but are not able to, itcan be a very painful experience and one difficult tomanage (1–3).
Infertility is an extremely isolating experience. Thisis exacerbated because infertility and the death of achild are taboo subjects. As a society we have diffi-culty in dealing with these sad experiences. Infertilepeople need medical and social choices to help themdeal with infertility. Some pursue adoption and forover 20 years, assisted reproductive technology(ART) has provided in vitro fertilization (IVF) andrelated treatments as another way of overcominginfertility and childlessness.
The limited recognition of infertility as adisease or medical condition
Governments worldwide have demonstrated areluctance to acknowledge that infertility is a disabilityor medical condition (Appendix A). In most countries,infertility treatment is viewed as an elective procedureand therefore not worthy of reimbursement. In
Bangladesh, despite the fact that infertility isconsidered a curse that brings couples bad luck, themajority is unaware of the possibility of treatment(Appendix A). The need to have access to health careis balanced against the need for governments toresponsibly manage scarce resources and to distributethem justly and equitably for the good of the wholecommunity. The challenge for consumers of infertilityservices is to persuade governments that infertility isa medical disability which causes suffering and, assuch, is worthy of inclusion in their national healthplan. This is one of the objectives of the InternationalConsumer Support for Infertility (iCSi) network whichbrings patient leaders together to discuss commoninterests and concerns. There are also nationalpatient associations in many countries which providesupport for infertile people and advocate for accessto affordable infertility treatment. The InternationalFederation of Infertility Patient Associations (IFIPA)is another international group, whose membership ismade up of national patient associations.
The emergence of patient support networksworldwide
Like any life crisis, infertility can be best understoodby those who have experienced it. Therefore, infertilityself-help groups play an invaluable role, as there is
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comfort in speaking with someone who reallyunderstands. It can ease the feeling of isolation. Manyinfertility self-help groups have been establishedaround the world since the early 1980s (Appendix A).These groups seek to provide information to infertilepeople, their families and friends and also to govern-ment, media and the medical and scientific community.The iCSi network is a global family of patient leadersfrom support associations in more than 30 countriesand strives to expand the number of countries reachedeach year, particularly to include developing countries.New contacts have been established recently withpatient leaders in Bangladesh, India and Japan.
Equity of access to ART
The United Nations Declaration of Human Rightsrecognizes that, “Men and women of full age, withoutany limitation due to race, nationality or religion, havethe right to marry and found a family” (4). This issupported by the European Convention on HumanRights which guarantees respect for family life and theright to found a family (5).
It can be argued that these provisions create apositive right to access ART to achieve this goal, onetaken for granted by fertile people in the community.For those who need medical assistance to form theirfamilies, infertility causes immense suffering. Forthose who finally remain without a child, infertility canbe a lifelong disability.
The objective of a health system is to deliverhealth care to all those in need. However, in somewestern countries, the limitless demand for health carecan often not be met due to the scarcity of resourcesto service it (Appendix A). This has been exacerbatedby an ageing population and costly advances intechnology which have exceeded our ability to payfor them. Therefore, the need for rationing or microallocation of health resources becomes apparent. Nosystem of allocating limited resources at the level ofthe individual patient can work without resorting tonotions of utility. While rationing is a necessity, it isimportant that the system used to decide who getshealth care be one that promotes equity of accessbetween people with health needs.
The question “Who shall be eligible for assistedreproductive technologies?” signals the oneroustask of health professionals and governments toallocate scarce resources equitably. This raises thequestion of what criteria can be used to distribute
resources fairly.A utilitarian perspective, which argues that justice
involves trade-offs to ensure that the greatest goodcan be delivered, can present a conflict for the medicalpractitioner who seeks to act in the best interests ofthe patient (6). Notions of utility are inevitably resort-ed to when practitioners make decisions to ensure thatthe maximum benefit can be obtained for the greatestnumber of those in their care.
Many criteria are used in deciding which patientwill receive health care. It has been argued, as in NewZealand, that determining an initial eligible pool ofpatients based on substantive standards andprocedural rules is preferable to the decision-makingprocess being left to the final selection of an individualfor a particular procedure (7). However, this processdoes not remove the possibility of value judgementsimpacting on selection. Governments in somecountries that reimburse ART treatment, such asAustria, France and the United Kingdom, impose agecriteria. Israel is currently debating this issue(Appendix A).
Methods of rationing that introduce notions ofutility can use medical or social criteria. The use ofsocial criteria is necessarily subjective, arguablyimmoral and is contrary to the principle of individualautonomy. However, it is difficult to see how thosemaking decisions about rationing resources can avoidsuch judgements. Value judgements can be madebased on an individual’s past and potential contribu-tion to society or, in the case of ART, on old-fashionedprejudices masquerading as new ethical dilemmas (8) .
For example, there has been discussion aboutwhether it is ethical to allow single women, lesbian orhomosexual couples access to ART. Many believe thatthis is morally wrong, arguing that it is preferable fora child to be raised within a stable, heterosexualrelationship. Whatever our personal views, those whoargue that the traditional concepts of family shouldbe maintained, fail to recognize a different reality. AnAustralian government statistical report found that69% of households had no children, 32% of house-holds comprise two persons, 19% had two or morechildren and 13% of households had one child.Marriage rates continue to fall, divorce occurs in morethan 40% of marriages and 27% of births were to singlewomen (9). These figures demonstrate the diversityof family arrangements that can exist.
It is important to distinguish public funding fromlegal access to health services in situations wherepeople without a medical condition could pay for
Consumer perspectives 257
needed services, irrespective of the social choicesthat they have made.
Decisions about who will access health careresources can be complex and difficult. The scarcityof resources available to meet the needs of everyoneseeking them compels health professionals andgovernments to make decisions about which indivi-duals should have priority access to them and we aremindful that there is “very little distance betweenpolicy and politics” (10). While this dilemma may bea practical necessity, it is important to be aware of themoral conflict and to aspire, wherever possible, to adeontological perspective such as the Kantian idealor the biblical exhortation, of treating others as wewould like to be treated if we were in their circums-tances.
Success rates·how can we be sure oftreatment quality?
Success, like happiness, can be different things todifferent people. For some, success of IVF is aconfirmed pregnancy, for others it is a healthy babynine months later and some may suggest that successis a few years down the track when your child isenrolled in medical or law school.
In considering what success means to consumersof IVF services the familiar model of the HumanFertilisation and Embryology Authority (HFEA) in theUK provides a perspective. ISSUE, the NationalFertility Association in the UK, has reported on theHFEA publication, The patients’ guide, claiming thatthe practice of publishing success rates of identifiedclinics has impacted on the range of treatmentsavailable. An example cited was of one clinic thatceased to offer natural cycles because they impactednegatively on their success rates (personal communi-cation with ISSUE, CEO, 1998). As a result, consumersare denied access to a less invasive treatment becauseof the commercial impact caused by the misleadingway in which success rates have been reported. Whileexplanations are given for the way statistics arereported, they have little meaning for most consumerstrying to make a decision about where they shouldgo for treatment.
When the patrons of ISSUE were asked about thePatients’ guide (11), Professor Ian Cooke from theJessop Hospital for Women in Sheffield, UK foundthat there was very little information about thestatistical data, making it vulnerable to the media to
rank clinics, ignoring all statistical ranges. He foundthat the data from a very large number of clinics didnot differ significantly.
Doctor Peter Brinsden from the Bourn Hall Clinicin Cambridge, UK said that while the Guide was avaluable source of information, he was not in favourof league tables. He noted that while the HFEA didnot rank clinics, the press did, and this had hadunfortunate consequences for some clinics whoseeffectiveness had been misrepresented.
Doctor Simon Fishel from CARE at the ParkHospital in Nottingham, UK commended the sectionwith suggested questions for prospective patients toask clinics but he also found a real problem with thedata. He questioned the fairness of the adjusted live-birth rate as there was no information about theformula used to determine this. He also identified asignificant disadvantage in the way clinics couldmanipulate these figures by driving a certain kind ofpractice that may be more “successful” rather thanbeing concerned about specific treatment that couldbe tailored for the individual couple. He suggestedthat age divisions would provide more relevantinformation for couples considering treatment.
How then can success be determined?
The conflict of clinics to provide the best informationfor their patients while presenting their units in apositive light has been discussed, as has the problemof how best to present that information (12). Theinadequacies of the simplistic scenario of dividing thenumber of pregnancies by the number of patients whounderwent treatment have been improved by amethod of identifying a monthly pregnancy rate andcumulating the outcomes (13). This has been furtherdeveloped by expressing results as a “life tableanalysis” which has become an accepted method ofreporting results for donor insemination (14), ovula-tion induction (15) , and IVF (16) . This providesinformation to couples about the prospects of successover a specified number of treatment cycles. However,many variables remain including questions about whatis a pregnancy. Should success be regarded as apositive beta-hCG test 14 days after treatment? Or itcould be when a fetus is visible on ultrasound—butthis includes ectopic pregnancies and early mis-carriages. Is success determined when a normal fetalheartbeat can be detected? Is it more realistic toexpress success as a live birth, often referred to byconsumers as the THB or “take home baby” rate?
258 SANDRA DILL
Success rates can seem better if expressed “pertransfer” rather than “per oocyte pick-up” (per OPU)or “per cycle commenced”. Other variables include
• that the probability of success is higher in the firstfew cycles so programmes with new patients willhave higher success rates;
• younger women are more fertile;• multiple pregnancies increase reported success
rates;• cancellation rates have a negative impact on
success rates; and• the number of embryos transferred will also impact
on reported results.
When reporting success rates should clinicsbe identified or anonymous?
An integral function of accrediting bodies andlicensing authorities is to collect results for a specificgroup of patients, who have a similar likelihood ofhaving a live-birth pregnancy, to compare successrates at different units (17). The use of these data tomeasure performance for accreditation purposes is auseful means of identifying ways to improve practice,while maintaining confidentiality. However, publishingsuccess rates that identify clinics in league tables canweaken the quality of the information available forconsumers, as the UK examples have shown.
One strength of the annual Australian Institute forHealth and Welfare (AIHW) report in Australia is,arguably, its anonymity (18). There is no incentiveto manipulate data so consumers can be confident ofits reliability. Patient associations encourage consumersto approach individual clinics, perhaps more than one,to discuss the options available for their individualneeds and the clinic’s ability to meet them. Becausethere are wide differences between patients, specificinformation about an individual’s chances of successshould be obtained from the clinicians. This approachseems preferable to selecting a clinic based on statis-tics that do not reveal the full picture.
At the heart of a consumer’s question about aclinic’s success rates is the need to know where thebest chance of success can be assured. This lies inthe quality of the health care delivered by the clinicapproached for help. If quality is effectively monitoredthrough an accreditation process, where the data canbe rigorously scrutinized, then consumers can beconfident of having the best chance of realizing theirdream of having a healthy baby.
It can be argued that the self-regulation model isweak as the locus of control lies with doctors.However, a strength of the Reproductive TechnologyAccreditation Committee (RTAC) model in Australiais that consumers participate as equal partners. Thisis unique in medicine in Australia and possibly in ARTpractice worldwide. Any successful attempt by ahealth professional to inappropriately manipulate theprocess would destroy the credibility and effective-ness of the RTAC.
What should the role of the law be in reportingsuccess rates?
Emerson said over 100 years ago, “the less governmentwe have, the better—the fewer laws and the lessconfided power” (19). As consumers, we are carefulnot to be seduced by the assumption that the law willnecessarily protect us from harm. The adoptionexperience in some countries is one historical exampleof this where, during a 30-day cooling-off period afterthe birth prescribed by law, many mothers who hadchanged their minds about relinquishing their childrenwere told falsely by health professionals that theirchild had already been adopted.
In determining how success rates can best bereported, a model which delivers the most reliable datato assist informed decision-making is preferred byconsumers to one which seeks by statute to makeindividual clinics accountable but fails to delivermeaningful data.
In working towards a model that meets the needsof all stakeholders, consumers seek a spirit of coopera-tion, which will ensure transparency and quality in thedelivery of infertility services. Justice Hand of the USSupreme Court said that such a spirit is one “which isnot too sure that it is right, which seeks to understandthe minds of other men and women and weighs theirinterests alongside its own—without bias” (20). Sucha spirit of cooperation is crucial to achieving goodoutcomes and ensuring public confidence in theregulation and oversight of ART.
The impact of legislation on ART treatment
While some are proponents of restrictive legislation,others have argued that there is too much legislationfor ART and cite existing legal choices for women inrelation to human reproduction which respect indivi-dual autonomy. These include contraception,
Consumer perspectives 259
abortion, where it is permitted (the father has no say),tubal ligation and tubal reversals. There is only inter-vention when the child is at risk as in adoption (21).
However, the Canadian Royal Commission tookan opposing view, which claimed that, “Given rapidlyexpanding knowledge and rapid dissemination oftechnologies, immediate intervention and concertedleadership are required as citizens in provinces withinsufficient regulation may suffer harm” (22).
Fertile people have been free to determine theirown meaning of family and to live their lives accord-ingly. Where there is no evidence of detriment to thechild, there appears to be no need for society to inter-fere in these arrangements.
Adherence to the “best interests of the child”principle, while laudable, can be difficult to apply inpractice. It would be difficult to argue that it would bein the best interests of a child not to be born at all. InSouth Australia, the Reproductive Technology Actrequires that a couple seeking assisted conceptionmust demonstrate that they have no outstandingcriminal charges or a history of an offence that wassexual or violent in nature. It also states that a couplemust have no disease or disability which couldinterfere with their capacity to parent a child. DeLacyargues that “while plausible, such requirements areextraordinary and unjust, and are likely to be bothineffective in protecting the welfare of children andharmful to individuals in the long term”. She identifiedthe assumptions on which these requirements rest.Firstly, that “a parental history of crime of violencewill result in the child being exposed to violence” (23).Secondly, that parents who have had a child removedfrom their care have been proven to be abusive orneglectful. This does not account for children removedfrom care for reasons other than poor parenting.
The requirement about a disability that couldinterfere with the capacity to parent offers no para-meters with which to make that judgement. Given thatreproductive medicine is called upon to intervene insituations of infertility caused by disease anddisability, this presents a paradox for practitioners.This is supported by Douglas who argues thatinstituting a “fitness to parent” code is “difficultenough to apply in cases concerning children who arein existence, let alone those who are only a twinkle inthe doctors’ eye and it is open to many differentassessments, depending on the person making thejudgement” (24). DeLacey asserts that judgementsare being made about a child who does not exist whenclients who do exist and to whom the practitioner owes
a fiduciary duty, are being refused treatment, whichmay not be in their best interests, leaving a practitionervulnerable to an accusation that she may have actedin an ethically questionable manner (23).
Sometimes, specific treatments such as eggdonation and surrogacy are prohibited. Surrogacy isnot new. One of the earliest recorded instances ofsurrogacy appears in the Bible in the book of Genesis(25). However, both these treatments are forbiddenin some countries, such as Denmark, Germany, Norwayand Switzerland, and in the state of Queensland inAustralia (Appendix A).
Surrogacy is permitted under Buddhist law butquestions may arise about family ties as well as legaland moral issues. While Jewish law does not forbidsurrogacy, questions about the status of the child areraised when one of the women involved is not of theJewish faith (26). When traditional surrogacy is used,the resulting Jewish child belongs to the donor of thesperm but this question remains unresolved in thecase of IVF surrogacy. In the case of Islam, the practiceof surrogacy is not permitted. In New Zealand, theMaori culture of whanau (extended family) sanctionsinformal surrogacy arrangements. There is noevidence in the literature to suggest that in the vastmajority of such arrangements there is any detrimentaleffect on the child or the other parties involved.
Current law in most countries recognizes thewoman giving birth as the legal mother, even whereshe has no genetic link to the child. This leaves thegenetic mother no option but to apply to adopt thechild to secure legal parentage and leaves the womanwho gestated the child in the position of needing togive up for adoption a child that she never intendedto raise.
The Australian Capital Territory (ACT) introduceda fresh approach with the Substitute ParentAgreements Act 1994 , making it the only jurisdictionwhere specific legislation has been enacted to allownoncommercial IVF surrogacy. The Act prohibitscommercial surrogacy but does not prohibit thefacilitation of pregnancy where there is a non-commercial agreement. Children have been bornthrough IVF surrogacy in the ACT since 1994, withfull knowledge and contact between the children andthe women who gave birth to them. There has beenno evidence of harm done to any party, except byinadequate legislation with unintended consequences,which left the children being raised by their biologicalparents but not recognized as such in law.
In 1996, the Chief Minister of the ACT introduced
260 SANDRA DILL
the Artificial Conception (Amendments) Bill. Itspurpose was to allow biological parents to obtain legalparentage of a child born to another woman as theresult of a surrogacy arrangement. The Bill imposedfive conditions, including that at least six weeks andno more than six months must have elapsed since thebirth and the birth parents were required to haveagreed freely and with full understanding of what wasinvolved. Both genetic and birth couples wererequired to have received assessment and counsellingfrom a service other than that which carried out theIVF procedure and the biological parents wererequired to be residents of the ACT.
After lengthy public discussion, the Bill waspassed in August, 2000 and provided for the ACTSupreme Court to issue a parentage order to allow thebiological parents to be recognized as the legal parentsof the child. The effect of the Act has been to ensurethat the courts, known for their conservativeapproach, retain control of judging what are the bestinterests of the child. Primarily, it provides certaintyto any children born as permitted under the Act, as tohis/her parentage, thus allowing their best intereststo be served. Importantly, it ensures that the wishesof the gestational mother are considered in anyapplication for a parentage order. It has also, humanely,provided closure for the biological parents who mayhave undergone many years of medical treatment inorder to have a child and who have lived withuncertainty from the outset.
The question is whether particular legislation willnecessarily protect citizens from harm and, where it isconsidered necessary, what degree of protectionshould be imposed by the law in a society where mostcitizens are free to make a multitude of choices abouttheir lives or health care, including reproduction. InAustralian States free from restrictive legislation, therehas been no evidence that consumers or society havebeen disadvantaged. It can be argued that wheregenuine informed decision-making occurs and thereis a process for legitimate ethical review, restrictivelaws make little sense and in some cases deny accessto appropriate treatment for some couples who haveno other means of forming their families. History hasdemonstrated that governments can often make ill-informed, politically expedient decisions, which arenot necessarily in the best interests of their consti-tuents. Furthermore, legislation is difficult to repeal.Even the most well-intended legislation in a high-tech,rapidly evolving area such as ART, can quickly proveobsolete.
Australia is the only country in the world withunrestricted access to public reimbursement for ARTtreatment. Crucial to securing this coverage has beenthe genuine involvement of consumers in all compo-nents of regulation, legislation, accreditation, andpolicy development. The inclusion of a consumerrepresentative on the Federal Council of the FertilitySociety of Australia (FSA) and on the RTAC, ensuresthat consumers have access to reliable informationabout treatment outcomes, possible drug side-effectsand the quality of service provided by individualclinics. Despite the initial skepticism of the govern-ment, RTAC has demonstrated that self-regulation canwork. Access to government funded drugs used intreatment in Australia is provided only to those clinicswhich have been accredited by RTAC. The availabilityof counselling is a requirement of accreditation, as isprovision of detailed, written information on treat-ment, prior to its commencement. Clinics mustdemonstrate compliance with guidelines laid down bythe National Health and Medical Research Council,the Australian Health Ethics Committee and a code ofpractice, together with relevant statutes in someStates. To gain approval to conduct research orundertake new treatment with ethical considerations,individual clinics must apply to their local InstitutionalEthics Committee. This ensures that the concerns ofthe community are addressed and that the interestsof consumers are protected. In those states withregulatory authorities, their personnel accompany theRTAC team on clinic site visits in order to examine theclinic’s state licence renewal. Benefits of self-regulation include its flexibility as it is more able torespond to emerging scientific advances and allow fora greater degree of autonomy for consumers in thedecision-making process.
It also removes the need to rush to legislationevery time a new procedure becomes available. Insome countries, this has resulted in strange anomalies,such as:
• allowing sperm donation but not in an IVF cycle(Norway and Sweden), or
• allowing sperm donation but not oocyte donation(Denmark and Germany), or
• recommending that use of her frozen embryo by awoman if her husband dies be disallowed butallowing that same woman to receive donor sperm(Canada, France, Germany and UK).
Consumers of ART services seek politicians with
Consumer perspectives 261
integrity who have the courage to act fairly rather thanexpediently. In addition, almost one million ARTchildren have been born worldwide. Some of themhave reached voting age and will show great interestin how their elected officials value their existence.
Developing effective partnerships withproviders
A significant factor in the success of negotiationswith government in relation to regulation andreimbursement issues in Australia has been thecommitment of consumers and providers to work inpartnership to achieve common goals. This hasproved to be a powerful tool in the political arena andhas provided a model for similar representation inother countries. In the late 1980s, this coalition ofconsumers and physicians successfully lobbied theAustralian federal government for recognition ofinfertility as a medical condition and reimbursementfor ART treatment. In 1990 the Prime Ministerannounced the provision of reimbursement of ARTprocedures through Australia’s national health plan.This has helped to provide equity of access to healthcare for infertile people in Australia. The continuingparticipation of consumers in public policy and theregulation of IVF clinics is a reassuring demonstrationof openness by health ministers, physicians andbureaucrats in ensuring transparency and quality inthe delivery of infertility services.
This paradigm shift from consumers as passiveparticipants to partners has been difficult for IVFphysicians in some countries but the political benefitsfor consumers and providers can be significant. Thesepartnerships are also appropriate as they recognizethat consumers of ART services must live with theconsequences of policy and treatment decisions.
The challenge for consumers is to ensure that allstakeholders have confidence in our integrity, profes-sionalism and our ability to work effectively with themedical profession, government ministers and seniorpublic officials. This may not always be an easy taskbut the suffering of those who come to all of us forsupport, compels us to commit to nothing less.
Real costs of infertility: emotional, social,societal
Governments have argued that the costs of providing
reimbursement for infertility treatment are too high butit can be argued that the financial costs are lesssignificant than the real costs of infertility.
The Royal College of Obstetricians and Gynaecol-ogists and the British Infertility CounsellingAssociation found, based on papers by infertilityspecialists and interviews with medical, scientific andpsychological experts, that infertility costs the nationin absenteeism, poor productivity and wastedresources (27).
There are also social costs to consider such asmarital relationships, taking time off from work,refusing promotions, strained family relationships,exclusion from inheritances or family mementos andisolation from friends. The quality of life for someinfertile people can become marginal when they havedifficulty coping with a friend’s pregnancy, seeingbabies and young children or watching televisionadvertisements featuring babies. Events such asChristmas, Mother’s Day and Father’s Day can bepainful reminders of other people’s fertility andsuccess and are times to be endured. Many couplesdo not participate in these family celebrations.
The emotional costs can be the most significant.Nicol, in examining the impact of maternal loss, foundthat—on average—10% of women suffered some formof reproductive loss each year. Furthermore, she foundthat the death of a child had an emotional and physicalimpact on a woman that was as significant as thatcaused by the death of a spouse and that with multiplelosses the impact was exacerbated (28). It is easy tosee the implications for women who have undergonesuccessive attempts at assisted conception.
In 1993, the London newspaper, the Daily Mailreported on the 15th birthday of “Bubbly Louise”(Brown), the world’s first baby born through IVF (29) .A few pages away appeared a story headlined Tragicteacher who longed for a baby. Gillian Martine, a 34-year-old primary schoolteacher from Southamptonand her husband Michael, after trying to conceive forsome years, had been told by their doctors theheartbreaking news that they would never have achild. Depressed and discouraged, Gillian committedsuicide (30). On the same day, the joy of assistedparenthood and the desperation and despair ofinfertility were graphically contrasted. The questionis not whether infertile people have a right to infertilitytreatment reimbursement but rather, why they shouldbe discriminated against in being denied access toappropriate health care services.
The profound impact which infertility and
262 SANDRA DILL
involuntary childlessness has had on millions ofpeople worldwide, means that the global family ofinfertility associations will continue to lobby andrepresent the needs of our constituents. We will notrest until all those we represent are treated with thedignity enjoyed by others in the community. Infertilepeople, as citizens and taxpayers of our respectivecountries, seek rather to claim our right to equity ofaccess, with fellow citizens, to affordable qualityhealth care and appropriate recognition of ART as astandard, proven treatment for infertility.
References
1. Page H. Estimation of the prevalence and incidence ofinfertility in a population: a pilot study. Fertility andSterility, 1989, 51:571–577.
2. Greenhall E, Vessey M. The prevalence of subfertility.Fertility and Sterility , 1990, 54:978–983.
3. Templeton A, Fraser C, Thompson B. The epidemiol-ogy of infertility in Aberdeen. British Medical Journal,1990, 301 :148–152.
4. Universal Declaration of Human Rights, Article 16.1,United Nations, 1948.
5. European Convention on Human Rights and its FiveProtocols, Articles 8 and 12.
6. Beauchamp T, Childress J. Principles of biomedicalethics. Virginia, USA, Oxford University Press, 1989:266.
7. Beauchamp T, Childress J. Principles of biomedicalethics. Virginia, USA, Oxford University Press, 1989:292.
8. Tizzard J. The deserving and the undeserving. In: BiggH. et al (eds) . Progress in reproduction. London,Progress Educational Trust, 1996.
9. Madden R. Women’s Health Australian Bureau ofStatistics, 1994, Cat No 4365.0, Canberra. AustralianBureau of Statistics, Marriages and Divorces, 1995, CatNo 3310.0, Canberra.
10. Shenfield F. Justice and access to fertility treatments.In: Shenfield F, Sureau C, eds. Ethical dilemmas inassisted reproduction. London, Parthenon PublishingGroup, 1997.
11. ISSUE newsletter, Spring 1998.12. Kovacs G. What is the best strategy for presenting
results in assisted reproductive technology? Journal of
Assisted Reproduction and Genetics, 1999, 16:461–463.
13. Chong AP, Taymor ML. Sixteen years’ experience withtherapeutic donor insemination. Fertility and Sterility1975, 26:791–795.
14. Kovacs GT, Lording DW. Artificial insemination withdonor semen. A review of 252 patients. Medical Journalof Australia, 1980, 2:609–612.
15. Kovacs GT et al . Induction of ovulation with humanpituitary gonadotrophins: 12 years experience. MedicalJournal of Australia, 1984, 140:575–579.
16. Kovacs GT et al . In vitro fertilisation and embryotransfer. Prospects of pregnancy by life-table analysis.Medical Journal of Australia, 1986, 144:682–683.
17. The Reproductive Technology Accreditation Com-mittee (RTAC), Australia; The Human Fertilisation andEmbryology Authority, United Kingdom.
18. Lancaster P, Hurst T, Shafir E. Assisted conception inAustralia and New Zealand. Annual report. 1999, 2000.Australian Institute for Health and Welfare, NationalPerinatal Statistics Unit and The Fertility Society ofAustralia.
19. Emerson, RWE. Ralph Waldo Emerson, “Politics”.Cambridge, University Press, 1876.
20. Pederson W, Provizer N, eds. Great Justices of the U.S.Supreme Court: series X Political Science, 1993:365.
21. Keane L. In: video link from the USA at the annualscientific meeting of the Fertility Society of Australia,December, 1997.
22. Proceed with Care. Final Report of the Royal Commis-sion on New Reproductive Technologies. Ottawa, CanadaCommunications Group, 1993:19.
23. de Lacey S. Children’s interests: has social policy gonemad? Paper presented at the Fertility Society ofAustralia annual conference, 2–4 December 1997,Adelaide, South Australia.
24. Douglas G. Law, Fertility and Reproduction. In:Kennedy D, Grubb M, eds. Medical law, 2nd ed. London,Butterworths, 1994:119–122.
25. Genesis 16:1–14: Genesis 30:1–13.26. Schenker JG. Religious views regarding treatment of
infertility by assisted reproductive technologies. Journalof Assisted Reproduction and Genetics, 1992, 1:3–8.
27. Kon A. Infertility: the real costs, ISSUE, CHILD forNational Fertility Week, 1993.
28. Nicol M. Loss of a baby, understanding maternal grief.Transworld, Moorebank, NSW, 1989:4.
29. The Daily Mail, 27 March 1993, p. 15.30. The Daily Mail, 27 March 1993, p. 9
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Appendix A
(The information in this Appendix is the positions and opinions of the organizations and individuals indicated.)
Country Legislation, regulation, access and social issues Reimbursement
Argentina Concebir, Estela Chardon
In Argentina there is no law about infertility treatments, No reimbursementthat is the reason why patients have no reimbursementsfor their treatments
Australia ACCESS Australia Infertility Network, Sandra Dill
While some are proponents of restrictive legislation, The Australian experience has shown that beforeothers have argued that there is too much legislation for governments are willing to reimburse from the publicART and cite existing legal choices for women in relation purse, the medical community must demonstrate thatto human reproduction which respect individual autonomy. quality standards of health care are met and that theFor Australians, the question is whether particular practice of assisted reproductive technology (ART) islegislation will necessarily protect citizens from harm and, effectively monitored. A significant factor in thewhere it is considered necessary, what degree of success of negotiations with government in relation toprotection should be imposed by the law in a society regulation and reimbursement issues has been thewhere most citizens are free to make a multitude of commitment of consumers and providers to work inchoices about their lives or health care, including partnership to achieve common goals. This hasreproduction. In Australian States free from legislation, proved to be a powerful tool in the political arena inthere has been no evidence that consumers or society Australia and has provided a model for similarhave been disadvantaged. It can be argued that where representation in other countries.genuine informed decision-making occurs and there is aprocess for legitimate ethical review, restr ictive laws make In the late 1980s this coalition of consumers andlittle sense and in some cases deny access to appropriate physicians successfully lobbied the Australiantreatment for some couples who have no other means of federal government for recognition of infertility as aforming their families. History has demonstrated that medical condition and reimbursement for ARTgovernments can often make ill-informed, politically treatment. In 1990 the Prime Minister announced theexpedient decisions, which are not necessarily in the best provision of reimbursement of ART proceduresinterests of their constituents. Legislation is difficult to through AustraliaÊs national health plan. This hasrepeal. Even the most well intended legislation in a high- helped to provide equity of access to health caretech, rapidly evolving area such as ART, can quickly for infertile people in Australia.prove obsolete.
In November 2000 the restriction of six cycles ofIn Australia, crucial to achieving good outcomes in the IVF treatment in a womanÊs lifetime in AustraliaÊsregulation and oversight of ART has been the genuine national health scheme was removed, making thisinvolvement of consumers in all components of regulation, the only country in the world with unlimitedlegislation, accreditation and policy. The inclusion of a government reimbursement for infertilityconsumer representative on the Federal Council of the treatment. This followed successful representation,Fertility Society of Australia (FSA) and on the Reproductive by consumers of infertility health care and providers,Technology Accreditation Committee (RTAC), ensures that to the federal Health Minister and his Department.consumers have access to reliable information abouttreatment outcomes, possible drug side-effects and the The continuing participation of consumers in publicquality of service provided by individual clinics. Despite the policy and the regulation of IVF clinics is ainitial scepticism of the government, RTAC has reassuring demonstration of openness by healthdemonstrated that self-regulation can work. Access to ministers, physicians and bureaucrats in ensuringgovernment-funded drugs used in treatment in Australia is transparency and quality in the delivery of infertilityprovided only to those clinics which have been services. It is also appropriate as it recognizes thataccredited by RTAC. The availability of counselling is a ultimately it is consumers who must live with therequirement of accreditation, as is provision of detailed, consequences of policy and treatment decisions.written information on treatment, prior to itscommencement.
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Clinics must demonstrate compliance with guidelines laiddown by the National Health and Medical Research Council,the Australian Health Ethics Committee and a code ofpractice, together with relevant statutes in some States.To gain approval to conduct research or under take newtreatment with ethical considerations, individual clinicsmust apply to their local Institutional Ethics Committee.This ensures that the concerns of the community areaddressed and that the interests of consumers are protected.Clinics inspected by RTAC can receive full accreditationfor three years or preliminary accreditation for twelve oreighteen months and there are therefore ministers,physicians periodic mechanisms for reviewing general orspecific concerns. Only those clinics with RTAC accreditationare included on the ACCESS referral list. Benefits of self-regulation include its flexibility as it is more able to respondto emerging scientific advances and allow for a greaterdegree of autonomy for consumers in the decision-makingprocess.
Austria Wuki Kiwu, Norbert Rickmann
An ART law was passed by the Parliament in 1991, In Austria there exists reimbursement for ART costsincluding several restrictive provisions. by the social security system since 1 January 2000,
when a new law came into effect, so called „in vitrofertilization-fund-law‰. For affected couples there isnow a takeover of 70% of the particular costs(treatment as well as medication), which areregulated all over Austria, but the followingconditions must be present: women must be youngerthan 40, men younger than 50, the only medicalindications are male infertility or (female) dysfunctionof the tubes. In our opinion, the law is very restrictiveand does not address the needs of the majority ofthe infertile people. While the law was a significant step,further revisions are needed.
Bangladesh Infertility Awareness Network (IAN), Mizanur Rahman
There is no government law governing ART in Bangladesh. There is no insurance at all to reimburse couples forHowever, religious law prohibits egg and sperm donation. treatment. As the population explosion is a majorNinety-nine per cent of couples are unaware of these problem in Bangladesh, the government would needpossible procedures and ART is a very new idea, in courage to allocate funds for reimbursement of infertilitypractice unknown to patients. treatment.
Infertility is considered a curse and brings bad luck tocouples.
We need A to Z information about infertility and to focusattention on raising awareness in the media.
Country Legislation, regulation, access and social issues Reimbursement
Consumer perspectives 265
Canada Infertility Network, Diane Allen and Infertility AwarenessAssociation Canada, Alison Conley
At present, there is no legislation governing ART; the Most infertility treatment is provided free undergovernment has indicated that it plans to ban: commercial government-paid health insurance; in large cities,surrogacy, the sale, purchase, barter or exchange of eggs, physicians/clinics often charge administrative fees.sperm, embryos, fetuses, genes; reasonable reimbursement Some procedures are usually not covered (e.g.for expenses will be allowed, sex selection for nonmedical sperm wash, the cost of donor sperm). Ontario is thereasons, use of cells from an embryo, fetus, corpse or only province to pay for any IVF: women with bothperson 18 year of age, use of sperm, eggs, embryos, fallopian tubes completely blocked or missing (otherfetuses for assisted reproduction or research without the than from sterilization) are covered for 3 completeconsent of the donor, cloning, maintenance of an embryo treatment cycles. Some people have privateoutside the human body after the 14th day following insurance through their job which covers fertility drugsfertilization, animal/human hybrids, germline alteration. but there is usually a pre-set limit on the number of
cycles, the period of time or the total cost.The government has indicated that legislation will alsoestablish a regulatory body to deal with: licensing of clinicsand staff, information registries for donors and offspring,outcomes and success rates of clinics, surveillancesystems to track the risk–benefit profiles of fertility drugsand monitor the health of patients and their children.
Human rights legislation protects patients in some provincesagainst discrimination on the basis of marital status orsexual orientation. However, access to treatment is limitedby how much money you have, as well as where you live,since clinics are located in only a few large cities; traveladds additional stress and not everyone can afford the costor get the time off work.
In Canada egg donation for postmenopausal women israrely performed in those over 50 years of age. Eggdonation is performed for women with premature ovarianfailure on the condition that the recipient provides her owndonor (friend or relative) and that she can cover the cost ofthe donor who will undergo IVF and share the eggsretrieved. An embryo bank or egg donor bank has not asyet been established in Canada.
Denmark Landsforeningen for Ufrivilligt BarnlŒse (LFUB), Martin Kristensen
Egg donation is so far forbidden in Denmark. LFUB has The legislation allows couples to have treatment freeurged politicians to vote for it, but so far without of charge at hospitals in Denmark. The waitingsuccess. time is up to two years. Private clinics have
been established in recent years and many couplesprefer private treatment to avoid long waiting lists.
Finland Lapsettomien Tuki, Pirre Saario
There is not yet any law concerning infertility treatment Infertile people pay 25%–40% of infertility/IVF treat-in Finland and there is a wide choice of treatment available. ments. The National Pension Institute covers the rest.That is why it has been possible to concentrate on themental welfare of infertile couples. With private health insurance there are no common
standards of covering infertility/IVF treatments.
Country Legislation, regulation, access and social issues Reimbursement
266 SANDRA DILL
France Association Pauline et Adrien, Chantal Ramogida
IVF treatment is reimbursed for women under 43 years of The Government reimburses infertility treatment up toage. The couple must be married or living together for 100% if it is done in a public hospital. In a privatemore than two years. Infertility treatment is not provided clinic the treatment may be more expensive and thefor single or lesbian women. Oocyte and sperm donation couple then need a private insurance to cover themust be anonymous and the donor cannot be paid. extra cost.Postmortem transfer is prohibited (from frozen spermor embryos). Social security reimburses six artificial inseminations
and four IVF treatments (meaning embryo transfer).After the birth of a baby the patient can obtain theseagain for a second child.
Germany Wunschkind, Petra Thorn
In 1990 the Embryo Protection Act (EPA) was introduced. Health insurances in Germany (and there is littleThis Act is a penal law forbidding the following: difference between private and state insurances)• Full and gestational surrogacy reimburse the following:• Oocyte donation • 8 inseminations without hormone treatment• Transfer of more than 3 oocytes • 6 inseminations with hormone treatment• Sex selection unless a severe hereditary disease • 2 cycles of GIFT
can be avoided • 4 cycles of IVF• Use of the sperm of a man known to be dead• Manipulation of human genetic information Until April 1999, health insurances also reimbursed• Cloning, formation of chimera or hybrid 4 cycles of ICSI. As budgets get tighter and as
there are insufficient German data on the risk ofCurrently, a new act on assisted human reproduction malformation of children born after ICSI, currently nosupplementing the EPA is being discussed. In May 2000 health insurances reimburse this treatment. However,the first public hearing took place debating gamete there are several ongoing legal cases which may changedonation, preimplantation genetic diagnosis, the use of this sitaution. To be eligible for reimbursement,human stem cells, quality standards and patient care. couples have to be married or be in a de facto
realtionship and the male partner must not haveFour cycles of ICSI are reimbursed by the health undergone sterilization. In addition, only the costs ofinsurances. treatment using the gametes of the couple are
rembursed. DI is therefore not reimbursed.
Ireland National Infertility Support and Information Group (NISIG),Helen Browne
Presently, there is no legislation on assisted reproduction Infertility treatment in Ireland is almost exclusivelybut the Irish Government has convened a Commission to privately funded. Many couples borrow the moneylook into all aspects of ART, except funding, with a view for IVF treatment but they can apply for taxto seeing whether legislation should be brought in or not. refund at the end of the tax year. Under the Drug
Payment Scheme, the costs are covered by thegovernment, except for £ 42.00 per calendar month.
The two private health companies in Ireland do notcover infertility treatment but do cover investigationssuch as testicular biopsy, laparoscopy andhysterosalpingogram.
The cost of IVF treatment in Ireland is approximately£ 2000 per cycle but this does not include the fee for
Country Legislation, regulation, access and social issues Reimbursement
Consumer perspectives 267
first consultation, hormone analysis or semen analysis.Costs vary from clinic to clinic.
Israel CHEN, Ofra Balaban-Kasztelanski
We are working to submit new laws and regulations We are campaigning so that the government willregarding infertility. On our agenda is to change the update the National Health Bill so it will includeregulations regarding egg donation. In Israel only a woman new medications and treatments.who is undergoing the IVF process can donate an egg.Because of this, there are 2000 women today waiting for The state insurance pays IVF costs until twoan egg donation and the waiting time is between 6 and 12 children have been born. However, some new malemonths. The law we are submitting will allow every woman infertility treatments are not reimbursed.who wants to donate eggs to do so. To achieve thispurpose we are lobbying the Israeli Parliament members Current public debate is ongoing to decide at whatfor their support and we are doing a lot of PR work in age the state will pay for treatment. It has beenthe media. suggested that the ages should be 45 years for IVF
and 52 years for donor oocyte treatment.
Italy Associazione Madre Provetta, Monica Soldano
A very restrictive law was passed mid-2002 in one House In Italy it is possible to have reimbursement forof the Parliament in Italy and will be debated in the Senate infertility treatment.in order to become law.
Japan Kidsless Party, Jahana Mari and Friends of FINNRAGE,Yukar i Semba
• There is no legislation governing ART treatment in Japan. There is no reimbursement for ART in Japan.• Professional guidelines limit IVF to only legally married
couples therefore they indirectly prohibit donor gametesand surrogacy. Donor gamete procedures will bereconsidered within two years but surrogacy will not beconsidered in the near future.
Republic of Agimo, Eunhee Pack and Dr Kichul KimKorea
• Surrogacy, egg and sperm donation are allowed but There is no reimbursement for ART in the Republiccommercial trade is forbidden. of Korea
• Nuclear transfer and cytoplasmic transfer are viewednegatively.
• IVF, GIFT, blastocyst transfer, co-culture, ICSI,assisted hatching, PGD and IVM are available.
Latvia No patient g roup, Gints Treijs, MD
There is no reimbursement for infertility treatment in Unfortunately most of the couples cannot affordLatvia. IVF treatment. Therefore all three IVF centres
together perform no more than 170 cycles per year,on about 1/4 or 1/5 of all couples needing thiskind of treatment.
Country Legislation, regulation, access and social issues Reimbursement
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Mexico Asesores en Infertilidad, Yolanda Secades
• A special multi-institutional committee, headed by • ART procedures are performed at two or threerepresentatives of the Mexican Ministry of Health, has public health insitutions, all of them in Mexico City.been formed to address issues related to ART and create However, they do not recieve enough economica regulation. So far, they have not published any official support and do not operate on a constant basis.policies or guidelines. ART clinics have a lot of latitudein their work, they just have to comply with the General • Reducing population growth is a priority in Mexico,Regulation for Medical Services Providers. so the government has no interest in supporting ART.
• Surrogacy is not encouraged but some clinics allow it. • There is no reimbursement or private aid for ARTTo avoid possible complications of a legal nature or bad treatment in Mexico.publicity the infertile couple has to contact and make thenecessary arrangements with the surrogate mother on theirown, relieving the clinic of any responsibility for sucharrangements.
• According to the last population census (INEGI. XIICenso General de Población y Vivienda, 2000) Mexico´spopulation is 97.5 million. There are around 16 millionwomen between 20 and 39 years old and 14 million men inthe same age group. If the incidence of infertility isestimated at 8%–10%, then approximately 2.4 to 4.6millions of persons are in need of some kind of infertilitytreatment. It is important to note that 57% of the Mexicanpopulation do not have access to public health services.
The Netherlands Freya, Truuske Dijkstra-Hazelhorst
Almost all infertility treatments are legal.IVF laboratories in the Netherlands have to obtain a The public health service pays for three IVFspecial dispensation. There are 13 clinics permitted to treatments; most other treatments are paid for asexecute the laboratory procedure of IVF/ICSI. well. In the Netherlands, there are many differentApproximately 25 other clinics cooperate with these 13 private insurance companies, each with their ownclinics. For MESA/TESE a moratorium has been declared, range of policies. Most private insurance companiesso it is not possible to get this treatment. Surrogacy on a also pay for 3 IVF treatments, but charge thecommercial basis is prohibited by law, as well as any patient a contribution of Nlg 800 (+US$ 400).assistance for making contact between surrogate mothers Private insurance is needed when one earns moreand would-be parents. than approximately Nlg 60 000 per year. Nearly
all medication for infertility treatments is paid for bypublic health service as well as private insurance,except for some new preparations which have to proveto be useful first.
New Zealand New Zealand Infertility Society, Robyn Scott
There are two Bills currently before the Parliamentary Law Access to publicly funded infertility treatment in NZSelect Committee with the aim of regulating assisted varies, depending on where you live. Criteria forreproductive technology. There is no legislation specifically acceptance for treatment varies widely, although eachcovering ART, though aspects of other legislation (e.g. the area does provide consultations and some tertiaryHuman Tissues Act) covers aspects of ART. The two treatment. Criteria are fixed in some areas, i.e. youBills are very different·one, a Private MemberÊs Bill seeks must meet all criteria to access treatment, while into regulate ART through the intoduction of a Licensing other areas points are awarded within both subjective
Country Legislation, regulation, access and social issues Reimbursement
Consumer perspectives 269
Board and has a number of regulatory features that the and objective criteria·this is less absolute. FundingNZIS does not support. The second Bill, introduced by the commitment to infertility treatment varies betweenformer Minister of Justice is more flexible and contains 3 0.78 cents per capita in the Northern region to 0.37main parts·it seeks to place the National Ethics cents in the Central region. In some areas drugs areCommittee within a proper legal framework, it sets up a funded as part of the treatment, while in othernumber of provisions to allow for storage and access to areas co-payment for drugs is required. In someinformation about donors and their offspring, and outlaws areas there is a 3-year wait for two cycles of IVFcertain procedures. We are presently waiting for the while in other areas you may have a shorter wait,opportunity to present an oral submission on the Bills, but receive one cycle of treatment. The healthfollowing our submissions in 1998/99. system is undergoing its fifth restructuring in nine
years and the Health Funding Authority is soon to bereplaced by 26 District Health Boards. Provision ofinfertility services in NZ has been reviewedcomprehensively on several occasions, but thereview recommendations have yet to be acted upon.Little reimbursement by private medical insurance ispossible, although the Police Health Fund providesa one-off life-time payment of $ 5000 for infertilitytreatment. Some health care funds will cover thecost of investigations such as a laparoscopy.
Norway Foreningen for ufrivillig barnlŒse (FUB), Kaja Graff Huster
Norway was one of the first countries to have legislation In Norway medical treatment in general is free, butto control and regulate infertility treatment. The main this is only true for treatment which is offered byoutlines of the legislation are as follows: and within the public health system. Although IVFi. Infertility treatment is only given to heterosexual couples, treatment is free in public hospitals, people often
either married or living together in a stable relationship. have to pay for medication.ii. IVF and ICSI are allowed treatments. But treatments
which involve operational collection of sperm are not Large costs for medical treatment can be deducted allowed. from an individualÊs income tax but the following
iii. Fertilized eggs can be stored for up to three years. three conditions must be satisfied:iv. Sperm donation is anonymous. The couple must be 1. The medical condition, which is treated, must be
married. a disease.v. Egg donation is not allowed. 2. The treatment must be legal in Norway.vi. Surrogate motherhood is not allowed 3. The treatment is not available in the public healthvii. No research on fertilized eggs is allowed. system.
• Many couples are going abroad for treatment becauseof long waiting times.
• Many couples are going abroad because sometreatments are not allowed and not available inNorway (PESA, TESA, MESA, egg donation).
• Several couples are using alternative treatment fortheir infertility, spending a lot of money withoutgetting any tax reduction or other refundsbecause infertility is not regarded/accepted asa disease.
Sweden IRIS, Lena Gimbergsson
In Sweden, couples can get all kinds of treatment·IVF It was a great victory for us when on 16 April 1997and ICSI, and insemination with donor sperm. Egg the government decided that the treatment of
Country Legislation, regulation, access and social issues Reimbursement
270 SANDRA DILL
donation and sperm donation with IVF is illegal. All infertility should be placed in group 3 within thethe questions and answers have been ready since 5 years National Health Maintenance Organization. Thisto take a new decision about this illegal treatment. IRIS is category refers to „Treatment of chronic diseases andnow fighting with the government and the Social ministry diseases of a non-acute nature‰. At last, infertilityto make them change this law at the earliest. In the Nordic was accepted as an illness! However, in real life, acountries, legislation on human reproduction and embryology beautiful legislative text does not always help. In ourvaries from one country to another. But the case of country the Swedish Health Maintenance Law alsoSweden is still unique, since we are the only country in the states that „Everybody in Sweden shall have the rightworld to have a special law on donor insemination. Donor to treatment under the same conditions wherever theyinsemination is not allowed for single women or lesbians live‰. But in fact, every day district and countryand can only be performed in general hospitals. Children councils break this law, as reimbursement is stillborn following donor insemination can have access to the uneven between different countries. Reimbursementidentity of their genetic father once they reach majority. of IVF treatment cycles can vary from 1 to 3,
depending where people live. Within the public system,couples very often have to wait 2–3 years to getaccess to treatment. In one of our districts couples haveto wait 6–8 years for treatment and then they are tooold to get treatment. In the case of infertility, manypeople still make huge financial sacrifices to be ableto pay for treatment in private clinics. The cost forone treatment in private clinics is between 15 000 to30 000 Skr.
Switzerland Azote Liquide, Ghila Zoutter
Assisted reproductive technology methods·notably The present situation: the Federal Insurance Tribunalhomologous and heterologous artificial insemination and in was confirmed that health insurance companiesvitro fertilization (IVF) with embryo transfer—are at have no legal obligation to reimburse the cost ofpresent authorized in Switzerland. ART treatments, arguing that these are not
„scientifically recognized‰ diagnostic or therapeuticThe donation of embryos and all other forms of substitute measures as defined by law and Swissmaternity, such as surrogate motherhood, are illegal. jurisprudence.
Transparent use and practice of assisted reproductivetechnology is desired.
United Kingdom ISSUE, Lydia Pollard and CHILD, Clare Brown
Clinics offering treatment involving the handling or storage The situation with reimbursement in the UK hasof gametes require a licence from the HFEA which is a always been complicated. However, devolution in thestatutory organization. They do not decide who should UK resulted in Scotland becoming self-governingaccess reimbursed infertility treatment/assisted conception which has made the situation even more complicated.services. The HFEA produces a Code of Practice to which Before that time the UK was divided into more thanclinics must adhere. They also publish an Annual Report. 100 HAs who are each given a budget by theThere are no laws on who should have access to infertility Department of Health (DoH), from which theytreatment. The Health Authorities (HAs) decide what purchase the health care needed by peoplefunding they will provide as described above and set the residing in their area. There was no centraleligibility criteria such as upper age limit and previous guidance from the DoH on what infertility treatmentchildren, which also vary enormously around the UK. they should provide. On 10 February 2000, theThey therefore ultimately decide who should access Department of Health in Scotland published aNHS-funded treatment. Clinics also set their own guidelines Framework for the provision of infertility servicesas to whom they will treat and these do vary a little from setting out criteria to which every Health Board inclinic to clinic. Scotland is expected to work towards implementing.
Country Legislation, regulation, access and social issues Reimbursement
Consumer perspectives 271
Subject to eligibility criteria, each couple is entitled toa maximum of 3 National Health Service (NHS)-funded assisted conception cycles. However, thesituation in the rest of the UK remains the samewith no central guidance and each HA makingdiffering decisions as to the funding they provide,resulting in huge variations around the country. NoHA provides sufficient levels of funding to meetdemand. Therefore, patients living in an HA whichdoes not fund infertility have to pay the total coststhemselves. Private health insurance does notcover infertility treatment.
United States American Infertility Association (AIA), Pamela Madsenof America
There is no federal legislation ensuring treatment of In the United States of America, insurance coverageinfertility. for infertility varies greatly. There is no federal legislation
ensuring treatment of infertility. Thirteen states havesome kind of mandate that allows for limited toliberal coverage of infertility. Presently, coverage ofinfertility is patchy at best, and is often left in the handsof the individual employer and private insurancecompanies. The end result is that most couples areleft paying on their own for treatment.
Country Legislation, regulation, access and social issues Reimbursement
272 ELLEN HARDY, MARIA YOLANDA MAKUCH
Gender, infertility and ART
ELLEN HARDY, MARIA YOLANDA MAKUCH
Introduction
Human sexual life had a simple and predictableoutcome: a man and a woman lived together and hadsexual intercourse, frequently followed by pregnancyand the birth of a healthy baby. Having children is afundamental part of the life project of men and womenand is seen as a necessary step to reach maturity andpersonal development, and to respond to what is theirsocially expected role, leading to the preservation ofthe human species (1,2).
The outcome referred to above is not alwayssimple and predictable; in some countries, there mightbe an increasing number of couples facing difficultyin reproducing. Estimated percentages of infertilewomen in the USA show an increase between 2000and 2025 (3). Part of the apparent increase in thenumber of infertile couples may be the result of betterdiagnosis of this condition, as until a few decades agothere were no diagnostic procedures or treatmentsavailable. On the other hand, during the past 30 to 40years, women have had access to modern and highlyeffective contraceptive methods, which allow them tocontrol their fertility, postponing their first pregnancyuntil an older age, when they are less fertile.
The couple’s inability to produce an offspring hasbeen described in a variety of clinical, epidemiologicaland demographic definitions of infertility. Infertility,when considered in the context of women and men’s
lives, has also been defined as an experience of“biographic disruption”. This definition emphasizesthe suffering and emotional conflicts of those whohave this condition (4). The impossibility of having adesired child becomes a loss in couples’ lives: a lossthat has been compared to the loss of a very dearperson (5). Lauritzen (6), in the description of hisexperience as an infertile male states: “The emotionwe felt most acutely was that of loss over a child webelieved we would have together.”
While in the past, couples who could not have achild tried to adopt one or remained childless,currently more and more sophisticated procedures areavailable to help them have a baby that is biologicallyrelated to both, or at least one, of the parents. Suchpossibilities have become available over the past fewdecades, when knowledge and understanding ofreproductive physiology experienced a great expan-sion, following research in reproductive technologythat resulted in new therapeutic alternatives.
The impact of infertility and assisted reproductivetechnology (ART) on the persons affected has to beconsidered within the broader context that includessocial, historical, economical, political and culturalaspects. At the same time, so as to understand theactual meaning that infertility has on the life of anindividual woman or man, it has to be consideredwithin the context of gender roles.
Gender, infer tility and ART 273
Gender and parenthood
The term “gender” is derived from the Latin “genus”.Initially it was used to distinguish sex (in theanatomical sense) from identity (in the social orpsychological sense). Sex defines the anatomicalorganization of the difference between male and femalewhile gender designates the feeling (social orpsychological) of sexual identity (7).
In a broader sense, gender is socially constructedand the term refers to the social relationships and rolesthat men and women have in society (9). Accordingto Matamala and Maynou (8), the four principalconcepts that integrate this definition, and throughwhich the social relationships and the symbolicmeaning of being a woman or a man are defined, aresexuality, reproduction, sexual division of labour andcitizenship. Gender basically refers to the sociallyconstructed difference of power between men andwomen.
In the early 1970s, during the period when thequestion of gender roles and women’s rights becamea more prominent issue, the new modern, effectivecontraceptives became widely available. The accessto efficient means to control fertility gave women thepower over procreation that they were demanding. Thecapacity to decide when to conceive affected the mostfundamental role attributed to the female gender: tobe a mother and to take care of the children. Accordingto Rich (10), a major fact in women’s lives is theirstatus as childbearers. Any further identity has beennegated by terms such as “barren” and “childless”while the term “nonfather” does not exists as a socialcategory.
Traditionally, motherhood has been definedbiologically and the mother is the woman who deliversthe child while the definition of fatherhood is socialand elusive: the father is “normally” the husband ofthe mother (10,11). However, women are more likelyto define the term “mother” according to the inter-action established between a woman and a child andnot only in terms of biology (11). Motherhood isearned first through pregnancy and childbirth andlater through nurturing (10).
Men, on the contrary, seem to define their relation-ship to a child according to their participation inconception (10,11,12). The concept of fatherhood isprimarily related to the ownership of children, as menare given father’s rights over offspring who come fromtheir sperm (13). However, the roles of mothers andfathers are changing at the same time as categories of
feminine and masculine are being revised. Modernfathers, in many societies, are increasingly involvedin the upbringing of their children, a responsibilitywhich traditionally was exclusively maternal (14).
Assisted reproduction and gender
Until the 1950s, many cases of infertility wereexplained through an emotional rather than a biologicalcause. During the following 20 years the developmentof diagnostic techniques and laparoscopy created newpossibilities of exploring women’s internal anatomyand physiology. With these new resources it becamepossible to identify biological causes of infertility thatin the past would have been considered to be of anemotional nature. In addition, better understanding ofreproductive endocrinology allowed interventions inwomen and men’s bodies to “correct” alterations ofthe physiological process. Thus, many of the un-explained causes that were considered emotionalbecame treatable.
Although this scientific progress has the potentialto disrupt conventional gender roles and familystructure, it has not yet changed social norms relatedto gender roles (15). Thus, women and men who areinfertile feel socially inadequate in a predominantlyfertile society. Society continues to require women tobe mothers and to “give” children to their husbands,grandchildren to the couples’ parents and continuityto a family (16,17) . Thus, the desire of the couple tohave a child is a complex one, determined by manyfamily expectations. In this context, the emotionalconsequences of infertility, which affect women andmen differently, began to be understood and tobecome a subject of research.
Having children, becoming parents and establish-ing a family when a couple decides to do so isconsidered part of adulthood for women and men(1,2) . When the expected family model is not achieved,each partner and both as a couple must go through aprocess of psychological re-organization to cope withthis new unexpected reality
When a couple is infertile, some societies still tendto blame the woman and even accuse her of havingbeen promiscuous, having had too many abortionsor of having a sexually transmitted disease (13). Thewoman is the first to consult a doctor for a solution tothe problem. Until not so long ago, women had to gothrough a long and painful diagnostic procedurebefore men were submitted to the simple procedure
274 ELLEN HARDY, MARIA YOLANDA MAKUCH
of obtaining a spermiogram. In some societies,irrespective of the cause of infertility, childless womencan be easily divorced or abandoned.
ART has greatly improved the chances of infertilecouples having children, but they have increased theimbalance in the share of the burden of treatment,relying more heavily on women. At the same time thesetechnologies may have even greater emotional conse-quences than infertility for the couple.
As reproduction technologies are based oninterventions into women’s bodies, they reinforcemotherhood as a biological rather than a socialrelationship. According to Lorber (18), as referred byLasker and Borg (19), infertility treatment relies on theimperative that women must be mothers and on a socialstructure in which “motherhood” only applies towomen who have a biological relationship with a child.However, in her study of women participating in an invitro fertilization (IVF) programme, Crowe (11) foundthat all the women considered social motherhood moreimportant than the transference of genetic traitsinvolved in biological motherhood. Simultaneously,they perceived motherhood as well as marriage asnecessary social relations.
When childlessness is the result of a woman’sinfertility, she will need to persuade her husband tocollaborate with the treatment. According to Laskerand Borg (19), Lorber (18) considered that, a fertilewoman who undergoes assisted reproduction to tryand have a child with an infertile man, may be express-ing love but is more likely to be making a patriarchalbargain. Consequently she feels obliged to have ababy within the constraints of monogamy, thestructure of the nuclear family and the value ofbiological parenthood.
The social and psychological consequences ofinfertility for the couple have increased with theadvancement of ART. While the media haveoccasionally been critical of some of these newtechnologies, it mostly tends to present them as a kindof magic bullet that will solve the infertility problemof almost everyone (20) . Given the increasedexpectations (21), the higher economic and emotionalcost for the couple and greater physical demand onwomen, the failure of ART leads to greater psychol-ogical and social consequences for the couple thanthe unavailability of these technologies.
The high cost of establishing an ART clinic andthe known association of greater success rate withlarger number of cases treated per month or per year,stimulate the expansion of the indications for the use
of these technologies. While in the early days of ART,the treatment was confined to women withoutfallopian tubes or with tubal obstruction not eligiblefor surgical treatment, today ART is used for a numberof conditions, including male infertility. Furthermore,it has been argued that ART could be an acceptablesolution for couples with no infertility problem, butwho wish to improve their chances of having a babyof a specific sex (22).
In contrast with the advances in ART, theirpsychosocial implications have attracted littleattention. There is an imbalance between the level ofsophistication and the care given to every small detailof the technologies used for assisted reproduction andthe attention given to the feelings, fears and anxietiesof the infertile couple, the psychosocial consequencesof infertility and of treatment failure, as well as to thegender difference between the effects that thesetechnologies have.
Survey of methodological approaches usedto address the issues: interdisciplinaryperspectives
A survey was done of published studies carried outover the past 20 years on the psychosocial aspectsof assisted reproduction and which evaluated bothwomen and men. The methodological approachesfollowed by these studies were diverse.
Sample and selection of subjects
The sample size of these studies varied from 40 to 1149couples, though sometimes not all the male membersof the couples participated. Subjects were recruitedin hospitals and private infertility clinics, usuallyconsecutively. Criteria for inclusion as well as the timewhen subjects were invited to participate varied. Forexample: couples whose treatment had been success-ful; those who were initiating their first IVF cycle; threeweeks after the IVF procedure; after the first cycle ofIVF; and having completed all its phases throughembryo transfer; all patients entering IVF treatmentover an eight-month period; and couples who hadbeen through at least one IVF attempt. In one study,couples were located using a modified snowballtechnique (23).
Gender, infer tility and ART 275
Instruments
Data, in general, were collected through standardizedinterview schedules, questionnaires, scales, inven-tories, checklists, guides or a combination of theseinstruments. For only a few studies had the servicestaff developed the questionnaire. Many of thesequestionnaires were self-reporting and scales wereself-rating. For one of the studies reviewed, a male andfemale version of a questionnaire had been developed.
Time of response
Mostly couples responded or received a package ofinstruments during the assessment visit to theinfertility clinic. Others were provided with instru-ments during their final hospital visit or three weeksor more after embryo transfer. For some studies,participants were given instruction sheets, question-naires and stamped envelopes and were asked toreturn them to the programme after completion or toreturn them by mail at the end of the current treatmentcycle or when the pregnancy status was known. Otheralternatives of response were to complete part of theinstruments at the clinic and the rest at home. Inanother case, couples completed three assessmentsat six-month intervals. Information was also obtainedthrough telephone interviews.
Data were elicited from subjects at differentmoments during the infertility diagnosis and treatmentprocess, sometimes even within the same study. Forexample, in one case, women undergoing IVF wereevaluated on the second day of a cycle, those whowere to receive donor insemination were evaluatedjust before the procedure and their partners respondedat home. In other studies, subjects were evaluatedduring their initial attendance at the clinic, before anymedical investigations were begun, and seven to ninemonths later when in most of the cases the diagnostictests were completed.
Data collection
A joint, hence potentially affected, interview wascarried out with both partners, when the answers ofone could have influenced the other. Sometimes,separate interviews followed the joint one. In only onestudy of 40 couples about to begin treatment, subjectswere requested to keep daily records that allowedprospective data to be collected. For another study,interviews were taped and transcribed verbatim.
Answers to proposed questions throughcritical review of data; identification ofgaps; identification of limitations
The results of the studies reviewed were organizedaccording to the association of gender issues todifferent assisted reproduction variables.
Reactions to infertility
Practically every author found that both men andwomen who experienced infertility were more distress-ed than the general population. However, with almostno exception, the studies found that women reactedmore strongly to infertility than men. Depression,anxiety, cognitive disturbance, lower self-esteem,greater guilt, blame, hopelessness and hostility weresome of the emotional reactions described by variousauthors (24–27) but were no more common in thosewith unexplained infertility than in others with aspecific diagnosis (21,28–-32). Psychiatric morbiditywas also significantly more common among femalesthan males in one study (33).
In addition, women rated themselves as experien-cing greater social effects of infertility than men (21) .Men referred to feelings of losing the power of beingable to reproduce as well as worry about their partner’sreaction (32). One study found that men experiencedextreme worry significantly more often than womendid—19% of men versus 3% of women (5). Both sexes’most common coping strategy was the active pursuitof treatment (29).
Reactions to treatment of infertility
A comparison of couples who were initiating treat-ment and others who were in a repeat cycle found thatabout a third of husbands and wives experiencedclinically elevated anxiety, regardless of stage oftreatment (30). While there was remarkable similarityin the type and pattern of the couple’s reactions tothe different stages of treatment, women were moredistressed than their partners during IVF (25,30,31).Many husbands expressed fears for their wives’safety during the laparoscopy, guilt that their wiveswere the ones who bore all the pain and discomfort,and helplessness in the face of their wives’ grief whentreatment was unsuccessful (34). In general, thescores of the General Health Questionnaire indicatedmore emotional distress for women than for men in
276 ELLEN HARDY, MARIA YOLANDA MAKUCH
relation to the diagnosis and treatment of infertility(28) .
Long-time effects of infertility
In this review, only one study evaluated distress overa period of three years of infertility treatment. Duringthe first year, emotional strain was moderatelyelevated, returning to normal levels during the secondyear and increasing during the third (35). No studywas identified referring to the long-time effect of failureor success of treatment.
Response to male and female infertility
No differences were found among women in theiremotional response to infertility, regardless ofwhether a female or a male infertility factor waspresent. Men with a male factor experienced morenegative emotional response and a higher state ofanxiety over time than those without a male factor(36,27). Among women, when the cause of thereproductive difficulty was female or unexplained,depression scores decreased significantly at thefollow-up assessment (27).
Effect on marital relationship and sexualfunctioning
Stress related to fertility problems appeared toincrease marital conflict (37). The satisfaction inmarital relationship was determined in part by thedegree of stress that men and women experiencedduring treatment. Men’s marital satisfaction was notdetermined by their wives becoming pregnant or bytheir own sexual satisfaction, but in part by the degreeof stress that they experienced. Women’s maritalsatisfaction was partly determined by their degree ofsexual satisfaction regardless of the stress theyexperienced (38). Both these studies looked at maritalfunctioning during treatment. Other authors did notfind any significant increase in psychologicalabnormalities or family dysfunction. Both men andwomen were in general well adjusted and enjoyedgood stable relationships with their partners (39,27).Some studies described improvement rather thandeterioration of the marital relationship with infertility;subjects reported that problems related to infertilityhad resulted in a closer relationship with greateremotional intimacy (40,32). Women described maritalrelationships more positively than men and men
scored higher on achievement orientation (41).Results with reference to the effect of infertility
over sexual function were also contradictory. Someauthors found that, as a group, these infertile coupleswere within the normal range of sexual functioning(37). Others found that infertility treatment hadchanged the sexual relationship of 46% of the womenand 32% of the men. Two-thirds of those who reportedchange stated that sex had become less pleasurable(24). Another study that reported changes found thatmen felt that infertility had a greater negative impacton their sexual relations than that observed by theirwives (30).
Perception and desire for social support bygender
Women sought more social support than did men(21,32) and there was a tendency for them to expressthe desire for counselling and support (42). Both menand women perceived their partners as providing themost support, followed by doctors, nurses and friends(42,32). Related to support within the couple, womenreported receiving greater emotional and physical carefrom their husbands in their relationship than theirhusbands did from their wives (30). Significantly moremen than women had not confided in anyone abouttheir infertility problems (32). Information routinelyprovided about the practical aspects of IVF couldimprove knowledge and passage through a treatmentcycle (42).
Effect of treatment failure
The results indicate that IVF offers hope for infertilecouples and that, when unsuccessful, it can beemotionally traumatic (34). Both males and femalesagreed that negative outcome and waiting for resultsduring the period of time between embryo transfer andthe outcome of the procedure were the most stressfulaspects of IVF. Immediately after failure, both men andwomen presented increased levels of anxiety anddepression, and appraised their life situation morenegatively (41,28) . However, women reported morestress at different stages of the IVF procedures (28)and showed increased depression after failure (41).Women with children had less anxiety than thosewithout, while all men had increased anxiety,irrespective of their reproductive history (41).
One study, which followed couples for two to fourweeks after a positive or negative outcome of the
Gender, infer tility and ART 277
procedure, found that more than half of the womenwho failed to become pregnant reported initialdisappointment and sadness. These subjects also saidthat they were recovering and adjusting to this fact.However, one-fourth reported feeling very distressed(43). Although the study collected information fromcouples, only results related to the women werereported.
No studies were found evaluating the long-termconsequences of treatment failure or success on thepsychological and social life of the couples.
Sex selection
The desire to control the sex of children, with preferencefor males, has been observed throughout history, withpreference for male offspring among monarchs andinfanticide of newborn girls being described in variouscultures (44–46,63). However, until recently, most ofthe literature referred to selective abortion of femalefetuses and not to selection of sex through ART (47).Ultrasonic diagnosis of the sex of fetuses has allowedthe practice of selective abortion of females, allegedlybeing carried out in Northern India (48). In summary,the capacity to select the sex of children has evolvedfrom infanticide to selected abortion of female fetuses(48,49) to preimplantation selection of embryos (50).
Preconceptional sex selection has been tried fordecades and recent progress in sex identification ofpre-embryos before implantation and separation of X-bearing and Y-bearing spermatozoa by flow cyto-metry, combined with ART, appears to offer realpossibilities for pre-conception determination of thesex of the fetus (51–53). This has meant shifting thepossibility of determining the offspring’s sex awayfrom selective abortion and infanticide. At the sametime, it has raised new ethical issues resulting fromthe potential for social problems caused by the sexualimbalance, as has already been observed in somecountries in Asia (49).
The Committee for the Ethical Aspects of HumanReproduction and Women’s Health of the Interna-tional Federation of Gynecology and Obstetrics(FIGO), the American College of Obstetricians andGynecologists (ACOG), and the American Society ofReproductive Medicine (ASRM) have maderecommendations on how their associates should actwith reference to sex selection, which refers mostlyto preimplantation diagnosis and selected transfer.Such recommendations vary from complete banningof sex selection for nonmedical reasons (50,54) , to
discouragement of its practice while not favouring itslegal prohibition (55,56).
These recommendations have caused debateamong physicians (22). Those who have a moreglobal view of the social and cultural implications ofsex selection appear to be more strongly against itspractice, based on the situations in China and partsof India, which has led to a distortion of the sex ratioin those countries (49). Globally, it has been estimatedthat 100 million women have died prematurely due toa variety of discriminations (57,58). Others, with greatclinical practice experience, but a more restrictedwestern perspective, do not see a major risk in allowingcouples to choose the sex of their offspring for socialor personal reasons (59,22). Wertz and Fletcher (60)already found a trend to increasing acceptance of thecouples’ rights to choose the sex of their children,among geneticists from all around the world. Theauthors conclude that the geneticists believe they areserving their clients’ needs.
The rights of the parents to wish for a baby of agiven sex have been defended with several arguments.Warren (61) presented some of the most articulateclaims for sex choice. She gave three reasons to justifythe parent’s desire for sex selection. First, it wouldenhance the quality of life of the child that wouldsupposedly be better if it is of the wanted sex than ifit were of the sex unwanted by the parents. Second, itwould improve the family’s quality of life if it is formedwith the desired balance of sex among the children.Third, it would also enhance the quality of life of themother, as she would need to give birth to fewerchildren to have those of the desired sex.
Although these arguments appear rather convin-cing and come from a feminist writer, the three claimsinvolve the concept that there is one sex that is moredesirable than the other. Sex selection tends toperpetuate a sexist society because it implies that onesex is better than the other and would contribute togender discrimination.
Those who defend the couples’ right to choosetheir children’s sex do not see a risk of changes in thesex ratio. They claim that couples attending infertilityclinics already have two or three children of one sexand want to have at least one of the opposite sex, withno particular preference for boys or girls (53,62) . Theyargue that this is part of reproductive freedom whileothers claim that there is evidence for a heavypreference for males (46,63).
The most striking evidence comes from theobserved changes in the sex ratio at birth indicating a
278 ELLEN HARDY, MARIA YOLANDA MAKUCH
reduction in the number of female births in India andChina, which have been attributed to selective abortionof female fetuses diagnosed through ultrasound(48,49). The differences between the various authorsreflect the different cultures they refer to. For example,in Asia there is strong evidence for the preference ofmale offspring, while this is not necessarily the casein western countries.
Limitations of studies reviewed
Several limitations affected most of the studiesreviewed. Almost every study was descriptive,convenience samples were used, and the resultscannot be generalized but are valid only for thespecific sample. In some studies the only selectioncriterion for the couples was the time availability ofthe nurse who carried out the interviews. Sometimescouples at their first visit were pooled together withthose who had already had one or more cycles ofassisted reproduction, generally IVF, in the same orin an institution different from that where the studywas carried out. In most cases the couples wereinterviewed during the first visit or later during thetreatment period. Information is lacking about thereactions of couples after the treatment had ended andwhen they were confronted either with failure or witha pregnancy and a child.
There seems to be a total lack of information aboutthe possible consequences of the economic stress onthe family caused by the high cost of the new ART.Sometimes the wife has had to stop working to be ableto follow the requirements of several cycles ofassisted reproduction.
The question of sex preference in sex selection indifferent cultures, factors associated with sexpreference and consequences of sex selection, havebeen subjects mostly neglected by research.
In spite of all these limitations, there are someissues where the consistency of the results of practi-cally every study, carried out in a variety of settings,with different methods, allows valid conclusions tobe drawn. This is so for the greater emotional impactof being infertile, as well as the greater psychologicalconsequences of the treatment, for women than men.
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Family networks and support to infertile people
PIMPAWUN BOONMONGKON
Introduction
Millions of women and men worldwide are confrontedwith infertility. It is estimated that between 8% and12% of couples around the world have difficultyconceiving a child at some point in their lives (1). How-ever, the incidence of primary and secondary infertilityvaries enormously in each region (2,3). Globally, theWorld Health Organization (WHO) estimates that sixtyto eighty million couples experience unwantedinfertility (4).
Although data on the etiology of infertility varyin their accuracy from region to region, it is estimatedthat worldwide about 5% of infertile couples areinfertile due to anatomical, genetic, endocrinologicalor immunological factors (1). The remainder sufferfrom involuntary infertility related to preventableconditions including: sexually transmitted, infectiousand parasitic diseases; iatrogenic health carepractices; exposure to potentially toxic substances inthe diet or environment; and medical neglect ofprecursor conditions (5,6).
Recent studies show that in resource-poorcountries, where children are highly valued forcultural and economic reasons, childlessness oftencreates enormous problems for couples; especiallywomen who are generally blamed for the infertility.Motherhood is often the only way for women toenhance their status within their family and commu-
nity. In some places, the stigma of childlessness is sogreat that infertile women are socially isolated andneglected. Studies from communities in Egypt (7),Nigeria (8), Mozambique (9), the Gambia (10) andIndia (11) showed that infertile women are oftenexcluded from societal events and ceremonies or mayeven be despised and perceived as inauspicious (12).In some cases, they are feared as casting the “evil eye”on pregnant women. The psychological conse-quences of infertility have been well described in theliterature. Infertile women often feel guilt andworthlessness leading to low self-esteem, depressionand anxiety. In terms of the economic impact ofchildlessness, childless women and their families mayfeel that they have a lack of social security andsupport in their old age.
Conjugal relations often become stressful due toinfertility. Infertile women often receive disrespectfultreatment by husbands, and the husbands’ familiesmay encourage them to divorce or take a second wife.At the family and lineage level, childless womenreceive disrespectful treatment and maltreatment byin-laws due to the concern for their family lineagedying out. In more extreme cases, acts of violence arecommitted against them.
Women develop various mechanisms to cope withinfertility. A significant role in such mechanisms isplayed by the family and other social networks,although such a role could be positive, constructive
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or negative. There is limited information regardinghow family and social networks support women andmen to cope with the problem of infertility. Suchknowledge could be useful in developing culturallysensitive programmes to help infertile women copewith their problems and improve their lives.
This paper summarizes findings from studies onthe role of supporting networks in coping withinfertility. The studies vary considerably in terms ofdesign, scope, site, study population and othermethodological issues. Both quantitative and qualita-tive research methodologies were used. In somestudies, such as in Bangladesh, Mozambique andThailand, data originate from the exploratory phaseof more extended research projects, while data drawnfrom other research studies including those in Mexico,Nigeria and Zimbabwe were collected as part of larger,long-term (two- or three-year) studies on variousreproductive health concerns. However, what thesestudies have in common is that they allow peopleconfronted with infertility to speak out about theirpersonal experiences and views regarding their infertilityas well as suggest strategies to cope with the problem.
Sources of support and their impact
Family support
Most studies showed that childless couples find intheir spouse, family and relatives sources of supportfor solutions and stress. In the Mexican society,among the Tjolabal women, if no pregnancy occursafter several months of living together as a couple,the mother, mother-in-law or another older women inthe family will recommend a series of home remediesto warm the woman’s body. In Pakistan, coercion byin-laws had a strong effect on women who experienceinfertility and was an important motive for seekingtreatment (13). In the family context of infertile womenin the Thai society, family support for the infertilewoman has both positive and negative aspects.Family members including the mother, mother-in-law,sisters and sisters-in-law may speak negatively towomen about the potential of a broken marriage. Thefollowing narrative from the Thai study demonstratesthis point (14):
Chem: “My relatives teased me that my husband willhave a new wife, for I have no baby for him, Iget very hurt.”
Mala: “Because I do not have a child for myhusband’s family, I get insulted from my mother-in-law. My husband is the only child of hisparents.”
Together with the negative criticism within thewoman’s family, family members also suggest waysto conceive, such as herbal medicine for self-treatment,sources of western treatment in clinics and hospitalsand religious practices.
Sri: “I prayed to the spirit of Prince Pichai, with apig’s head. It was my parent’s advice but I amstill infertile.”
Tang: “I choose to go to this hospital because mysister recommended it to me.”
Chaem: “My mother-in-law is the one who told meto get the sperm of my brother-in-law to use inthe treatment.”
In Thai cases, women will usually get pressurefrom and be criticized by the husbands’ familymembers or relatives if they delay or if they do notseek treatment. For example, Sri, one of the womeninterviewed for the study, stated:
Sri: “My husband’s parents who stay in anothertown once visited me and they criticized me thatI do not have a child. They say that when myhusband and I get old, we will suffer and havehard lives. My husband’s parents want to havea grandchild very badly and encourage me to seethe doctor. For my husband, he does not caremuch. If I do not conceive, it is O.K. for him.”
Mala, another woman in the Thai sudy felt that:
Mala: “The fact that I do not have a child for myhusband’s family is a really important matter. If Ihave only one child and no more it is O.K. Mymother-in-law wants one because she has onlyone child herself. I am really mad and want tocriticize my mother-in-law. For my husband, hereally does not mind, it is only because of mymother-in-law’s pressure. If it were not for her, Iwould not go through this treatment process. Itis really painful and I feel very embarrassed whenthe doctor investigates my cervix. This time if itdoes not work, I will give up” (14).
The advice may be encouraging but may also bring
Family networks and support to infer tile people 283
too much pressure, stress and psychological harm towomen. Society and often family blame women for nothaving done enough to conceive a child. Chaem,another informant, said:
Chaem: “Everybody asked me—‘Why don’t youconsult the doctor? Why don’t you pray to thespirit for having a child?’ When they questionedme, I felt so bad. I don’t want anybody to askme like that, it makes me angry. Why do theythink that I did nothing?”
The Thai cases show that women get more blameor more negative than positive support from theirfamily network. Support for infertile couples includesinformation regarding sources of treatment or otherpractical solutions, often given without understandingand sharing of the emotional problems involved.Infertile women may get criticized by the family as wellas by the community for being deficient, althoughthey have struggled very hard and may have sufferedphysical and psychological pain from the treatments.The data from Thailand show that childless womendo not get enough support from their families. In theinterviews, many women expressed the feeling that nofamily member sympathized with them or wanted toshare experiences and emotions with them.
The Thai study is only one among very fewstudies that look at women’s lives in the context ofinfertility over the life course. It showed that infertilitycauses a prolonged state of crisis that changesthroughout the life cycle. In the first stage, womenreceive blame, criticism and pressure for treatment.Such pressure often pushes women to seek informa-tion and medical treatment. After women have gonethrough several coping strategies, they may gain anew moral identity and sense of self-worth. Some turnto religious explanations of “karma” to interpret theirlife suffering, some redirect their energies to their workand look forward to succeeding in their careers, othersgive new meaning to their infertility by realizing thattheir karma is good and they are lucky not to have theburden of children; and still others choose to adopt achild. In addition, during the later stages of theirinfertility, women receive more support from theirfamilies which at this stage seem to sympathize morewith the problem of infertility and to show a ratherneutral attitude toward the women.
A study in the UK by Boivin et al. (15) showedthat infertile couples relied primarily on their spouse,family and friends as sources of support when
distressed, rather than on formal support resourcessuch as psychosocial counselling, support groupsorganized by professional staff or the media. In theUK study, women used significantly more sources ofsupport than men. There is a tendency for women toevaluate the discussions with family and friends asmore helpful than those with their partners. Althoughpatients were given the opportunity to list additionalsources of support, none mentioned their family doctoror general practitioner. It is interesting to state that inthe UK study, using a standard weighted rating, therank order for the different sources of support fromthe highest to the lowest were: spouse, family/friends,media information, library books, counsellors andsupport groups. The rank was similar for men, exceptthat discussion with families and friends was ratedlower than media information, indicating that the menin this study relied more on nonhuman sources ofsupport, i.e. media information, than on family andfriends (15).
SpouseÊs reaction and support
It is necessary to understand the spouse’s reactionto understand the spouses’ support. Childlessnessstrongly affects the relationship of the couple in termsof both sexual and marital life. Most studies inresource-poor countries found a similar pattern ofnegative reactions rather than positive support fromchildless women’s husbands. In the Bangladeshstudy, it was found that women who are abandonedby their husbands due to their childlessness have tofind work to survive, as the parents refuse to bear theirliving expenses. Deprived of education or appropriatejob opportunities, some turn to commercial sex forincome generation. Childless women complain aboutdomestic violence and disrespectful treatment byhusbands and family in-laws, sometimes being treatedby their husbands as a servant. Others are abandonedby their husbands or end up as a second wife in apolygamous marriage (16). In Mexico, the lack ofchildren was found to be an excuse for domesticviolence against the wife and for drunkenness of thehusband. In southwest Nigeria, women are most oftenblamed for infertility with a common consequence ofa couple’s infertility being the expulsion of the womanfrom the husband’s house (8).
Similarly, studies in Bangladesh (16), Nigeria (17),Mexico (18) and Zimbabwe (19) showed that infertilewomen expressed fear of being divorced because theycould not give their husbands a child. Men often face
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social pressure from their own relatives to divorce theirwives who are held responsible for the problem ofinfertility. The husband’s relatives may also maltreat,taunt and threaten the childless women. On thecontrary, in the Thai study it was found that husbandsof childless women did not criticize or blame theirwives, but were supportive. Many of them promisedtheir wives they would never leave them because ofthe infertility problem. The differences in husband’ssupport in Thailand, compared to Bangladesh, Nigeria,Mexico and Zimbabwe, may be due to the fact thatwomen’s social status in Thailand is relatively higher.
Nevertheless, Thai women still fear abandonmentby their husbands, as do the infertile women in thestudy carried out in Mozambique. Many of theMozambican infertile women had been married anddivorced earlier. However, past divorce of infertilewomen in Mozambique was often not related to theirinfertility (9).
Studies in resource-poor countries revealed thatwomen have an active fertility-seeking behaviour inboth the medical and traditional health systems, butthey seek help alone. There is a lack of male involve-ment in solving the infertility problem even in casesof male factor infertility. For example, all infertile womenin the Bangladesh study (16) sought medicaltreatment, but their husbands did not. This is the caseeven if a woman had clearly stated evidence of herhusband’s impotence. In Mexico (18), the Tjolabalwomen stated that when weakness or coldness of theman’s body is diagnosed, he frequently refuses toaccept such treatments because it puts his masculinityin doubt. On the contrary, when Tjolabal women donot become pregnant after several months of livingtogether as a couple, a series of treatments is givento warm the women’s body and men cooperate in thistreatment as assigned by mothers, mothers-in-law, orother older women. In the Gambia, very few womenbring their husband along for formal treatment and thehealth care providers do not usually ask for this (20).The situation is similar in the Thai society; womenalone are usually blamed for the reproductive failureand must carry the burden of solving the problemthrough a therapeutic process that is sometimestraumatic and often unsuccessful. The woman is thefirst one to get tested when she “fails” to conceive.This is the case even though testing the man’s spermis easier, less invasive and less costly. Medical doctorsdo not request the husband’s presence at the begin-ning of the treatment process. Women themselves alsofollow this dominant ideology without being aware
that infertility treatment should be the treatment of thecouple. The following narrative from the Thai studyillustrates the point:
Pern: “My husband never got checked up but he ishealthy and fertile because he got anotherwoman pregnant when he lived in Libya. Thiswoman had to go for an abortion because shewanted to have a new husband. I believe thatthe problem comes from me. It is about myoperation [tumour at the side of her cervix].”
Srikarn: “I never blame my husband, I think theproblem comes from my side, although I knowthat he has a problem also. I used to warn himabout his smoking and drinking habit but I donot blame him … he told me that I already givethem [sperms] to you but you cannot keep themyourself. From the sperm count, his sperms havetwo heads and no tail. The doctor told me thatthe problem comes from both of us. But I thinkthe problem comes from my side. I have a ‘bad’cervix, I travel a lot, I got an infection andabnormal discharge and have an inflammation ofthe ovary tube. Later I had to have an appendixoperation…. To travel often makes me havefrequent reproductive tract infections and it ischronic.”
However, in the Thai case the situation is relativelybetter than in Bangladesh. In studies in India (21) aswell as in Thailand, it appeared that husbands weresupportive of their infertile wives. Some Thai menaccompanied their wives to the infertility clinic fortreatment or diagnosis, although this is not verycommon. The degree of active involvement isgenerally not great. Some husbands accompany theirwives and sit outside the patient’s room waitingwithout participating in any process of treatment.Most Thai men generally cooperate with the testsunless their masculine identity is threatened. Forexample, if the man has been asked to give semen toooften, he will refuse to cooperate. The case of Srikarnreflects this point:
Srikarn: “When I ask him for his sperm several times,he will get upset, he told me that he felt like amouse in an experiment. The first few times thatI asked for his semen, he cooperated very well,but later when I asked him again and again, hesaid no to me, he said he has feelings, he is upsetand feels humiliated, I was mad when my husband
Family networks and support to infer tile people 285
refused to cooperate but I feel sympathetic tohim. He told me that even if I had a child for him,he can still get a minor wife.”
In western countries, infertility seems to be acouple’s problem for which both men and women willseek treatment together, and male involvement in thetreatment does not appear to be a problem.
Community support
Community support for infertile couples is not givenmuch attention in studies on infertility in developingcountries. Childless women and men are found to bestigmatized because of their infertility. Exclusion fromcertain social activities and ceremonies was observedfor infertile Macua women in Mozambique, whilechildless men in Dhaka, Bangladesh, are not treatedas equal to other men in their society. For women, beingchildless is worse, as the studied communities offerwomen very few or no alternative roles to that of mother.However, considerable variation is found amongregions. For example, among the matrilineal Macua inthe north of Mozambique, men are quite often blamedfor infertility, which can lead to divorce initiated bythe women or their relatives. An interesting exampleof this was described by Bharadwaj (21). In a multi-sited research study among couples visiting infertilityclinics in India, he found that—contrary to the popularbelief—men are no less affected by the stigma ofinfertility than women, and the fear of being consideredimpotent was found central to the anxiety that somemen experience. Miall (22) also found that males areseen as more stigmatized by infertility than females,who generally receive sympathy. Couples perceivedboth the infertility and the clinical management of itas stigmatizing conditions. Therefore, several of hisrespondents accepted donor egg or sperm only if itwas kept secret, because in this way others wouldconsider their offspring as biological, while adoptionwould make their infertility most visible for the public,and was therefore seen as a more problematic andstigmatizing option. Differences between countriesand regions regarding social isolation and rejectionof childless women seem to be, among others,influenced by the specific kinship systems, family andconjugal ties, by moral and legal rules and religiouscustoms. Generally speaking, a relatively low statusof women compared with men is associated with astrong negative response to infertile women.
None of the studies reported the community’s
mechanisms of support to infertile couples. The onlyknown examples of community assistance for womenwho are childless because they have lost manychildren come from the Gambia and Senegal. In theGambia, it is pointed out that community members ofthe Mandinkas and Jolas have organized an associa-tion named the Kanyaleng group. The group recruitswomen who have lost many children or who havenever given birth. The social significance of theKanyaleng has been described as enhancing thesurvival of children through different rites andbehaviour (10).
Media and written documentation as asource of support
A study in the UK by Boivin et al. (15) also revealedthat media and written documents are other importantsupport resources for infertile couples, especiallychildless men. In this study, the couples soughtsupport from written documentation on the emotionalaspects of infertility provided in clinics, as well as suchinformation provided through the media. This modeof intervening with patients remains unexploreddespite the fact that many patients have requestedmore written psychosocial information in past surveys.In this study, almost 50% of women had used writteninformation provided at the clinic, newspaper articlesand/or television documentaries on the emotionalaspects of infertility as a way of coping with thismedical problem and/or its treatment. While documen-tation and information in the media would seemunlikely to provide some aspects of support (e.g.comfort), these may fulfil other important supportfunctions. For example, television documentaries oncouples undergoing in vitro fertilization (IVF) werewatched by many of the patients in the study, whocommented that they felt reassured in discovering thatthey were not the only ones having difficulty copingwith infertility. In addition, many felt that suchdocumentaries or articles helped their families andfriends better understand the impact that infertilitywas having on their lives. This finding suggests thatthe importance of psychosocial documentation,whether developed by the clinic or provided by themedia, should not be underestimated because it hasalready been used by patients and can be a cost-effective way for the clinic to provide psychosocialservices to patients.
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Parenting and the psychological development ofthe child in ART families
SUSAN GOLOMBOK
Introduction
Advances in assisted reproduction procedures havehad a fundamental impact on the way in which mothersand fathers may be related to their children. AsEinwohner (1) has pointed out, it is now possible fora child to have five parents: an egg donor, a spermdonor, a birth mother who hosts the pregnancy andthe two social parents whom the child knows as“mum” and “dad”. In addition, a small but growingnumber of lesbian and single heterosexual women areopting for assisted reproduction, particularly donorinsemination (DI), to allow them to conceive a childwithout the involvement of a male partner. Children inthese families grow up without a father right from thestart, and many children in lesbian families are raisedby two mothers. This paper will examine research onparenting and the psychological development ofchildren in assisted reproduction families withparticular attention to the issues and concerns thathave been raised by creating families in this way.
IVF families
Concerns about parenting in IVF families
It may seem that having a genetically related child byin vitro fertilization (IVF) is just the same as having a
child by natural conception; all that is different is theprocess of conception. However, there are a numberof reasons why having a child by IVF may result in arather different experience for parents than having achild in the usual way. One very apparent differenceis the higher incidence of multiple births, pretermbirths and low-birth-weight infants following IVF (2–10) . Whereas only 1% of natural births involve twins,triplets or more, this is true of more than one-quarterof births resulting from IVF. Parents who have multiplebirths not only have to cope with two or more infantsborn at once but also with infants who may havegreater needs as a result of prematurity and low birthweight (11) . The impact of these factors on parentingand child development must be considered separatelyfrom the impact of IVF per se. Many, but not all, of theempirical investigations described below havefocused on families with a singleton child born as aresult of IVF to avoid the confounding effect of amultiple birth.
It has also been suggested that the stress associ-ated with the experience of infertility and its treatment,often lasting for many years, may result in parentingdifficulties when a long-awaited baby is eventuallyborn. According to Burns (12), the stresses producedby infertility are likely to result in dysfunctionalpatterns of parenting. She argued that parents whohad difficulty in conceiving may overprotect andemotionally overinvest in their much longed-for child.
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Other authors have also suggested that those whobecome parents after a period of infertility may beoverprotective of their children, or may have un-realistic expectations of them, or of themselves asparents, due to the difficulties they experienced in theirattempt to give birth (13–16). Psychological disordersand marital difficulties have also been predicted forthose who become parents following IVF (14).
Research on parenting in IVF families
In a prospective study of IVF families in Australia,psychological adjustment to first-time motherhoodwas assessed when the baby was 4 months old (17).Sixty-five IVF families were compared with 62 familieswith no history of infertility. The aim of the study wasto determine whether mothers who conceived by IVFdiffered from the matched comparison group of naturalconception mothers with respect to adjustment toearly parenthood, specific adjustment to the maternalrole, and quality of the parent–child relationship. Therewere no differences between the two groups ofmothers for anxiety, postnatal depression, maritaladjustment or feelings of attachment toward theinfant. In addition, an observational assessmentshowed no difference in maternal behaviour betweenthe two groups of mothers. However, the IVF mothersreported lower self-esteem and lower maternal self-efficacy. The authors concluded that the overallfindings were reassuring for parents who conceive byIVF, and that the specific differences identifiedbetween the IVF and the natural conception mothersmay be explained by the IVF mothers judging them-selves too harshly.
These families were followed up when the babieswere one year old (18,19). At that time, the two groupsof parents did not differ on measures of anxiety,depression or social support, or on measures morespecific to parenthood such as attachment to the child,attitudes to childrearing, separation anxiety, inter-action during play and parenting stress. There was,however, a nonsignificant trend towards the IVFmothers reporting lower self-esteem and less parentingcompetence than the natural conception mothers. Inaddition, although there were no group differences inmaternal protectiveness, the IVF mothers saw theirchildren as significantly more vulnerable and“special”. The IVF fathers reported significantly lowerself-esteem and marital satisfaction but no lesscompetence in parenting. It was concluded that theIVF parents’ adjustment to parenthood when their
child was one year old was similar to that of the naturalconception families. However, there were minordifferences among the IVF parents that reflectedheightened child-focused concern and less confi-dence in parenting for mothers, less satisfaction withthe marriage for fathers, and vulnerable self-esteemfor both parents. The authors emphasized thatalthough the IVF mothers continued to have higherlevels of concern over child well-being and notionsof child “specialness”, their concerns did not appearto be associated with more protective parentingcompared with mothers who had conceived naturally.In addition, these parenting attitudes did not seem totranslate into differences or impairments in the qualityof mother–child interaction. They did suggest,however, that the IVF mothers’ concerns may causethem to be preoccupied with the child and exclude theirhusbands, thereby contributing to the fathers’ lowermarital satisfaction and self-esteem.
In France, Raoul-Duval et al. (20) studied 33families with an IVF child in comparison with matchedgroups of 33 families with a history of infertility (whoconceived their child through ovarian stimulation),and 33 families with a naturally conceived child. Thefamilies were first seen in the hospital after delivery,and then followed up at home after nine months, 18months and three years. There were no significantdifferences among the three family types in theincidence of either maternal depression or problemsin the relationship between the mother and the childat any of the assessment periods. It should be noted,however, that by the time of the three-year-oldassessment, only 39% of the natural conceptionmothers and 33% of the mothers with a history ofinfertility remained in the study, although a higherproportion of IVF families (76%) was retained. As theauthors point out, if the other types of family were lostdue to difficulties in family functioning, this wouldgive greater weight to the conclusion that the IVFfamilies were not at risk.
Twenty couples in the UK who had conceived byIVF were compared, when their babies were between15 and 27 months old, with a matched group of 20couples who had conceived without medical assist-ance (21). There were no differences between the twogroups of parents for emotional health or maritaladjustment, and their scores were closely comparableto general population norms. The IVF parents reportedsignificantly more positive feelings toward theirbabies than the natural conception parents, and ratedthemselves as feeling significantly less tied down.
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However, the IVF parents reported being more protec-tive toward their child than the natural conceptionparents. It may be relevant that these parents were thefirst to give birth to an IVF child in this area of thecountry. It should also be noted that these findingswere based on questionnaire data only.
IVF families with children between 24 and 30months of age in Belgium were studied by Colpin etal. (22) using both self-report questionnaires andobservational measures of mother–child interaction.Thirty-one families with an IVF child were comparedwith 31 natural conception families with no history ofinfertility. No differences were identified between theIVF families and the natural conception families forany of the measures of the parents’ psychologicalfunctioning or the mother’s relationship with her child.The only difference to emerge related to the subgroupof IVF mothers who were employed; those who wereemployed were less encouraging of their child’sautonomy during problem-solving than both thenonemployed IVF mothers and the employed naturalconception mothers. A possible explanation for thisfinding put forward by the authors was that it may bemore difficult for IVF mothers to resume work outsidethe home than it is for natural conception mothers,and that they may compensate by inhibiting their childfrom being autonomous. Certainly, the IVF motherswho resumed work were more likely to have done sofor financial reasons than the mothers of naturallyconceived children. Nevertheless, an alternativeexplanation is that this finding represented a chanceeffect resulting from the large number of groupcomparisons carried out.
In a study of IVF families with two-year-old to four-year-old children in the Netherlands, van Balen (94)included a comparison group of formerly infertileparents with a naturally conceived child to control forthe experience of infertility, in addition to a comparisongroup of natural conception families with no historyof infertility. Forty-five IVF parents, 35 formerlyinfertile parents and 35 fertile parents completedquestionnaires on parenting behaviour and on theirchild. The IVF mothers and the previously infertilemothers differed from the natural conception motherswith respect to emotional involvement with their child.They reported experiencing more pleasure in theirchild and stronger feelings toward their child thanmothers with no history of infertility. The IVF and thepreviously infertile mothers also reported greaterparental competence than the fertile mothers. Therewere no differences regarding the mothers’ reports of
parental concern, parental expectations or parentalburden. Fathers did not differ on any of the measures.It seems, therefore, that where differences existed thefindings of this study pointed to positive outcomesfor mothers of two-year-old to four-year-old childrenwith a history of infertility, whether or not the childwas conceived by IVF. It is important to point out thatthese results are based on self-report questionnairesand the response rate was low (ranging from 69% forthe IVF mothers through 52% for the previouslyinfertile mothers to 35% for the fertile mothers). Anadvantage of the study, however, was the inclusionof a comparison group of previously infertile coupleswho did not conceive by IVF.
The European Study of Assisted ReproductionFamilies examined the quality of parenting in familiescreated as a result of both IVF and DI, in comparisonwith families with a naturally conceived child andadoptive families. In the first phase of the study,conducted when the children were between four andeight years of age, representative samples in the UKof 41 families with a child conceived by IVF and 45families with a child conceived by DI were comparedwith 43 families with a naturally conceived child and55 families with a child adopted in the first six monthsof life (23). The findings relating to the DI familiesare presented below. It was found that parents with achild conceived by IVF obtained significantly higherratings for mother’s warmth to the child, mother’semotional involvement with the child, and bothmother–child and father–child interaction, than thenatural conception parents. The adoptive parents’ratings on these variables were closely comparable tothose of the IVF parents. In line with these findings,mothers and fathers of naturally conceived childrenreported significantly higher levels of stress associ-ated with parenting. Thus, the findings of this studyindicated that the quality of parenting in families witha child conceived by IVF was superior to that shownby families with a naturally conceived child. Whereparents in the different family types differed withrespect to anxiety, depression, or marital satisfaction,this reflected greater difficulties among the naturalconception parents.
In the second phase of the research, the study wasexpanded to include an additional country fromnorthern Europe (the Netherlands) and two countriesfrom southern Europe (Spain and Italy) to increase thesample size and to allow the examination of theinfluence of culturally determined attitudes towardassisted reproduction on the functioning of families
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that have resulted from these techniques. Identicalprocedures were employed in the Netherlands, Spainand Italy as had been used in the UK. The inclusionof these three countries brought the total number ofIVF, DI, adoptive and naturally conceived families,respectively, to 116, 111, 115, and 120 (see below forfindings regarding DI families). The results of theextended study confirmed the findings of the originalinvestigation (24). Mothers of children conceived byIVF were found to express greater warmth to their child,to be more emotionally involved with their child, tointeract more with their child and to report less stressassociated with parenting than the comparison groupwho conceived their child naturally. In addition, IVFfathers were reported by mothers to interact with theirchild more than fathers with a naturally conceivedchild.
The families were followed up as the childrenapproached adolescence (25,26). One hundred andtwo of the IVF families, 102 of the adoptive familiesand 102 of the natural conception families wereassessed as near as possible to the child’s 12thbirthday, representing response rates of 92%, 91%,and 93%, respectively, excluding those who could notbe traced. The focus of the study was on parent–childrelationships with an emphasis on warmth and control,two aspects of parenting that are considered importantfor the psychological adjustment of the adolescentchild. The IVF parents generally continued to havegood relationships with their children characterizedby a combination of affection and appropriate control.The few differences found between the IVF familiesand the other family types reflected more positivefunctioning among the IVF families, with the possibleexception of over-involvement with their children ofa small proportion of IVF mothers and fathers.
In the first study to be conducted in a nonWesternculture, Hahn and DiPietro (16) compared 54 IVFfamilies with 59 natural conception families when thetarget child was between three and seven years of age.The quality of parenting was generally found to besimilar for the two types of family, although IVFmothers showed greater protectiveness, but notrestrictiveness, of their children. The children’steachers, who were unaware of the nature of thechild’s conception, did not report the IVF mothers tobe more protective or more intrusive in their parentingbehaviour, but did rate them as more affectionatetowards their children than the natural conceptionparents. The expectation that mothers would be moreprotective and indulgent of boys than girls due to the
higher value placed on sons was not supported bythe findings of this study.
Research on children in IVF families
Cognitive development
The early studies of the cognitive development of IVFchildren did not employ comparison groups. However,the children were administered standardized measuresof cognitive development for which normative datawere available. In a study of 33 children in Australia,the Bayley Scales of Infant Development wereadministered to one- to three-year olds (13,28). Thesescales produce a mental development index (MDI) anda physical development index (PDI), each with anaverage score of 100. For the IVF children, the scoreswere within the normal range with a mean MDI of 111and a mean PDI of 105. With one exception, those withthe lowest scores had been born prematurely or witha medical disorder. In another Australian study (29),20 IVF children were assessed using the GriffithsDevelopmental Scales. The Griffiths scales give adevelopmental quotient (DQ), again with an averagescore of 100. After correcting for prematurity, the meanDQ for the IVF infants was found to be 117. Only oneinfant, born at 33 weeks’ gestation, obtained a below-average score. The Griffiths Scales were alsoadministered to 99 IVF children 33–85 months of agein Sweden (30). The mean DQ was above average,and only one child had a DQ of less than 85.
A number of controlled studies have now beenreported. The Bayley Scale scores of 65 IVF infantswere compared with those of a matched control groupof 62 naturally conceived infants at 12 months of age(31). There was no significant difference between theIVF and natural conception children for either mentalor physical development as assessed by the MDI andPDI, respectively. Other studies with large samples andmatched comparison groups have reported similarfindings using the Bayley Scales. No difference inBayley Scale scores was found between 116 IVFchildren and 116 non-IVF matched controls between12 and 45 months of age in Israel (32). In the USA, nodifference was found in MDI scores between IVF andmatched non-IVF infants between 12 and 30 monthsof age, and significantly higher PDI scores were foundamong those conceived by IVF (33).
Using different measures of cognitive develop-ment, similar findings have been reported by a numberof other researchers. In France, no evidence of psycho-
Parenting and the psychological development of the child in ART families 291
motor deficit was found in 31 children as assessed bythe Brunet-Lezine test at nine months and 18 monthsin comparison with 31 children conceived by ovulationinduction and 31 naturally conceived children (34).Similarly, in a comparison between 26 IVF infants and29 naturally conceived infants in Israel using theGeneral Cognitive Index, no difference in either theoverall score, or in the subscale scores of perception,memory and motor skills, was identified betweenchildren from the two family types (35).
With respect to school-age children, the WechslerIntelligence Scale for Children and tests of visual–motor coordination, visual memory and readingcomprehension were administered to IVF children anda comparison group of naturally conceived childrenwith an average age of nine years in Israel (36). All ofthe children were born at full term. The two groups ofchildren did not differ with respect to any of themeasures of cognitive development. Similarly, in aninvestigation of the scholastic achievement of 370children 6–13 years of age in France, there was noevidence of low educational attainment amongchildren conceived by IVF in comparison with generalpopulation norms (37).
Socioemotional development
In their prospective study of 65 IVF families and 62families with no history of infertility in Australia,McMahon et al. (17) first assessed children’s socio-emotional development at the age of four months. Allof the babies were singletons. IVF mothers rated theirbabies as more temperamentally difficult than did thenatural conception mothers (although these ratingswere within the normal range), and the IVF babiesshowed more negative behaviours in response tostress. In a follow-up of the families when the babieswere one year old, assessments were made of socialdevelopment, temperament, behaviour problems andtest-taking behaviour (31). No differences betweenthe two groups of children were found for socialdevelopment or test-taking behaviour. Althoughmothers in both groups reported low levels of beha-viour problems, the IVF mothers rated their childrenas having more behavioural difficulties, and moredifficult temperaments, than the control mothers. Theauthors concluded that these findings may be relatedto the greater anxiety of IVF mothers about theirchildren’s well-being. The security of the infant’sattachment to the mother was also assessed at 12months of age using the Strange Situation procedure
(19) . IVF children showed predominantly secureattachment relationships, and there was no differencebetween groups in the proportion classified asinsecurely attached.
Thirty-one children between 24 and 30 months ofage were compared with 31 natural conception childrenin Belgium (22). The child’s behaviour was ratedduring an interaction task with the mother on fourtask-oriented scales (enthusiasm, persistence,reliance on mother and compliance) and three mother-orientated scales (avoidance of the mother, hostilityand positive feelings towards her). No differenceswere found between children from the two family typesfor any of the scales. In a study of two-year-old tofour-year-old children in the Netherlands, 45 IVFchildren were studied in comparison with 35 naturalconception children whose parents had experiencedinfertility and 35 natural conception children whoseparents had no history of infertility (103). The IVFmothers, but not fathers, rated their children as moresocial and less obstinate than the other mothers, asassessed by a self-report questionnaire. In a large butuncontrolled study of 743 IVF children between 4 and14 years of age in the USA, a standardized question-naire of emotional and behavioural problems, theAchenbach Child Behaviour Checklist, showed noindication of raised levels of psychological problemsin children conceived by IVF in comparison withgeneral population norms (38) . Also using theAchenbach Child Behaviour Checklist, no differencewas found in the incidence of emotional or beha-vioural problems between IVF children 33–85 monthsof age and a general population control group inSweden (30).
The European Study of Assisted ReproductionFamilies (24) has obtained data on the socioemotionaldevelopment of 116 IVF, 111 DI, 115 adopted and 120natural conception children four to eight years of agein Italy, Spain, the Netherlands and the UK (findingsrelating to DI children are reported below). Standard-ized questionnaires of behavioural and emotionalproblems were completed by mothers and teachers,and the children were administered tests of self-esteem and of their feelings towards their parents. TheIVF children did not differ with respect to thepresence of psychological disorders or in theirperception of their relationship with their parents inany of the four countries studied. In the UK, anassessment was also made of the children’s securityof attachment to their parents using the SeparationAnxiety Test. In addition, interview transcripts
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relating to children’s psychological functioning wererated by a child psychiatrist who was “blind” to thechild’s family type. No group differences were foundfor either security of attachment relationships or forthe incidence of psychological disorder as assessedby the child psychiatrist (23). When followed up atthe age of 12 years, the IVF children were continuingto function well (25,26) .
One study, conducted in Israel, has found a higherincidence of emotional problems among IVF children(36). In a comparison between IVF and naturallyconceived children of middle-school age on measuresof school adjustment, hyperactivity, trait anxiety,depression, aggression and behavioural problems, theIVF children, particularly the boys, were found toshow poorer adjustment to school as rated by teachersand reported themselves to be more aggressive, moreanxious and more depressed. The authors were carefulto exclude children born prematurely. However, thisfinding may be explained by the older age of the IVFparents.
Conclusion
Contrary to the concerns that have been raisedregarding the potentially negative consequences ofIVF for parenting, studies of these families havegenerally found IVF parents to be well adjusted andto have good relationships with their children. To theextent that differences have been found between IVFand natural conception parents, in the early yearsthese have tended to reflect higher levels of anxietyabout parenting by IVF mothers. For example, (17) IVFmothers of four-month-old infants were found to reportlower self-esteem and lower maternal self-efficacy thannatural conception mothers, although these differ-ences had lessened by the child’s first birthday (19).In addition, several studies indicated that IVF motherswere more protective of their child (21) , allowed theirchild less autonomy (22), and saw their child as morevulnerable and “special” (19).
These findings must be viewed in the context of alack of difference between IVF and natural conceptionfamilies with respect to other measures of maternalfeelings, attitudes and behaviour such as separationanxiety and observational measures of maternalbehaviour (17,19), maternal interaction with the child(20); acceptance, overindulgence, and rejection of thebaby (21); maternal attitudes and emotions andobservational measures of maternal interaction (22);and maternal concerns, expectations and burdens
(103). There were also more positive results for IVFmothers with respect to feelings toward their baby(21) and emotional involvement with their child (103).No differences were identified between IVF and naturalconception fathers, with the exception of lower self-esteem and marital satisfaction among IVF fathers ofone-year-old children in the Australian study (19).
As IVF children enter the early school years,findings from the European Study of AssistedReproduction Families (23,24) indicate that positiveeffects prevail. IVF mothers and fathers were foundto be more involved with their children than naturalconception parents. By the age of 12 years thisadvantage had disappeared. However, the quality ofparenting in IVF families continued to be good,characterized by affection and appropriate control.The few differences in parenting identified betweenIVF and natural conception mothers and fathers didnot reflect dysfunctional relationships between theparents and the child.
With respect to the children themselves, there isno evidence from any of the studies conducted to dateto suggest that IVF children are at risk for cognitiveimpairment. These studies have used a variety ofstandardized assessments of cognitive ability inchildren of different ages. The social and emotionaldevelopment of IVF children also appears to be withinthe normal range, with only one study reporting ahigher incidence of psychological problems amongchildren conceived by IVF. Nevertheless, furtherresearch is required to enable conclusions to be drawnabout the psychological well-being of IVF children inthe middle and later school years.
A number of methodological problems have beenassociated with studies of IVF families. In particular,mothers of IVF children are generally older thanmothers who have given birth without medicalintervention, and attempts to match natural concep-tion mothers for maternal age has presented difficul-ties, as has matching for birth order of the target childand the number of children in the family. Theseconfounding factors may well explain the differencesidentified between IVF and natural conceptionparents, although some researchers have attemptedto control for these variables statistically. Furthermore,some of the samples studied have been small and thecooperation rates have been less than ideal, and fewstudies have included an additional comparison groupof natural conception parents with a history ofinfertility. Nevertheless, the available data on parent-ing and child development in families created by IVF
Parenting and the psychological development of the child in ART families 293
are generally reassuring. Even if the more positivefindings for IVF parents can be explained by factorssuch as fewer children in the family, there is noevidence to suggest that IVF mothers and fathersexperience marked difficulties in parenting comparedwith their natural conception counterparts. Neither isthere evidence for a higher incidence of marital orpsychological problems among IVF parents. To thecontrary, where differences have emerged, thesereflect greater psychological adjustment and maritalsatisfaction among parents of an IVF child.
DI families
Concerns about DI families
There are concerns additional to those expressed inrelation to IVF regarding potentially negative conse-quences for families where donated sperm have beenused in the child’s conception. Although DI has beenpracticed for more than a century to enable coupleswith an infertile male partner to have children, themajority of adults and children conceived in this wayremain unaware that the person they know of as theirfather is not their genetic parent. In recent years therehas been growing unease about the secrecy thatsurrounds families created by DI. It has been arguedthat secrecy will have an insidious and damagingeffect on family relationships and, consequently, onthe child.
Findings suggestive of an association betweensecrecy and negative outcomes for children havecome from two major sources; research on adoption,and the family therapy literature. It is now generallyaccepted that adopted children benefit from knowl-edge about their biological parents, and there is acommonly held view that children who are not givensuch information may become confused about theiridentity and at risk for emotional problems (39,40,41,103). In the field of assisted reproduction, parallelshave been drawn with the adoptive situation, and ithas been suggested that lack of knowledge of, orinformation about, the donor may be harmful for thechild (42–46). Family therapists have argued thatsecrecy can jeopardize communication between familymembers, cause tension and result in a distancing ofsome members of the family from others (47–49). Inrelation to DI, Clamar (50) has argued that keepingthe circumstances of conception secret will separatethose who know the secret (the parents) from those
who do not (the child). A further concern is thatparents may feel or behave less positively towards anongenetic than a genetic child. It has been suggestedthat the child may not be fully accepted as part of thefamily which may have an undermining effect on thechild’s sense of identity and psychological well-being. Fathers, in particular, are expected to be moredistant from their nongenetic child (45).
Research on parenting in DI families
Rather fewer studies have been carried out of parent-ing in families created by DI than of parenting in IVFfamilies where the child is genetically related to bothparents. This is perhaps not surprising given theparents’ desire to maintain secrecy about the natureof their child’s conception. In a review of the 12studies of parents’ disclosure of DI published between1980 and 1995, Brewaeys (51) found that few parents(between 1% and 20%) intended to tell their childabout her or his genetic origins and, in eight of thetwelve studies, fewer than 10% of parents intendedto tell. Although it might be expected that a higherproportion of parents in the more recent studies wouldbe open with their children, this was not the case, afinding replicated by van Berkel et al. (52) in acomparison between recipients of DI in 1980 and 1996.The trend towards greater encouragement of dis-closure does not appear to have resulted in moreparents telling their child. Even in Sweden, wherelegislation gives individuals the right to obtaininformation about the donor and his identity, a recentsurvey found that only 11% of parents had informedtheir child about the donor insemination (52). It isnoteworthy that, in spite of their decision to opt forsecrecy, almost half of the parents included inBrewaeys’s review (51) had told at least one otherperson that they had conceived as a result of DI, thuscreating a risk that the child would find out throughsomeone else. Many parents regretted their earlieropenness once the child had been born (53–55).
Brewaeys also examined studies of the character-istics of DI parents (51). She found that in the largemajority of cases, DI was felt by parents to be apositive choice and, with few exceptions, fathersreported that DI did not influence their relationshipwith their child and that they felt themselves to be“real” fathers. However, these investigations werebased on questionnaire data of variable quality andno control groups had been employed. With respectto psychological adjustment, there was little indica-
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tion of disorder in couples who opted for DI (55–59).In addition, these couples had a low divorce rate andhigh marital satisfaction (55–57,60).
Parenting in DI families was a major focus of theEuropean Study of Assisted Reproduction Families(23). Details of the samples investigated and themeasures used are described in the section on IVFfamilies. In addition to these measures, mothers ofchildren conceived by DI were interviewed about theiropenness regarding their child’s genetic origins. Thefindings relating to the quality of parenting were thesame as for the IVF families, suggesting that geneticties are less important for family functioning than astrong desire for parenthood. Whether the child wasgenetically related to two parents (in the case of IVF),genetically related to one parent (in the case of DI),or genetically unrelated to both parents (in the caseof adoption), the quality of parenting in families wherethe mother and father had gone to great lengths tohave children was superior to that shown by mothersand fathers who had achieved parenthood in the usualway. It was striking, however, that not one set of DIparents had told their child that she or he had beenconceived using the sperm of an anonymous donor.Thus, none of the DI children was aware that theirfather was not their genetic parent. Nevertheless, halfof the DI mothers had told a member of their family,and almost one-third had told one or more friends, sothere would always be a risk of disclosure to the child.The main reasons for the parents’ decision not to tellthe child were concern that the child would love thefather less, protection of the father from the stigmaassociated with infertility, and uncertainty about whatand when to tell the child (61).
Similar results were obtained with the inclusion ofthe additional samples from Italy, Spain and theNetherlands (24). Once again, whether or not donorsperm had been used to conceive the child seemed tomake little difference to the quality of parenting inassisted reproduction families. Perhaps surprisingly,there was no evidence that attitudes toward assistedreproduction differed between predominantly Protes-tant northern Europe and predominantly Catholicsouthern Europe. Not one of the parents with a childconceived by DI in any of the four countries studiedhad told their child about the method of their concep-tion.
The families were followed up as the childrenapproached adolescence (26,62). It is at adolescencethat issues of identity become salient. Thus it is atadolescence that difficulties for DI families may be
expected to arise. To the extent that the experiencesof adopted children are relevant to children conceivedby DI, early adolescence is the time when adoptedchildren begin to show a greater incidence ofbehavioural problems in comparison with theirnonadopted counterparts (63,64) , alongside a greaterinterest in their biological parents (39). Ninety-fourof the DI families were examined when the child was11–12 years of age, representing a response rate of89% excluding those who could not be traced, incomparison with 102 of the adoptive and 102 of thenatural conception families. The measures are des-cribed above in relation to the adolescent follow-upof IVF children.
The findings suggest that DI families with an earlyadolescent child are characterized by stable andsatisfying marriages, psychologically healthy parents,and a high level of warmth between parents and theirchildren accompanied by an appropriate level ofdiscipline and control. No differences were identifiedbetween the DI and the IVF families for any of thevariables relating to the quality of relationshipsbetween parents and the child. Of particular interestis the finding that only 8.6% of the DI children hadbeen told about their genetic origins by the time theyhad reached 11–12 years.
Research on children in heterosexual DIfamilies
Cognitive development
Five studies, reviewed by Brewaeys (51) , haveexamined the cognitive development of childrenconceived by DI. The earliest study, conducted inJapan (65), reported higher IQ scores among 54 DIchildren up to 11 years of age when compared withgeneral population norms. Based on parental reports,two studies in Australia (66,67) and a study inSweden (68), found DI children to be above averagein terms of psychomotor development. In the onlycontrolled study, 3-month-old to 36-month-old DIchildren were compared with naturally conceivedchildren in France (69). The DI children were foundto be more advanced with respect to psychomotor andlanguage development according to parental reports.In a study conducted in the USA, 10% of school-ageDI children were considered, by their schools, to begifted (54).
Parenting and the psychological development of the child in ART families 295
Socioemotional development
The first uncontrolled studies found no evidence ofemotional or behavioural problems in childrenconceived by DI (66,67). Although a higher incidenceof psychological problems among DI than naturallyconceived children as assessed by an interview withparents has been reported (69), other controlledstudies that have used standardized measures haveshown no evidence of psychological disorder inchildren conceived by DI. DI children six to eight yearsof age were compared with matched groups ofadopted and naturally conceived children in Australia(70), and four-year-old to eight-year-old DI childrenwere compared with adopted, IVF and naturallyconceived children in the UK (23) and Europe (24).When the children were followed up at the age of 12years, they were found to be functioning well (26,62).In spite of the parents’ decision not to tell, the childrendid not seem to be experiencing negative conse-quences arising from the absence of a genetic link withtheir father, or from the secrecy surrounding thecircumstances of their birth.
DI families headed by lesbian and singleheterosexual mothers
With respect to lesbian mother families, there havebeen two main concerns; first, that the children wouldbe teased and ostracized by peers, and would developemotional and behavioural problems as a result, andsecond, that they would show atypical genderdevelopment, i.e. that boys would be less masculinein their identity and behaviour, and girls less feminine,than their counterparts from heterosexual homes.Although there is no evidence for either of theseassumptions (see 71,102 for reviews), the early bodyof research focused on lesbian families where the childhad been born into a heterosexual family and thenmade the transition to a lesbian family after theparents’ separation or divorce.
In recent years, controlled studies of lesbiancouples with a child conceived by DI have beenreported. Unlike lesbian women who had their childrenwhile married, these couples planned their familytogether after “coming out” as lesbian and the childrenhave been raised in lesbian families with no fatherpresent right from the start. In the USA, Flaks et al.(73) compared 15 lesbian DI families with 15 hetero-sexual DI families, and Chan et al. (74) studied 55 DI
families headed by lesbian parents in comparison with25 DI families headed by heterosexual parents. In theUK, 30 lesbian DI families were compared with 41heterosexual two-parent DI families and 42 familiesheaded by a single heterosexual mother (75). Similarly,in Belgium, Brewaeys et al. (76) studied 30 lesbianmother families with a four-year-old to eight-year-oldchild in comparison with 38 heterosexual families witha DI child and 30 heterosexual families with a naturallyconceived child. The evidence so far suggests thatDI children in lesbian mother families do not differ fromtheir peers in heterosexual families in terms of eitheremotional well-being or gender development. Themost striking finding to emerge from these investiga-tions was that co-mothers in two-parent lesbianfamilies were more involved with their children thanwere fathers in two-parent heterosexual homes. In theBelgian study, information was obtained from parentsregarding the decision-making process about whetheror not to tell the child about the method of theirconception. All of the lesbian mothers intended to telltheir children that they had been conceived by DI, and56% would have opted for an identifiable donor hadthat been possible (77) . The attitude of lesbianmothers toward this issue is in striking contrast to thatof heterosexual parents who prefer not to tell.
No studies have been carried out on the qualityof parenting of single women who opt for DI as ameans of having a child. A small, uncontrolled studyof 10 single women requesting DI (78) found that animportant reason for choosing this procedure was toavoid using a man to produce a child without hisknowledge or consent. DI also meant that they did nothave to share the rights and responsibilities for thechild with a man to whom they were not emotionallycommitted. Although rare, women who have neverexperienced a sexual relationship with either sex havealso had DI to produce so-called virgin births (79).
Research on single-mother families in general hasshown that difficulties in parenting are associatedwith both economic hardship and lack of socialsupport (80,81). In addition, emotional distress andan associated reduction in parental functioning iscommon among single mothers following divorce (83–85) . In single-mother families with a child conceivedby DI, it is important to take social context intoaccount. Single-mother families are not all the same,and anecdotal reports suggest that single womenrequesting DI tend to be financially secure and to haveaccess to social support from family and friends.Moreover, they have not experienced conflict with, or
296 SUSAN GOLOMBOK
separation from, the father of their child. Such circums-tances may reduce the potentially negative conse-quences for parenting or rearing a child alone.
Conclusion
From the information that is currently available, thequality of parenting and the psychological develop-ment of children in DI families do not appear to becompromised by the absence of a genetic link betweenthe father and the child. Nevertheless, in spite of thegreater encouragement of openness, it seems thatparents continue to withhold information from child-ren about their genetic origins. The areas presentingmost difficulty for disclosure include the stigmaassociated with DI, acknowledgement of the father’sfertility problem, uncertainty about the best time andmethod of telling the child, and lack of information togive the child about the genetic father (42,61,86).Unlike adoption, there are no generally acceptedstories of what to tell the child about DI, and parentshave to explain the facts of life and discuss the father’sinfertility for the child to understand. Moreover, if ananonymous donor has been used, they have littleinformation to give the child about the genetic father.Due to these factors, most heterosexual DI parentsseem to have concluded that nondisclosure isdesirable for the protection of both the father and thechild.
Although the absence of psychological problemsin children and of problems in parent–child interactionin DI families suggests that secrecy does not have anadverse effect on family functioning, this does notnecessarily mean that it is better for children not tobe told about the nature of their conception. It mustbe remembered that the children studied so far areyoung and have not yet developed a sophisticatedunderstanding of their relationship with their parents.Research on adoption has demonstrated that adoptedchildren welcome information about their geneticparents (87,88), and many adoptees do not begin toseek out their genetic parents until they reach adult-hood (89). As their children grow older, it becomesmore difficult for parents to tell them that they wereconceived using donor sperm. Some parents regretnot having told their children from the start but feelthat it would now present too much of a shock for themand that it is too late (90).
Little is known about children who are aware oftheir conception by DI, or about the impact of thisknowledge on their relationship with their parents, as
the only systematic study of such families did notdistinguish between parents who had actually toldtheir child about DI and those who simply intendedto tell (86). No association was found in this studybetween attitude towards disclosure and parentingquality. However, fathers who were most concernedabout the stigma associated with DI reported lesswarmth and less fostering of independence in theirchild, suggesting that perceptions of stigma may havean adverse effect on the relationship between DIfathers and their children. A major problem withinvestigations of DI families is the low cooperationrate associated with the parents’ desire to maintainsecrecy about their child’s conception. Parents whoare most concerned about secrecy are least likely totake part in research. Until families who have told theirchild have been compared with those who have not,it will not be possible to come to a clear understandingof the consequences of secrecy versus disclosure onparenting in such families. Interestingly, however, ina study of parents who had told their children, themajority (57%) reported feeling good about havingdone so (91). van Berkel et al. (52) also found thatparents who had been open with their child did notregret their decision to tell. An exploratory comparisonbetween the few DI children in the European Study ofAssisted Reproduction Families who had been toldand those who had not, pointed to less conflictbetween mothers and their children in families wherethe parents had been open with their child (26). Inlesbian DI families, where the child grows up withouta father, mothers are more open with their childrenabout the method of their conception. Whether or notsingle heterosexual mothers with a child conceived byDI opt for secrecy or disclosure remains to be seen. Astudy of single women requesting DI suggested thatthey were more likely than married women to intendto tell (57).
Anecdotal reports from adults who are aware oftheir conception by DI shed some light on the longer-term effects. Whereas some report good relationshipswith their parents (43), others report more negativefeelings including hostility, distance and mistrust(82,92,93). As these adults are not representative ofpeople conceived by DI in general, it is not possibleto generalize from their experiences. Most likely,children’s reaction to discovering that they wereconceived by DI will depend on a number of factorsincluding the quality of their relationship with theirparents before the disclosure and the manner in whichthey find out. Systematic studies of representative
Parenting and the psychological development of the child in ART families 297
samples are necessary to fully understand the long-term consequences of DI for the individuals concerned.
Egg donation families
Concerns about egg donation families
Although the use of donor sperm to enable coupleswith an infertile male partner to have children has beenpractised for many years, it is only since 1983,following advances in IVF, that infertile women havebeen able to conceive a child using a donated egg(95,96). Egg donation is like DI in that the child isgenetically related to only one parent, but in this caseit is the mother and not the father who is geneticallyunrelated to the child. Thus egg donation has made itpossible for children to be born to, and reared by,mothers with whom they have no genetic link.
The concerns that have been expressed about eggdonation are similar to those raised by DI. It is theabsence of a genetic bond between the mother andthe child, and the effect of secrecy about the child’sconception that have been the topics of greatestdebate. But unlike DI where the donor is usuallyanonymous, egg donors are more often relatives orfriends of the parents and may remain in contact withthe family as the child grows up. Contact with thegenetic mother has been viewed by some as a positiveexperience for children in that they have the opportu-nity to develop a clearer understanding of their origins.However, it is not known what the impact of twomothers will be on a child’s social, emotional andidentity development through childhood and intoadult life, or how contact between the genetic motherand the child will affect the social mother’s securityas a parent and consequently her relationship with thechild.
Research on parenting in egg donationfamilies
The first study of parenting in families with a childconceived by egg donation was conducted in France(20). All of the donors were anonymous. The authorsreported on 12 families assessed at nine months and18 months, and nine of these families at 36 months.The quality of the relationship between the motherand her infant was assessed using a procedure basedon the mother’s body language, vocal dialogue, visualdialogue and attitude toward breastfeeding. It was
reported that all of the mother–infant relationshipswere excellent. However, no details were given of theway in which an “excellent” mother–infant relation-ship was defined.
A group of 21 families with a three-year-old toeight-year-old child conceived by egg donation wasrecruited in the UK, and a contrast made betweenfamilies where the child was genetically related to thefather but not the mother (egg donation families) andfamilies where the child was genetically related to themother but not the father (DI families) (72). The onlydifference to emerge between egg donation and DIfamilies was that mothers and fathers of childrenconceived by egg donation reported lower levels ofstress associated with parenting than parents of a DIchild. Thus it seemed, from the limited informationavailable, that egg donation families, like DI families,were functioning well. However, most of the childrenin these families had been conceived using the egg ofan anonymous donor. What is not known is the effecton parenting of the child being conceived with the eggof a known donor—a relative or family friend—whocontinues to play a part in family life. Only one set ofparents with a child conceived by egg donation hadtold their child about his genetic origins.
In Finland, 49 families with an egg donation childbetween six months and four years of age werecompared with 92 families with a child born throughIVF (97). The large majority of egg donors (84%) wereanonymous. However, the eight known donors(sisters or friends) saw the child regularly with noreported difficulties in the relationship between thedonor and the mother. Thirty-eight per cent of allparents intended to tell their child that she or he hadbeen conceived by egg donation, a higher proportionthan is generally reported for DI parents. Of the eightparents who used a known donor, only two intendedto tell the child. As with the DI parents, many (73%)had told someone other than the child. With respectto parenting, significantly fewer egg donation parentsthan IVF parents expressed concern about their child’sbehaviour.
Research on children in egg donation families
Cognitive development
Data on 12 egg donation children at nine months and18 months of age, and on nine of these children at 36months of age, showed no evidence of psychomotorretardation for any of the children studied (20).
298 SUSAN GOLOMBOK
Socioemotional development
Fifty-nine egg donation children and126 IVF children,all between six months and four years of age, werecompared with respect to a number of developmentalindices as assessed by parental questionnaire (97).There were no group differences in the proportion ofchildren with eating or sleeping difficulties, and theegg donation parents were less likely than the IVFparents to express concern about their child’s beha-viour. In a study of 21 egg donation children betweenthree and eight years of age in comparison with 41 IVFchildren, 45 DI children and 55 adopted children,assessments were made of the presence of emotionaland behavioural problems by parental questionnaireand the children were administered a standardizedassessment of self-esteem (72). There was no evidenceof psychological difficulties among the egg donationchildren.
Conclusion
It appears from the few investigations carried out sofar that having a child by egg donation does not havea detrimental effect on parenting. However, most ofthe parents studied to date had conceived their childusing the egg of an anonymous donor. Little is knownabout the consequences of egg donation when thedonor is a relative or friend, a situation that may havemore far-reaching effects on family relationships. Withrespect to the children themselves, the limited dataavailable do not indicate adverse psychologicaleffects arising from the method of their conception.Nevertheless, conclusions cannot be drawn from thesmall number of existing studies.
Intracytoplasmic sperm injection ( ( ( ( ( ICSI)families
Concerns about ICSI families
The introduction of IVF has paved the way forincreasingly “high tech” reproductive proceduressuch as ICSI wherein a single sperm is injected directlyinto an egg to create an embryo. Specific concernshave been raised in relation to ICSI, including the useof abnormal sperm, the bypassing of the usual processof natural selection of sperm and the potential forphysical damage to the egg or embryo, all of whichmay produce changes in genetic material (98) and may
thus have implications for the child’s psychologicaldevelopment.
Research on children in ICSI families
Cognitive development
The Bayley Scales were administered to 201 ICSIchildren at two years of age in Belgium (100) and noevidence was found of delayed mental development,although the test was administered to only one-quarterof the original sample. Similar findings were reportedin the UK from the administration of the GriffithsScales to a representative sample of 12–24-month-oldsingleton ICSI children and a matched comparisongroup of naturally conceived children (101). The ICSIchildren scored within the normal range and did notdiffer from the control group. In contrast, however,significantly lower Bayley Scale MDI scores werefound among 89 one-year-old ICSI children whencompared with 84 IVF and 80 naturally conceivedchildren, particularly for boys (98). Seventeen percent of the ICSI children experienced mildly orsignificantly delayed development (MDI <85)compared with 2% of the IVF and 1% of the naturalconception children.
Conclusion
The findings regarding the cognitive development ofICSI children are inconsistent and inconclusive, andonly very young children have been studied so far.No investigations have been conducted of the qualityof parenting or of the socioemotional development ofchildren in ICSI families.
General conclusions
Creating families by means of assisted reproductionhas raised a number of concerns about potentiallyadverse consequences for parenting and childdevelopment. It has been argued, for example, thatdysfunctional patterns of parenting may be a featureof these families due to the difficulties experienced bythe mothers and fathers in their quest for a child. Itseems, however, from the evidence available so far,that such concerns are unfounded. Parents of childrenconceived by assisted reproduction appear to havegood relationships with their children, even in familieswhere one parent lacks a genetic link with the child.
Parenting and the psychological development of the child in ART families 299
With respect to the children themselves, there is noevidence of cognitive impairment in singleton childrenborn at full term as a result of IVF procedures. Thereports of superior cognitive functioning among DIchildren have not been supported by large-scalecontrolled studies but could conceivably result fromthe use of highly educated donors. The findingsregarding ICSI children remain unclear. In relation tosocioemotional development, assisted reproductionchildren appear to be functioning well. The greaterdifficulties of IVF infants are based on maternal reportsand probably result from the higher anxiety levels ofIVF mothers. Studies of children during the preschooland school-age years generally do not indicate ahigher incidence of emotional or behavioural problemsamong assisted reproduction children.
Nevertheless, few studies have included childrenat adolescence or beyond, and little is known aboutthe consequences of conception by assisted repro-duction from the perspective of the individualsconcerned. Moreover, the existing studies are ofvariable quality. Research in this area is hampered bysmall, unrepresentative and poorly defined samples,the absence of appropriate control groups, andunreliable and poorly validated measures. In addition,there are some types of assisted reproduction family,such as families created through a surrogacy arrange-ment or through embryo donation, about whom littleis known. The practice of surrogacy, where a womanbears a child for another woman, remains highlycontroversial. There are two types of surrogacy;partial surrogacy where conception occurs using thecommissioning father’s sperm and the surrogatemother’s egg, and full (IVF) surrogacy where both theegg and the sperm come from the commissioningparents. Although no evidence of speech or motorimpairment has been found in singleton children bornafter IVF surrogacy (27) , there are no controlledstudies of the consequences of surrogacy for familyrelationships or children’s psychological well-being.It is not known, for example, how the involvement ofthe surrogate mother with the family as the childgrows up will affect the feelings and behaviour of thecommissioning mother, particularly when it is thesurrogate mother and the commissioning father whoare the genetic parents of the child. Embryo donation(sometimes described as prenatal adoption), wherebya donated egg is fertilized by donated sperm in thelaboratory and the resulting embryo placed in thewomb of the mother-to-be, raises different concerns.Unlike children conceived by egg or sperm donation,
who lack a genetic bond with one parent, childrenborn through embryo donation lack a genetic bondwith both parents. Furthermore, they lack the informa-tion about genetic parents that is usually available toadopted children. Again, no empirical investigationsof embryo donation families have yet been carried out.
It is also important to stress that families do notexist within a vacuum; the social environment in whichassisted reproduction takes place can have a far-reaching effect on family functioning. In this respectit is noteworthy that assisted reproduction parentswho were raising their children under difficultcircumstances in Eastern Europe (Bulgaria) reportedgreater problems in psychological adjustment and inthe behaviour of their children than their WesternEuropean counterparts (61). Thus the outcomes ofassisted reproduction appear to be dependent, tosome extent at least, on the cultural context in whichthese techniques are carried out.
Although existing knowledge about the impact ofassisted reproduction for parenting and child develop-ment does not give undue cause for concern, thereremain many unanswered questions about the conse-quences of creating families in this way. It is onlythrough systematic, controlled studies of representa-tive samples that the outcomes of assisted reproduc-tion for both parents and children can be fullyunderstood.
Acknowledgement
Parts of this chapter have been adapted fromGolombok S. Parenting and contemporary reproduc-tive technologies. In: M. Bornstein, ed. Handbook ofparenting, second edition. New Jersey, LawrenceErlbaum, 2002.
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84. Chase-Lansdale PL, Hetherington EM. The impact ofdivorce on life-span development: short and long-termeffects. In: Baltes PB, Featherman DL, Lerner RM,eds. Life-span development and behavior. Hove, UK,Lawrence Erlbaum Associates, 1990:105–150.
85. Hetherington EM, Stanley-Hagan MM. Parenting indivorced and remarried families. In: Bornstein MH, ed.Handbook of parenting. Hove, UK, Lawrence ErlbaumAssociates, 1995:233–254.
86. Nachtigall RD et al. Stigma, disclosure and familyfunctioning among parents of children concievedthrough donor insemination. Fertility and Sterility,1997, 68:83–89.
87. Brodzinsky DM, Smith DW, Brodzinsky AB. Children’sadjustment to adoption. Developmental and clinicalissues. London, Sage Publications, 1998.
88. Grotevant MD, McRoy RG. Openness in adoption:exploring family connections. New York, Sage, 1998.
89. Howe D, Feast J. Adoption, search and reunion: thelong term experiences of adopted adults. London, TheChildren’s Society, 2000.
90. MacCallum F et al. “Parents’ attitudes towardsdisclosure in DI families.” (in preparation).
91. Rumball A, Adair V. Telling the story: parents’ scriptsfor donor offspring. Human Reproduction, 1999,14:1392–1399.
92. Donor Conception Support Group of Australia. Let theoffspring speak: discussions on donor conception .Donor Conception Support Group of Australia,George’s Hall, New South Wales, 1997.
93. Cordray B. Speaking for ourselves: quotes from menand women created by DI/remote father conception.11th World Congress on In-Vitro Fertilization andHuman Reproductive Genetics, 1999, Sydney,Australia.
94. van Balen F. Child-rearing following in-vitro fertiliza-tion. Journal of Child Psychology and Psychiatry,1996, 37 :687–693.
95. Lutjen P et al. The establishment and maintenanceof pregnacy using in-vitro fertilization and embryodonation in a patient with primary ovarian failure.Nature , 1984, 307:174.
96. Trounson A et al. Pregnancy established in an infertilepatient after transfer of a donated embryo fertilizedin-vitro. British Medical Journal, 1983, 286:835–838.
97. Soderstrom-Antilla V et al. Health and developmentof children born after oocyte donation compared withthat of those born after in-vitro fertilization, andparents’ attitudes regarding secrecy. Human Reproduc-tion, 1998, 13:2009–2015.
98. Bowen JR et al. Medical and developmental outcomeat 1 year for children conceived by intracytoplasmicsperm injection . Lancet, 1998, 351:1529–1534.
99. te Velde ER, van Baar AL, van Kooij RJ. Concernsabout assisted reproduction. Lancet , 1998, 351:1524–1525.
100. Bonduelle M et al. A. Mental development of 201 ICSIchildren at 2 years of age. Lancet, 1998, 351:1553.
101. Sutcliffe AG et al. Children born after intracytoplasmicsperm injection: population control study. BritishMedical Journal, 1999, 318:704–705.
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103. Sants HJ. Genealogical bewilderment in children withsubstitute parents. British Journal of MedicalPsychology, 1964, 37:133–141.
Section 5
Ethical aspects of infertility and ART
Patient-centred ethical issues raised by the procurement anduse of gametes and embryos in assisted reproduction
HELGA KUHSE
Introduction
Since 1978, when the world’s first in vitro fertilization(IVF) baby was born, the world has seen a rapidlyincreasing array of assisted reproductive technologies(ART). New IVF-based techniques, such as preimplan-tation genetic diagnosis (PGD), cryopreservation, andmicromanipulation of gametes and embryos haveprovided prospective parents with a range of newreproductive options.
There are various reasons why individuals andcouples might want to resort to ART. Estimates anddefinitions of infertility vary but figures generallysuggest that around one in ten couples are affectedby infertility at some stage in their lives. Given that itis widely believed that bearing and nurturing a childis a natural and valuable part of life, those unable tohave children will often feel a sense of loss andincompleteness and turn to ART for help. In addition,particular options within ART, such as the use ofdonor gametes and PGD, can help avoid the birth ofchildren suffering from various and sometimes severechromosomal or genetic abnormalities; and freezingof gametes and embryos can provide protectionagainst disease-related or age-related loss of fertility.In short, assisted modes of reproduction can offer anumber of benefits not only to the infertile, but also,increasingly, to various fertile individuals and couples.
ART, from fairly simple artificial insemination to
intracytoplasmic sperm injection (ICSI), involves theseparation of sexual intercourse and reproduction andwill include at least one other party. In addition, in IVFand related techniques, fertilization takes placeoutside the body, making gametes and embryosavailable not only for research, but also for testing andmanipulation prior to transfer.
The advent of IVF in the late 1970s sparked intensedebate about the use of ART, and the social and legalimplications they were predicted to have. Many of thecentral ethical questions raised then are still debatedtoday, and innovations within ART constantly addnew dimensions to the debate.
I shall address myself to only a limited set of ethicalissues raised for individuals and couples who makeuse of some forms of ART, such as embryo selectionand transfer, PGD, modes of obtaining and manipulat-ing gametes and embryos, cryopreservation, gameteand embryo donation and ovarian stimulation. Whenfocusing on the users of ART, questions of individualharms and benefits, and of respect for autonomy—considerations often captured in the notion of “inter-ests”—are of primary concern. While the interests ofthose who make use of ART and their possiblechildren, are not, of course, exhaustive of all theethical issues raised by ART (there are, for example,important questions of resource allocation, of justiceand discrimination as well), the interests of thosedirectly affected by ART must be considered the
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indispensable backdrop to any adequate overallevaluation of ART.
It is necessary to make explicit two presupposi-tions on which the provision of ART must necessarilyrest: first, that assisted reproduction as such isethically acceptable; second, that IVF embryos do nothave a “right to life”. If all assisted reproduction wereethically impermissible, then there would be no pointin discussing particular forms of ART and if IVFembryos had a right to life, there would be no point indiscussing new technologies, such as embryopreselection and PGD which involve the inevitabledestruction of embryos. I believe that there are goodgrounds for accepting the above assumptions and,in the next two sections, will briefly outline argumentsin support of them.
Assisted reproduction is ethically acceptable
Some reject ART as morally unacceptable in itself, thatis, as wrong, irrespective of any of the good or badconsequences it might have; others have categoricalobjections to particular modes of assisted reproduc-tion, such as the use of donor gametes. Such principledobjections are typically based on either religious beliefor traditional assumptions about the nature ofrelationships and the role of the family.
These categorical rejections of ART are problema-tic. First, there are fundamental philosophical problemsin seeking to derive ethical principles from religiousprescriptions (1,2) and, second, it is now widelyagreed that religious belief cannot serve as a properbasis for public policies and laws in pluralist andliberal societies. To the extent that no particular visionof how we ought to live can, in the ordinary sense ofthe term, be demonstrated to be the correct one,individuals must, other things being equal, be free tostructure their own lives in accordance with their ownself-chosen values and beliefs (3).
While it is true that ART has the capacity to altertraditional ways of forming families and of individualsrelating to each other, it is not clear that this is aninherently bad thing. There is no reason to assumethat the nuclear family and traditional relationships arethe only and best way for human beings to relate toeach other and to provide a nurturing environment for
children. It may, of course, be the case that certaintechnologies within ART have the potential toproduce more harm than good; but if this were thecase, then this would provide us with good reasonsto carefully evaluate and perhaps ban those technol-ogies. It would not, however, provide us with anygood reasons to reject ART as such.
Some religious and traditional thinkers haveappealed to natural law theory in an attempt to providea more secure grounding for their moral rejection ofassisted reproduction. Natural law theory assumessome connection between what is natural and what isgood. Particular theories will usually involve either aconflation of “is” and “ought”, that is, move illegiti-mately from claims about particular natural biologicalfunctions to what is morally good; or they fail toestablish why the affirmation of a range of plausiblehuman goods must lead one to reject certain (oftensexual) behaviours, such as masturbation, the use ofcontraception and the separation of the conjugal actfrom procreationi (4,5).
Gametes and embryos do not have interestsor rights
Basic research on IVF embryos is a necessary part ofthe scientific development of ART and their safeapplication. Couples often can, and frequently do,donate surplus embryos to research. Even countries,such as Germany, that prohibit all nontherapeuticresearch, but allow IVF-related treatments, benefitfrom embryo research conducted elsewhere (6). Inaddition, various selection procedures, such as PGDof embryos, are aimed at determining which embryosshould not be transferred—and embryos that are notbeing transferred to a womb cannot at present developbeyond a certain stage.
This has led to questions—some already wellknown from the abortion debate—about the moralstatus of IVF embryos. The fundamental issue iswhether it is wrong to experiment on early humanembryos or to dispose of them when, for example, PGDshows that they are developmentally inferior orcarriers of a chromosomal or genetic condition thatwould, if implantation and fetal development were toproceed, lead to the birth of an affected child.
i The Roman Catholic Church, for example, rejects any acts that separate the procreative aspect of human intercourse fromthe unitive, lovemaking aspect of the sexual act. This leads to a rejection of not only masturbation and contraception, butalso of all ART.
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There are good reasons for rejecting the view thatIVF embryos have a right to life. An early IVF humanembryo, consisting of no more than a few cells, lacksthe capacities that could reasonably ground such aright, or provide the basis for the attribution of anymorally significant interests. Lacking a central nervoussystem, the embryo has no conscious experiences; itcannot feel either pain or suffering, exercise itsautonomy, or have any sense of its own existence. Inshort, unlike more mature human beings or animals, itcannot be harmed or benefited by anything that isdone to it. If an IVF embryo is destroyed in the courseof experimentation, or simply discarded, no sufferinghas been inflicted on the embryo; it has not beenharmed in a morally significant way and no right tolife has been infringed (7).
A human embryo is, of course, derived from thejoint genetic material of a mature woman and a manii—and women and men, in distinction from embryos,have various interests or rights. They care, oftendeeply, about what happens to their genetic materialand, in that sense, have an interest in determining whatshould happen to itiii (8).
Given that the progenitors of an embryo have aninterest or right to decide what should happen to it, itfollows that it would generally be wrong to disposeof an embryo or conduct research on it without theprogenitors’ consent. But in this case, it would bewrong to do so not because the embryo has a right tolife; rather it would be wrong because the action lackedthe consent of those who contributed the egg andsperm.
It might be said, of course, that an embryo ismorally considerable not because of what it currentlyis, but because of its potential to become a child andperson—that it is this potential which forms the basisof the embryo’s interests or rights. The debate overthe moral relevance of potential is once again wellknown from the abortion debate. New complexities are,however, raised if that debate turns from fetusesdeveloping in a woman’s womb to IVF embryos (9).Not only do early embryos have the potential tobecome more than one individual (7,10), but for anIVF embryo to have any potential at all, there must
also—in distinction from an in vivo fetus—be anadditional human intervention to activate theembryo’s potential: no natural process is already inplace that will, if all goes well, lead to the birth of achild. If an IVF embryo is not transferred to a woman’swomb, it has currently no chance of developing intoa fetus or child (9).
If one were to accept that an IVF embryo hasinterests on account of its potential, another complex-ity presents itself. Would one, then, not also have tosay that an egg and sperm, considered jointly, have arather similar potential? This can perhaps most clearlybe seen when we consider a technique, such as ICSI,where a single sperm is injected into an egg. ICSI isvery successful in achieving fertilization, and byalready having selected a particular egg and sperm wehave also already preselected the genetic complementthat will be the embryo’s. And yet, few of those whobelieve that embryos have a right to life are worriedabout the separate disposal of the egg and the spermthat could, if combined, form a unique embryo with aparticular genetic code. But if it is not morally wrongto thwart the potential of the egg and sperm, consi-dered jointly, before fertilization has taken place, it isdifficult to see why it should be wrong to thwart thispotential shortly afterwards.
If human gametes and IVF embryos do not haveinterests, either on account of what they currently are,or on account of what they have the potential tobecome, then they cannot be harmed by either destruc-tive embryo experimentation, by practices such ascryopreservation, or by being selected for pre-implantation disposal. Many people accept this. Somewould, however, want to draw a distinction betweenexperimentation on so-called “surplus” embryos, thatis, embryos initially produced with the intention ofimplanting them, and embryos created specifically fornontherapeutic researchiv (11). I find it difficult tothink of any reasonable grounds that could possiblysupport this moral distinction (12).
There is a different sense, however, in which thefact that human gametes and embryos have thepotential to develop into fetuses, babies and childrenis morally significant. If gametes or embryos are
ii This would change, of course, if reproductive cloning or parthenogenesis were to become a safe mode of reproduction, or ifeggs from female fetuses, for example, were to be used.
iii Considerations such as these may have led the Warnock Committee and subsequent drafters of policies and laws to generallyagree that consent to embryo research be required as “a matter of good practice”.
iv The Victorian Infertility Medical Treatment Act 1984, for example, prohibits the creation of embryos specifically for research,but permits experimentation on “surplus” embryos.
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damaged during experimental procedures and aresubsequently transferred, this may lead to unsuccess-ful pregnancies or the births of impaired infants. Onceagain, this does not show that it is wrong to experi-ment on in vitro gametes and embryos, or establishtheir interest in, or right to, life; it shows, however,that future children have interests and can be harmedby events that precede their becoming morallyconsiderable beings. It indicates that extreme cautionis indicated when performing experimental procedureson embryos or gametes that are destined for reproduc-tion.
Reproductive autonomy and assistedreproduction
Minimally necessary conditions forautonomous choice
I can think of no plausible ethical theory that does notregard personal autonomy or self-determination as animportant moral value. Self-determination hasinstrumental value in so far as it allows people tostructure their lives in accordance with their self-chosen values and beliefs, and is also sometimes seenas having intrinsic value. These differences need not,however, concern us here (13–16).
Ideally, health care decisions, including thoseinvolving ART, should be autonomous—an idea thatis generally captured in the notion of informedconsent. To be autonomous, consent requires, at thevery least, that it be based on adequate and accurateinformation and understanding of the potential risksand benefits of alternative courses of action, and thatit be voluntary (that is, free from coercion and undueinducement). When it comes to making choices aboutART, it has, however, been suggested, that it may bevery difficult, if not impossible, for individuals toautonomously choose to enter ART programmes.
One area that has attracted considerable criticalattention is the ambiguous and sometimes confusingway in which the success rates of various treatments,and any potential risks associated with them, arepresented to would-be parents. But if individuals andcouples do not adequately understand the relevantinformation (or are inadvertently or deliberatelymisled about potential risks and the likelihood of asuccessful pregnancy by commercially driven fertilityclinics), then they cannot autonomously consent toan ART procedure.
Success rates can be stated in various ways—forexample, in terms of a successful pregnancy test, interms of the birth of a child, or in terms of the birth ofa healthy child. In an increasing number of countries,national registers collect and publish data on theoutcomes of ART. These registers are important, butthe mere availability of data is not enough to ensureautonomous decision-making. In light of this, manyinstitutional policies, professional guidelines andlaws have recognized the need to provide accurateand understandable information to prospectivepatients, and for mandatory discussions with indepen-dent counsellors. A counsellor can help patientsunderstand the risks and benefits of particular ART,and alert them to alternative reproductive choices.
The above points about the minimally necessaryconditions for individuals to be able to autonomouslydecide for or against making use of ART apply to bothwomen and men. There are, however, significantsexual asymmetries when it comes to burdens andrisks associated with assisted reproduction (17,18) .On the basis of these asymmetries, it has been arguedthat women, in particular, cannot autonomouslyconsent to assisted reproduction (19).
Can women autonomously choose to makeuse of ART?
Invasive modes of collecting sperm present some risksto the men concerned, but in most cases, sperm canbe produced in a relatively straightforward way, bymasturbation. There is, however, currently no non-invasive and entirely safe way in which eggs can becollected from women. Moreover, prior to egg retrieval,women commonly undergo superovulation regimes toincrease the number of eggs available for collection.Superovulation methods pose their own potentialhazards, foremost among them the danger of ovarianhyperstimulation syndrome, which has been estima-ted to range from somewhere between 0.6% to aworrying 14% after IVF. In addition, there is thepossibility of adverse long-term effects. While thereis no conclusive evidence that drugs used in hyper-stimulation contribute to an increase in breast andovarian cancers in women, or to congenital orembryonic tumours, some disturbing uncertaintiesremain.
Women, not men, carry pregnancies to term. Thesepregnancies may fail, and may involve another cycleor cycles of ovarian hyperstimulation, compoundingboth the physiological and psychological risks. To
Patient-centred ethical issues in assisted reproduction 309
increase the success rate of IVF, and to decrease thelikelihood of repeated hyperstimulation, it is commonpractice to transfer multiple embryos, giving rise toincreased rates of multiple pregnancies. Multiplepregnancies pose threats to the health of pregnantwomen as well as that of their fetuses/babies. Variouscountries, professional bodies, or institutions haveestablished protocols that set limits on the number ofembryos that may be transferred, but serious problemsremain elsewhere.
Intrauterine insemination (IUI) preceded byhyperstimulation poses particular concerns becausethe number of embryos that may implant is, indistinction from embryo transfer in IVF procedures,more difficult to control. Women who carry anexcessive number of fetuses will often undergopregnancy reduction—again a procedure thatpresents considerable physiological and psychologi-cal burdens, and which may result in the loss of thepregnancy. Moreover, abortion (of healthy fetuses)is sometimes regarded as morally objectionable, andin some countries it is also illegal.
In light of the considerable burdens imposed byART on women, and the sometimes slim chances oftaking home a baby, the question has been raisedwhether women are autonomously choosing to resortto ART. The question must also be asked, of course,whether reproductive medicine, in its attempts toproduce pregnancies, is failing women. As one writersummed it up in 1987: “Looking for mothers, you onlyfind fetuses.” (20).
Pronatalism (21,22) is pervasive in many societies.Those unable to have children will frequently beregarded (and regard themselves) as worthless, andgo to great lengths in their attempts to producechildren.
The role of women has traditionally been definedin terms of bearing and nurturing children. This makeswomen, much more so than men, subject to pronatalistpressures (17–19). In light of this, the idea that womenenter assisted reproduction programmes freely hascome under considerable criticisms, particularly fromwithin feminist perspectives. While not all feministsshare this view, some feminists reject all ART on thegrounds that they bolster the prevailing under-standing of women as “fetal containers”, and thatindividual women, enveloped by pervasive pronatalistattitudes, cannot correctly be said to choose auto-nomously to have children.
But is it correct to say that women cannotautonomously decide to enter assisted reproduction
programmes? There are good grounds for a negativeanswer. While it is correct to say that women aresubject to pronatalist pressures, it is not the case, if itever was, that these pronatalist pressures are so all-pervasive as to preclude autonomous choice. Sincethe advent of serious education and employmentprospects for women, and the availability of safecontraception and abortion, an increasing number ofwomen have chosen to remain childless, to findfulfilment in a wide range of occupations and roles thatwere closed to their mothers and grandmothers.
Sadly, these options are not open to all women.Some women are constrained by patriarchal socialstructures, by lack of education and other opportu-nities, and may find it difficult to resist pronatalistpressures. Nonetheless, it is unlikely that manycontemporary women will enter burdensome and oftenexpensive ART programmes unreflectively. Thedanger that some women may not be acting freely is areason to provide extensive counselling; it is, how-ever, not a good reason for preventing all women fromaccessing assisted reproduction (17).
There must be a presumption of patient autonomy.If patient autonomy could be overridden wheneverthere is a suspicion that a patient does not fully appre-ciate the balance of risks and benefits, or is assumedto act under some kind of social coercion, then therewould be enormous scope for wide-ranging coercivepaternalistic interventions by doctors (18). As onewriter has summed it up, attempts to protect womenfrom themselves “would treat [them] as legal incompe-tents, damaging women more than unwise reproduc-tive treatments” (17).
Ethical issues raised by the use of donorgametes and embryos
Ethical parallels between sperm, egg andembryo donations
Artificial insemination by donor sperm (AID) has longbeen used to achieve successful pregnancies whenthe male partner is unable to father a child, or whenthere is a danger of transmitting a hereditary disorderto the offspring. After the development of IVF, thedonation of eggs and embryos has also become apossibility.
There are clear ethical parallels between sperm andegg donations. Like sperm, donor eggs can helpinfertile individuals achieve a pregnancy and have a
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child who is genetically related to one parent, and—again like donor sperm—can be used to avoid passingon a hereditary condition to the future child. Donorembryos, enabling a woman to go through pregnancyand childbirth, are usually surplus cryopreservedembryos from couples who have completed theirfamilies, but can also be formed from separate egg andsperm donations. Sperm, egg and embryo donationsare successful assisted modes of reproduction.
Recourse to donor sperm or eggs might be thoughtto raise problems in so far as the social father or mothermay feel less attached to a child that is not geneticallyhis/hers—a problem which could be compounded bythe use of donor embryos. But any problems relatedto this should largely be able to be overcome byadequate counselling prior to the use of donorgametes or embryos.
One of the central ethical questions relating toegg, sperm and embryo donations is whether a childconceived in this way should or should not be told ofher or his origin, and what would happen in each case.Since this issue is discussed in the chapter on“Gamete and embryo donation”, I shall comment butbriefly. Traditionally (as also in past adoptioncontexts), it was the almost universal practice to keepthe identity of both the sperm donor and the recipientconfidential. This practice has been challenged on thegrounds that the child has a “right to know the truth”,or that it is too difficult to hide the truth. Severalcountries now allow children when they reach majorityto access at least nonidentifying information abouttheir genetic parent(s). Much has been written aboutthis (and about the related issue of whether donorsshould have access to their genetic offspring), butoften in the abstract. It seems clear that ultimately onlyempirical studies about the impact of different policieson children, their genetic parents and their socialfamilies, will be able to guide us towards a soundapproach.
Donating eggs
As noted above, women who want to become eggdonors must undergo superovulation and eggretrieval procedures. These procedures involve risksand are not in a donor’s best medical interests. In lightof this, it has sometimes been suggested that womenshould not be able to donate eggs to strangers. I takea different view. While donations—to the extent thatthey do not involve substantial payments—are clearlyaltruistic and beyond the call of duty, as commonly
understood, this is hardly a sound reason for paternal-istic intervention. Egg donations are not, in principle,different from other widely accepted altruistic dona-tions, involving tissues such as blood and bonemarrow. While blood donations involve only minorrisks, the same cannot be said about bone marrowdonations, where the risks might be comparable tothose involved in egg donations.
Things may change, of course, when largeamounts of money are offered to potential egg donors.Under such circumstances, it may well be the case thatwomen entering egg donation programmes aremotivated not so much by altruism as by monetaryconsiderations. Is this always a bad thing? And couldit be argued that poor women in particular are in somesense coerced by the offer of monetary rewards? Theanswers to these questions are complex. They havelong been debated in the organ donations literature,and I shall not attempt to provide an answer here (23) .
Egg-sharing is another way in which egg dona-tions can be effected. In this case, the donor is herselfundergoing IVF procedures and will share some of herusually limited number of eggs with another woman.In this case, it may, of course, be possible that thedonor herself will not succeed in having a baby,whereas the recipient of the donor egg might besuccessful. If this outcome is known to the donor, itmay well be experienced as tragic. Provided, however,that the donor was aware of this possibility, andunderstood the possible implications, there is noobvious reason why egg-sharing should not beallowed. Once again, it would certainly not be justifi-able to seek to prevent women from donating eggson paternalistic grounds.
Given the scarcity of donor eggs and the growingpool of potential recipients, scientists have begun tolook at alternative sources for donor eggs. There aresome indications that the maturation of eggs in vitroand the transplantation of ovarian tissue may soonbe clinical possibilities. This could not only solve theproblem of egg shortages, but would also avoid theburdens now resting on egg donors. Ethical objec-tions have, however, been raised to such donations.
Alternative sources of donor eggs
Some scientists in the UK have mooted the idea ofusing, for infertility treatment, eggs and ovariesretrieved from aborted female fetuses (24). The ideathat aborted fetuses might be used in this way hasstruck some commentators as grotesque (25). But the
Patient-centred ethical issues in assisted reproduction 311
mere fact that a potentially beneficial new procedurestrikes one as grotesque or in some sense morallyrepugnant is not by itself a good reason for rejectingit.
Intuitive or “gut-level” responses to what is newand may be experienced as unnatural and in some waythreatening will not take us very far. Simple, nowwidely used and accepted IVF procedures were initiallyperceived by some as repugnant. While feelings ofunease about a procedure may sometimes alert us tosubtle ethical considerations and should make uspause, they are ultimately unreliable and any claimsto a so-called “wisdom of repugnance” (26) or thenotion of “moral offence”, must be treated with greatcaution (27,28). After all, it is not so long ago thatthe “moral offence” experienced by the contemplationof, for example, mixed-race marriages, calls for theemancipation of women, homosexual acts, had givenrise to indefensible social practices and laws.
To constitute an ethical judgement, feelings ofmoral offence and repugnance must be supported byreasons and arguments. Without such reasonedsupport, expressions of offence and repugnance haveno persuasive moral force and must be regarded asexpressing ultimately no more than personal sentimentor public prejudice.
Rather than discuss at length the question ofwhether the use of fetal tissue would be ethicallyacceptable, let us focus on two less controversialpotential sources of donor eggs—donations that havea competent donor’s consent—donations of ovariesand eggs after a woman’s death, and donations ofovaries removed during unrelated surgery.
It has been argued that the donation of gametesand ovaries is substantially different from the dona-tion or other organs and tissues and should not beallowed—ovaries and eggs, it is said, give life; theydo not, like other organ donations, save life. But, as itstands, the distinction between life-saving and life-giving donations does not provide us with a goodreason for thinking that the donation of ovaries or eggsis wrong. After all, why should it be right to save alife, but wrong to give a life? Isn’t the giving of lifewhat parents normally do when they decide to havechildren?
Nor would it be terribly helpful to claim that itwould be contrary to the child’s best interest to beconceived from an egg retrieved from a donated ovary.It may well be true that children develop their identityand self-understanding, at least in part, through theirrelationships with their biological parents and might
face some psychological and social harm if they learntthat one of their “parents” was a donated ovary, or a“cadaver”. But if one wanted to rule out ovary or eggdonations on the grounds that the future child willhave no relationship with one of her biologicalparents, then this would, given contemporary dona-tion practices, seem to rule out all egg, sperm andembryo donations from living donors as well (25).
The potential psychological harm to children whohave an unusual genetic history should not beminimized. But it should not be overstated either. Inmany cases, I suspect, children are harmed more byattempts to hide their origins from them, than byhonest timely disclosure. In any case, it is unlikely thatany potential psychological harm experienced bythese children would be so severe as to render theirlives so miserable that it would be better if they hadnever been born. And if one cannot say that a childhas been harmed by her or his conception, in whatsense, then, can one claim that eggs retrieved fromdonated ovaries should not be used “for the sake ofthe child”? (The answer is complex and I will discussit more fully below under “Should some ART bebanned, for the sake of the child?”).
Disrespect for the dead
One other point. It has also been claimed that post-mortem use of donated tissues or gametes wouldamount to disrespect for the dead and the human body(25) . Again, this argument is unconvincing. Theseemingly most plausible way of showing respect forthe dead and their bodies is to respect the wishes ofthe deceased person as to how she or he would wantto be treated when dead. This is recognized in thegeneral acceptance of organ donations. Why shouldwe depart from this principle when the organ is not aliver or a heart, but an ovary or egg? Once again, theanswer is not clear.
Postmenopausal mothers
Egg donation opens up the possibility of pregnancyin postmenopausal women in their fifties and sixties.Should older women who want to become mothers bebarred from access to ART?
It has been shown that women in their late fiftiesand early sixties can achieve successful pregnancieswith egg donations. There is, of course, an increasedpossibility that older women do not live long enoughto raise children to adulthood. But this argument
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against older women becoming mothers will hold onlyif it is applied equally to older men (seeking assistancein) fathering children, and to younger women and menwho have an increased risk of dying before theirchildren reach adulthood.
It is true that there appears to be an age-relatedincrease in obstetrical risks—both for the womenconcerned and for their fetuses. It is, however, doubt-ful that an age-related increase in risks is sufficient tojustify the categorical exclusion of older women fromaccess to ART. Younger women are not generallybarred from accessing ART, just because they havean increased obstetrical risk. And while a line wouldhave to be drawn somewhere as to what magnitudeof risk is acceptable (particularly if public funding isinvolved, and there is a substantial risk that the childwill be born damaged), such a line could not plausiblybe drawn on the basis of age alone. Some youngerwomen are clearly at greater obstetrical risk than somefit older women. Moreover, we already allow womenwho make use of ART to take substantial risks in otherregards—for example, when it comes to consentingto the transfer of multiple embryos and ovarianstimulation followed by IUI, and to the well-knownrisks associated with multiple pregnancies.
Would there be other reasonable grounds for notmaking ART available to older women?
Answers are not easy to come by. As a societywe may decide not to provide funds for some ART,but to deny available technologies to groups ofindividuals on account of their age, their marital status,sexual preferences, and the like, is often based on littlemore than medical paternalism, or individual or societalprejudice that amounts to unjust discriminationv
(29,30). While it is frequently assumed that a justifica-tion for preventing postmenopausal women, singlewomen, or lesbian couples from accessing ART canbe found by appealing to “the best interests of thechild”, this justifications has—as I have alreadyhinted above and will discuss more fully below—itsvery own problems (31).
Many other quasi-legal issues raised in thecontext of using donor gametes and embryos stemfrom a lack of public policies to regulate the practice,and from broad administrative discretions being in thehands of individual doctors. In many countries,parentage and legitimacy questions are unresolved,
and more recent possibilities, such as those raised bycryopreservation and the postmortem use of gametesand embryos, also need regulatory resolution. Suchregulatory resolutions must not, of course, rest oneither religious or conservative principle alone; rather,to be acceptable from an ethical perspective, anyrestriction of reproductive freedom must be defensibleon universalist grounds.
Preimplantation genetic assessment ofgametes and embryos
The primary aim of PGD is to prevent the transmissionof genetic and chromosomal disorders to futurechildren. The list of conditions for which PGD ofembryos and gametes can be implemented is increasingrapidly. Gametes and embryos found to be wantingwill not be transferred, and PGD on embryos mightthus be described as the in vitro alternative to in vivoabortions. Given the link between certain genetic andchromosomal abnormalities and spontaneous abor-tions, PGD can also increase the success rate of IVFprocedures. While PGD itself does not appear to haveany detrimental effects, the situation is less clear whenit is used in conjunction with ICSI.
Embryos
Those who believe that IVF embryos have a right tolife will also generally hold the view that thedestruction of an embryo on account of a genetic orchromosal abnormality or reduced developmentalpotential is wrong, and will reject PGD and otherembryo preimplantation selection procedures onthose grounds. I have argued above that there aregood reasons for rejecting the view that IVF embryoshave a right to life and will not repeat these reasonshere.
It is, however, important to spell out some of thephilosophical and ethically significant implicationsunderlying PGD. In PGD, the cell-cluster whichdevelops after fertilization is biopsied, that is, a cell isremoved from the embryo. This cell is, in an importantway, like a fertilized egg—inchoate, undifferentiatedand totipotent. A totipotent cell has the potential todevelop into a separate identical individual, or mono-
v The Victorian Infertility Act 1995, for example, restricts access to ART to married couples or de facto heterosexual couplesin a stable relationship. This restriction was recently successfully challenged by a doctor in Federal Australian Court, renderingthe Victorian legislation inoperative.
Patient-centred ethical issues in assisted reproduction 313
zygotic twin, of the biopsied embryovi (7) . This meansthat embryo biopsy might be described as artificialtwinning (the German Embryonenschutzgesetz , forexample, prohibits embryo biopsy and defines thetotipotent extracted cell as an embryo (32) ). Theoriginal embryo is preserved, while the extracted cellis tested for abnormalities. Once the cell has beentested, it is destroyed; and, depending on whether anabnormality was found during the test, the originalembryo is either also destroyed or transferred in aroutine procedure.
Totipotent embryonic cells
As previously noted, PGD has essentially the sameaim as prenatal testing, that is, to prevent the birth ofan impaired child; but there is also a difference: itinvolves the destruction of an embryo, even wherethe test results do not show an abnormality. Theembryo on which tests have been performed isdestroyed, so that another embryo can be shown tobe healthy, but destruction of healthy embryos is notsomething to which traditional prenatal testing iscommitted (33). This will not worry those who thinkthat human embryos, despite their potential to developinto persons, lack a right to life; but the implicationsof the recognition that every totipotent cell mightquite properly be described as an embryo, will orshould, of course, provide food for thought to thosewho assert that early IVF embryos (but not each ofthe embryos’ totipotent cells) have such a right to life.
The fact that early embryonic cells are totipotenthas other implications as well. It may, for example,soon be possible to cryopreserve individual embryoniccells as clones of the embryo that is being transferred.Parents, concerned with the welfare of their futurechildren, might want to store such embryonic clones,to perhaps one day provide stem cells and othertissues or organs for the child, should this ever benecessary. The potential benefits could be significant.Those who would want to reject this technology needto provide reasons for their rejection; and while suchreasons may exist, they cannot, as I argued above, befound in either feelings of repugnance, or merely inthe argument that potential human beings have a right
to life.In turning the focus from the moral status of
totipotent cells to their potential to grow into fetusesand infants, other possibilities present themselves.Assuming that it would be safe to do so, would it bewrong to artificially induce twinning, or cloning, toallow parents to have monozygotic twins? Thesetwins could be born contemporaneously, but it wouldof course also be possible to cryopreserve one of theembryonic twins, to allow a later addition to one’sfamily. Monozygotic twinning happens naturallywithout human intervention, and is seemingly alreadyoccurring as an unintended by-product of ICSI.Artificial twinning would give prospective parents thechance to increase the reproductive potential of anembryo, and increase their chances of parenthood.Reasons for the rejection of this technology are againnot easy to find. Assuming that the procedure is safe,respect for parental reproductive freedom would seemto support it, as would a focus on the interests of thepossible twinvii (28) (see below “Should some ARTbe banned, for the sake of the child?”).
Other ethical issues
Various questions remain. Most parents choose PGDto avoid the birth of an impaired child, and to avoid alater abortion. PGD is fairly accurate (97%), but thepossibility of misdiagnosis means that those who wantto achieve a higher degree of certainty will have toundergo prenatal diagnosis as well, which could turnup a positive result. This entails that some women whohave made use of PGD will have to decide after allwhether they want to abort an affected fetus. While itwould, of course, be desirable to have a 100% reliablepreimplantation test, such a test is not available, andthe fact remains that a 97% reliable test gives at-riskcouples much better odds than they would have werePGD not undertaken.
Infertile couples who make use of PGD must ofcourse be adequately informed and counselled aboutthe reliability of PGD, the possibility that other not-tested-for impairments may be present, and theburdensome and risky treatments that will necessarilyprecede PGD. If fertile at-risk couples want to access
vi Strictly speaking, it has the potential to develop into a number of different individuals.
vii It might be said that even if twinning were acceptable if the twins were to be born contemporaneously, consecutive birthsshould not be allowed, because the second twin would lack what has been termed an “open future”: there would already be aperson who is living a life with the same complement of genes, foreclosing some of the options and opportunities for thelatecomer. I am not, however, convinced that this argument is sufficient to justify the prohibition of cloning.
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PGD, they must be put into a position where they canadequately weigh up the risks and benefits ofchoosing between PGD and natural conception,followed, perhaps, by prenatal diagnosis and abortion.If these conditions are met, it seems that here, as inother areas of reproduction, the decision as to whatconstitutes an acceptable risk–benefit ratio mustprimarily be the patients’.
PGD makes sex selection possible. While sexselection is widely accepted for the purpose ofpreventing the transmission of serious sex-linkedimpairments, many people regard it as ethicallyunacceptable if done for no reason other than parentalpreference for a child of a particular sex. I do not thinkthat a restriction of the practice can be ruled out onthe basis of either the best interests of the future child,the right to life of the to-be-discarded embryos of the“wrong” sex, or on the grounds that such parentalchoices are necessarily nonautonomous. The prohibi-tion of sex selection for the purpose of satisfyingparental preferences for a child of a particular sexwould have to be justified in some other way. Apossible candidate for such a justification would bethat widely shared societal preferences for a child ofa particular sex would create an undesirable imbalancebetween the sexes.
Special ethical concerns are raised in so far as PGDmay detect diseases of which the progenitors of theembryo are not aware. This can be particularlytroubling in the case of late-onset diseases, such asHuntington diseaseviii. I shall, however, not discussthese complex questions here. They are not uniqueto PGD. Essentially the same issues are raised byconventional prenatal and other genetic diagnoses,and there exists an extensive literature on the ethicalissues surrounding disclosure questions.
It has also been said that PGD raises eugenicconcerns and discriminates against people living withthe conditions for which embryos are now beingtested, or against parents who cannot afford PGD orother genetic services. These are important issues,but far too numerous and complex to be discussed
here. Moreover, they are once again not unique toPGD, but are raised also in various other areasinvolving genetics and reproductive choices. For anydiscussion to be adequate, it would need to focus onthis wider context, not just on PGD alone (34,35).
Should some ART be banned, for the sake ofthe child?
ART in general are associated with an increase invarious obstetrical risks and birth abnormalities. ICSIand the practice of transferring multiple embryos areof particular concern.
Multiple pregnancies
In the case of ART involving IVF, the majority ofmultiple pregnancies and births are due to the practiceof transferring more than one embryo per cycle. InART involving hormonal stimulation and in vivofertilization, multiple pregnancies are the result ofmultiple embryos forming in a woman’s womb. Oneimportant difference between the two practices is thatin IVF treatments, the decision to transfer multipleembryos is deliberate, whereas the number of embryosthat will form following in vivo insemination is not, orless, predictable.
The primary reason for transferring multipleembryos is to increase the chances of a pregnancyresulting from the cycle. Multiple pregnancies arelinked to obstetric complications, and may lead to thebirth of premature or disabled infants. Evidencesuggests that risks—for prematurity, perinatal death,congenital abnormality and neurological problems—appear to increase with each additional fetus carried.On the other hand, and most significantly, thereappears to be no scientific evidence that the transferof more than two embryos enhances the likelihood ofpregnancy. If this is correct, then the practice oftransferring more than two embryos lacks an empiricaljustification. It would not only be wasting embryos
viii As an aside: Gianaroli et al. (see chapter on “Preimplantation genetic diagnosis” in this volume) assert that a predispositionto late-onset disorders would “certainly not be compatible with the interruption of an ongoing pregnancy”, while, at thesame time, holding that “the selection for transfer of those embryos that do not carry the mutation under study [and presumablythe disposal of those who do] is an additional step towards the prevention of severe diseases.” If this is an ethical claim,rather than—say—a report on what the law does/does not permit, it needs to be supported by argument. It is far from clearwhy it should be ethically sound for doctors to dispose of an IVF embryo that carries the gene for Huntington disease, butnot ethically sound for a woman to decide on the abortion of an affected fetus. If this view were to be imposed on women,this might well be regarded as a case of unjustifiable medical paternalism.
Patient-centred ethical issues in assisted reproduction 315
which might be cryopreserved for future transfer, butwould also impose needless burdens on women, andbe causally related to the birth of premature ordamaged infants. And yet, Finnström points out (seethe chapter on “Outcome of multiple pregnancyfollowing ART: the effect on the child”), few centresor countries have programmes to reduce the incidenceof multiple births. Further research is needed to findways of reducing the incidence of multiple preg-nancies following hormone-stimulated IUI, but as faras IVF-preceded pregnancies are concerned, thenumber of embryos transferred to the womb is up tohuman decisions; and what that number ought to be,must, to be ethically sound, be based on the bestavailable empirical evidence regarding the likelyoutcomes of different-number decisions.
ICSI
In ICSI a single sperm is introduced into the egg, toenhance the chances that fertilization will occur, or tomake it possible at all, particularly in cases where thesperm is known to be deficient in some way. ICSI issometimes combined with oocyte activation, to bringabout fertilizations that cannot be achieved by ICSIalone.
Both ICSI and oocyte activation raise a numberof concerns. One concern arises from reports that therisk for monozygotic twins and for monozygousmonochorionic twins (identical twins that share thesame chorion) may be higher in the case of ICSI andother zona manipulation techniques. Monochorionictwinning in particular seems to be linked to low birthweight and poorer health and survival of infants. Ageneral concern is that ICSI and related technologiesremove natural barriers and allow fertilization bysubfertile and genetically dubious or deficient spermto occur. The latter fact is thought to explain, at leastin part, sex chromosome abnormalities in offspring.The outcome of using immature testicular sperm isuncertain.
It is sometimes said that in light of the increasedhealth-related risks that ART children face vis-à-vistheir normally conceived counterparts, prospectiveparents should not make use of ART, because to doso is contrary to the best interests of the child. Similararguments are frequently put to back up claims to theeffect that the use of donor gametes should bebanned, or that ART be restricted to married or de factoheterosexual couples “for the sake of the child”.
Are these arguments sound? An attempt to
answer this question raises some of the most complexquestions in philosophical ethics. Space allows me toprovide but a sketch of how such an answer mightproceed.
Harming possible children
The problem of harm in preconception cases is trickybecause, in distinction from individuals who alreadyexist, the child whose interests are at issue is merelya possible child, and when a possible child is broughtinto existence with the help of ART, it is far from clearthat the child has been harmed, even when she or heis worse off relative to a child conceived by normalmeans.
To illustrate the general point, imagine thefollowing scenario involving unassisted reproduc-tion:
A woman is advised by her doctor that sheshould not become pregnant now becauseshe has a condition that is certain to resultin a slight mental impairment in her child.There is a safe and effective medication thatcan cure the condition; if she takes themedication and waits three months beforeattempting a pregnancy, the risk of the childbeing mentally impaired will have beeneliminated and there is every chance that herchild will be normal (36).
Common sense morality holds that the womanought to postpone her plans to become pregnant.Many people would think this even if the impairmentof the child were not so severe as to make the child’slife utterly miserable. They would think that if thewoman did not wait, she would needlessly be harmingher child.
But in distinction from situations where an alreadyexisting individual is harmed after conception or birth,discussions of alternative reproductive choicesinvolve what has been called the “nonidentityproblem” (36). If the woman were to decide againstwaiting, she would be conceiving a different child fromthe one she would conceive if she were to wait. Thechild would be conceived from a different egg andsperm than the later child. The difficulty is that in acase like this, there seems to be no child that has beenharmed—for while the first child would have a mentalimpairment, she or he would have a subjectivelyworthwhile life. But if this is so, then it does not make
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good sense to suggest that it would have been betterfor the impaired child if the impairment had beenprevented—for that could have been done only bypreventing the child’s existence. And given that thechild has a subjectively worthwhile life, the womancannot be said to have harmed the impaired child byhaving brought her or him into existence.
The same kind of reasoning applies to variouspreconception reproductive choices involving ARTwhere there is an increased risk to the childrenconceived of physical or mental impairment, or ofpsychological or emotional problems. To be able tospeak about these different undesirable outcomes ina general way, I want to refer to them for now as“making the child worse off”.
Next, to allow us to focus on the central issuesinvolved, assume the following: that ICSI is the onlyway in which men with round-headed sperm can fatherchildren. Unfortunately, all children conceived fromround-headed sperm will suffer repeated bouts ofdebilitating depression, but are otherwise normal andregard their lives as worth living.
Men who produce only round-headed sperm andwant to embark on parenthood with the help of ARThave two main options: father a child with their ownsperm, or use donor sperm. While any child producedwith the man’s own sperm would experience bouts ofdepression, a child conceived with donor sperm wouldpredictably be healthy. A man in this situation, andhis wife, decide to conceive a child with the man’sown sperm. Although the couple knowingly bring achild into the world who will be worse off than thealternative child they could have had, the child’s lifewill be worth living. If the couple had chosen to usedonor sperm, they would have had a different child.
Someone might say that the couple’s decision touse the husband’s abnormal sperm was wrongbecause it failed to take the best interests of their futurechild into account: it would have been better for theirchild if it had been conceived with donor sperm. Butjust as in the case of the woman who refuses to waitfor three months before she attempts to becomepregnant, the couple’s decision to use abnormalround-headed sperm cannot be criticized on thegrounds that the child conceived from the abnormalsperm is worse off, or has been harmed, by theparents’ decision. It is better for the child conceivedwith the abnormal sperm that she or he lives ratherthan not live at all.
If one wants to criticize the decision as wrong, oneneeds to abandon what has been called a person-
affecting view of benefiting and harming and focusinstead on the harms and benefits resulting fromalternative reproductive choices that involve theexistence of the same number of people. From such anonperson-affecting view of benefiting and harming,it is, other things being equal, wrong to bring childreninto the world who are worse off than those who couldhave lived instead (37).
The nonperson-affecting view of benefiting andharming avoids the nonidentity problem, and can thusexplain why it would be wrong for the above coupleto use the man’s abnormal sperm rather than donorsperm. It might seem difficult, though, to square thenonperson-affecting view with the principle ofreproductive autonomy. Reproductive autonomymight be thought to license reproductive decisionsthat a nonperson-affecting view of ethics wouldcondemn. But there need not be any conflict here.Neither the principle of reproductive autonomy northe ethical requirement that we avoid nonperson-affecting harm can properly be understood as anabsolute. Rather, both considerations are best seenas being constrained by a principle of equality orjustice that gives equal consideration to the benefitsand harms, or interests of those immediately affectedby the decision—that is, to the interests of theprospective parents and any dependants they mightalready have, as well as the interests of the possiblechild. A principle of this kind would regard as wrongany reproductive choice that would make a possiblechild seriously worse off than an alternative possiblechild, when the prospective parents could haveconceived the alternative child without imposingundue burdens on themselves or any dependents theymight have (38).
This raises the obvious need to say what consti-tutes an “undue burden” for the parents. Some peoplewould, no doubt, regard it as an undue burden toforego having genetically related children and thinkit justifiable to risk making their future childrenseriously worse off. I am not, however, convinced thatwe should leave it at that. People sometimes fail todistinguish between having children, and havingchildren that are related to them. One reason forwanting children is to nurture, love and cherish them,to see them grow and develop their own personalities,and to set their own goals in life. Other reasons mightbe based on the desire for companionship, connected-ness to the next generation, or concerns aboutloneliness, particularly in old age. These and similarreasons for wanting children could undoubtedly be
Patient-centred ethical issues in assisted reproduction 317
satisfied by children to whom one is not geneticallyrelated. Some people would, however, also think it isimportant to have genetically related children becausethey see these children as perpetuating the family, ascarrying on the blood line, or as conferring some kindof immortality through the survival of genes. Thesereasons for having children may well be nonrational(39) and counsellors would, I believe, do well if theytried to talk prospective parents out of making suchnonrational choices in cases of substantial geneticrisk. While genetic counsellors are normally trainedto be nondirective, I take the view that it cansometimes be wrong for prospective parents to act inways that pose a substantial risk of harm for theirpotential children. If that is the case, nondirectivenessmay have to be abolished, for “the sake of the child”.
Counsellors will not always succeed. There arecurrently no public policies that insist that people’sunassisted reproductive choices meet the strict moralstandards of the nonperson-affecting view. Rather,people are free to have children with whom they likeand when they like. They do not need a licence toreproduce and will sometimes make choices that arenot for the best—and they will make these choicesfor seemingly trivial and nonrational reasons. Shouldattempts not be made to limit such decisions whenART are involved? But there is a problem: what mayappear to be a trivial reason for one person may wellbe a nontrivial reason for another—given thatperson’s values and beliefs. In such cases, reproduc-tive decisions that risk making a child worse off could,at least sometimes, be justified in terms of the parents’own projects, values and attachments. Religious orcultural belief in the wrongness of using donorgametes could, I reluctantly concede, sometimes besuch a justifying reason.
This is where the distinction between privatemorality and public policy can be seen to be important.Ordinarily, each person is best able to determine whatconstitutes a justifiable or an unjustifiable alternativereproductive choice, given that person’s projects,values and beliefs. As the abortion debate has madeabundantly clear, what is an unacceptable choice forone person may well be an acceptable choice foranother. It is difficult to see, however, how publicpolicies could ever be so finely nuanced as to distin-guish adequately between reproductive decisions thatwould be justified or unjustified in a particular caseon the basis of a nonperson-affecting view ofbenefiting and harming. I fear that the attempt tointroduce such coercive restrictive policies in the case
of ART would have worse consequences, other thingsbeing equal, than granting prospective parentssubstantial reproductive freedom.
Fortunately, the vast majority of parents will goto great lengths to ensure that any child that will beborn to them will have a good chance of being healthy.Some lines must, however, be drawn: strong groundswould exist for denying reproductive assistance toparents who are intent on bringing a child into theworld whose life would be so utterly wretched that itwould be better if the child had not been born, orwhere the child would be at substantial risk of seriousharm.
Clearly what is meant by it being better that a childnot be born, and what constitutes substantial risk ofserious harm, must be the subject of further discus-sion. Suffice it here to note that any acceptableanswer would have to be based on both the likelihoodof the undesirable outcome and its severity. If theundesirable consequence is very bad, then even asmall risk of that outcome eventuating would give usstrong grounds for preventing prospective parentsfrom being assisted in implementing their reproductivechoice; if the undesirable outcome is not so severe, ahigher statistical likelihood of the outcome eventua-ting would seem acceptable.
These general considerations need to be backedup by empirical data on the relative risks of the variousART, and what they amount to in particular patient-specific contexts and practices. ICSI, for example, maybe relatively safe in the case of some sperm abnormali-ties and unacceptably risky in others.
Reliable empirical data on the risks and severityof the potential psychological or emotional harmexperienced by people conceived with the help of ARTare also needed. But here the issues are, I believe,somewhat different from those pertaining to seriousphysical or mental damage. Emotional and psychol-ogical harm can, I believe, often be avoided by beingtruthful to one’s children about their origins. But evenif some children conceived by, say, donor eggs andsperm were worse off than their naturally conceivedcounterparts, I find it difficult to believe that thiswould offer sufficient grounds for preventing parentswho cannot, or for good reasons do not choose to,have children by making use of their own gametes.Little can be done about physical and mental damageonce it has occurred; but much can be done to preventemotional and psychological harm. In cases wheresuch harm cannot be prevented, it is unlikely that itwill be so all-pervasive as to prevent the person from,
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nonetheless, being able to lead a satisfactory life.
Conclusion
My primary focus has been on individuals who maywish to make use of various novel ART, and on thechildren they hope to conceive. In this context, someof the central unanswered questions relate to the highvalue placed on genetic parenthood, and on the kindsof risk that it is justifiable for prospective parents totake on behalf of their possible children. Other ques-tions relate to finding reasonable grounds for limitingthe novel uses to which individual ART, in theirseemingly endless permutations, may be put. It isdifficult to find such grounds in the principle of respectfor autonomy and the claim that certain applicationsshould be restricted “for the sake of the child”. If suchgrounds exist, then they are likely to be found in awider consideration of issues, such as the equitabledistribution of limited medical resources and ques-tions of justice.
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320 SIMONE BATEMAN
When reproductive freedom encounters medical responsibility:changing conceptions of reproductive choice
SIMONE BATEMAN
Introduction
Sex is no longer the only means of conceiving humanbeings. Ever since artificial insemination was first usedtwo centuries ago, a pregnancy can be obtainedthrough the use of techniques generally referred toas reproductive technologyi. These techniques havecreated new options for persons who would otherwisenot have had children, but they have also progres-sively altered the practices and relationships thatcondition and give meaning to reproduction in oursociety. This is primarily because reproductivetechnology is most often made available in a medicalsetting, where relationships are defined in therapeuticterms, where values give precedence to the quality,security and efficiency of a technical act, and wherephysicians are held responsible for the appropriatemanagement of procedures. Impregnation no longerhas to do with the privacy of one’s sex life, but withthe accomplishment of a medical act. This turningover of conception to professionals deemed compe-tent in reproduction leaves some would-be parentsdisoriented and even feeling dispossessed of theircustomary (often felt to be “natural”) liberty to makereproductive decisions (1).
Reproduction is today firmly established as anarea of legitimate medical intervention; we mustremember, however, that the presence of a (usuallymale) physician at childbirth dates back in WesternEurope to only two centuries—a presence whose soleinitial justification was the medical monopoly of a newinstrument, the forceps, designed to facilitate difficultbirths. More recent techniques and procedures in thearea of obstetrics and gynaecology, such as contra-ception, abortion, the monitoring of fetal growth ortesting for fetal abnormalities during pregnancy, havesince helped solidify physicians’ claim to professionalcompetence in this domain. Nonetheless, most of thesetechniques have given rise to much controversy: theidea that it is legitimate to control or interfere withconception and gestation, even under medicalauspices, is far from being a consensual issue in manysocieties.
In most countries, assisted reproduction tech-nology (ART) was originally introduced to treatinfertility. Today it is also being offered to fertileheterosexual couples as a means of avoiding the riskof transmitting hereditary disease to their offspring.Both of these circumstances are generally recognizedas legitimate indications for treatment. Occasionally
i This term can be applied more generally to include all kinds of techniques, including contraception and abortion, whosepurpose is to control or otherwise intervene in the reproductive process. In this paper, we are restricting its use to designateonly those techniques whose ultimate objective is to initiate a pregnancy.
Changing conceptions of reproductive choice 321
fertile heterosexual couples have resorted to ART asa solution to unusual circumstances (such as coupleswishing to select a compatible embryo as an organdonor for a living child) (2). Single women and lesbianshave also used donor insemination (DI), usuallywithout medical assistance, as a valid alternative tosex for conceiving children. These latter uses of ARTremain morally controversial in many countries. Butwhether or not an infertility problem exists, thequestion of medical responsibility will invariably beraised whenever a physician is asked to intervene.
Most societies grant physicians considerableauthority in deciding what is to be regarded as thebest way of implementing a medical procedure; theythus play an important role in defining the values thatguide the use of new technology. However, medicalreproductive and related genetic practices areprocedures whose immediate objective (conceiving achild) and ultimate consequences (demographic,psychological, economic, etc.) are not normallyincluded in the usual scope of a physician’s profes-sional competence and responsibility. A physician’sinvolvement in a patient’s choices about sexuality andchildbearing quite obviously bring into play a broaderscope of values than those immediately linked to theprofessionally responsible practice of medicine—values usually embodied in moral convictions regard-ing what constitutes a “good” life in terms of sexualityand procreation, family life, health and handicap. Thelegitimacy of medical authority in this domain maytherefore be open to question, creating possibilitiesfor conflict with conceptions of reproductive liberty.
Reproductive liberty (3) can be defined as thefreedom to make essential choices affecting one’sreproductive life. A major decision involves choosingwhether or not to have children which, in the case ofan affirmative answer, implies decisions concerningwith whom, when and in what circumstances. Ofcourse, having children is not necessarily the resultof a conscious decision-making process: socialpressure, interpersonal conflict and personal ambival-ence often interfere with complex biological processesnot totally under our control, making the final resultof our reproductive lives quite different from ouroriginal plans. A couple’s decision to have a child byno means guarantees that they will ultimately haveone, even when they appeal to medical assistance.Nonetheless, the development of techniques thepurpose of which is to increase control over theconsequences of our sexual lives and the differentaspects of our reproductive decisions—whether or
not, with whom, when and in what circumstances—has reinforced the idea of reproduction as a projectand a consciously controlled process.
But this increase in control paradoxically requiresentry into a new type of reproductive relationship,loosely if not inappropriately defined as therapeutic.Infertility is not strictly speaking a disease: it iscertainly a personal and social handicap for the personwho is thus affected, but it is not a life-threateningdisease. Moreover, the concept of infertility whichunderlies current use of reproductive technology is apeculiar construct, in which medical and social criteriaare closely interrelated: it describes as unable toconceive, not a person with a medically proveninfertility problem, but two particular persons—acouple—who are unable to conceive a child together,because one or both are infertile. Treatment, however,invariably concerns the woman, even when she is notinfertile, as she is the child bearer. Both DI andintracytoplasmic sperm injection (ICSI) make thispoint particularly clear: the procedure is carried outon a fertile woman, who could have become pregnant,had she chosen to do so, by having sexual relationswith another man. In fact, infertility is a relativeconcept whose limits are difficult to define: very fewpatients are diagnosed as completely sterile, and aperson diagnosed as infertile might have been able toconceive, had he/she found a more fertile partner.
The fact that infertility is not a disease does notmean that physicians should not try to treat thecondition. But assisted conception cannot beconsidered a cure for either male or female infertility:neither artificial insemination nor in vitro fertilization(IVF) enable their infertile beneficiaries to conceive achild on their own. In fact, although these techniquesare commonly presented as medical treatment, theyconstitute an evident deviation from the standardapproach to healing. Medical treatment aims, whenpossible, at identifying and eliminating the cause of apathological condition: this may be the case in the firstphases of an infertility work-up and treatment. Whendiagnosis has failed to determine a cause, or treatmentto provide a cure, a physician can attempt to eliminateor alleviate the symptoms of a disease by some formof palliative treatment. Assisted conception doesaddress infer-tility’s primary symptom, the absence ofa viable pregnancy, by replicating a defective functionit cannot cure. This, however, creates a totally un-precedented therapeutic position in that the immediatemedical objective goes beyond the alleviation ofsuffering: the aim of reproductive technology is to
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conceive a human being.Medical assistance with conception thus consists
essentially in providing technical expertise in fertiliza-tion and impregnation, a task that transformsphysicians, so to speak, into professionally competentreproductive partners. As such, they find themselvescalled upon to intervene in many crucial procreativedecisions. These choices and decisions are all themore difficult to make, in that the facts that inform themare still being accumulated or exist only as probabili-ties. Moreover, the complexity of the therapeuticrelationship, to which must be added the problemsraised specifically by the physician’s involvement ina reproductive act, concur to create potential forconflict in which it may no longer be evident who, inthis novel reproductive framework, should be makingfundamental decisions about the coming into exist-ence of a child. Should they be made by those who,as professionals, carry out fertilization andimpregnation; by those who, as donors, contribute thereproductive cells; or by those who, as future parents,will ultimately assume responsibility for the child tobe born? Deciding who will decide in case of dis-agreement may involve weighing the physician’sresponsibility for the safety and the favourableoutcome of the procedure against the patient’sfreedom to make reproductive choices.
Many would-be parents do not consider itnecessary to justify their request for assisted concep-tion: the reasons they wish to have children and theconditions in which they intend to raise them concerntheir private life. But numerous physicians feel that,given their responsibility as professionals, theyshould refuse or discontinue assisted conception, ifthey consider that the conditions in which the childis to be born are unacceptable. When would-beparents do not acquiesce to the physician’s point ofview, a conflict arises which usually leads to attemptsat arbitration: in France, this usually means theintervention of a psychologist, referral to an ethicscommittee, or recourse to a legal procedure (4).
Conflict may arise over questions of access toreproductive technology, in particular with respect toatypical requests for reproductive technology. Buteven in more conventional situations, there may beconflict over the procedure considered most appro-priate, or over the best solution to unforeseen conse-quences of an otherwise consensually decidedprocedure. Even though physicians, would-be parentsand even donors (5) are all apparently endeavouringto achieve the same goal—the birth of a child—there
may be significant differences in the way eachprotagonist approaches this goal. Regardless of thedifferences among protagonists involved in a conflict,their respective positions often highlight a concurringmoral preoccupation: in what physical and socialconditions is it acceptable to bring a child into theworld? Both physicians and would-be parents, injustifying their viewpoints, frequently refer to a child’sbest interest. This emotionally charged notion rarelyconveys a precise content or meaning, although itdoes eventually serve to articulate normative concernsabout a child’s future. Ultimately, the various versionsof this argument reveal competing visions of theperson, the family, and of life in society; their impacton the future of childbearing will depend on thepriorities established among these arguments asconflicts are resolved.
Deciding to have children
One of the main points of conflict between would-beparents and professionals—and usually a major issueon the political agenda—is the type of situation inwhich reproductive technology may be legitimatelyrequested. Generally speaking, there are two sorts ofrequests. The first usually comes from heterosexualpartners who, unable to achieve a viable pregnancy,seek medical help. Assisted conception is offered inthese cases to compensate for a couple’s physiol-ogical incapacity to reproduce, thus bringing society’ssupport to the conventional (often perceived as the“natural”) means of founding a family. The secondtype of request, more controversial but arising fromthe very existence of these techniques, comes frompersons who do not wish to entertain heterosexualrelationships (single, divorced or widowed men andwomen, gay and lesbian partners), but who nonethe-less wish to have children. Providing assisted concep-tion in these circumstances recognizes as legitimatethe wish for descendants of those who refuse marriage,partnership or heterosexuality as a way of life and asthe only suitable framework for raising children.
In many countries, only the first type of requestis considered a socially legitimate reason for accessto reproductive technology. Indeed, the whole notionof infertility treatment has been constructed aroundthis indication. And yet, despite apparent differencesbetween these two types of request, they do seem tohave three points in common: (i) the wish to avoidsexual relations considered personally, socially or
Changing conceptions of reproductive choice 323
morally unacceptable and the emotional complicationsthey might entail (fidelity to one’s partner appears asa common concern); (ii) the wish to overcome thelimitations imposed by one’s personal and sexualpreferences, in particular that of having chosen aninfertile partner or form of relationship; and (iii) thewish for a child of one’s own , understood as a childemanating from the would-be parents’ body and/orgametes. These three points often justify the first typeof request, but in many countries, they ofteninvalidate the second. But if they are consideredproblematic in one case, why is this not true in theother?
The distinction between appropriate and inappro-priate requests evidently uses the fecund sexualrelation between a man and a woman as the normativemodel of procreative behaviour—a model thatsupposedly refers to a “natural” order of procreation.In France, article L. 152-2 of the French 1994 bioethicslaw draws on this model, as well as on the social valueattached to voluntary procreation within a stablerelationship, to establish, apparently without ambi-guity, the conditions in which assisted conception maylegitimately be provided:
The purpose of assisted conception is torespond to a couple’s request to becomeparents. Its objective is to remedy infertility,the pathological nature of which has beenmedically diagnosed. It may also be used toavoid transmitting a particularly seriousdisease to a child. The man and the womanwho form the couple should be alive, be ofreproductive age, married or able to prove atleast two years of cohabitation, and theyshould give previous consent to the transferof embryos or to insemination.
[my translation]
The attempt to anchor the legitimacy of assistedconception on the supposedly natural norms of humanreproduction (participation of two live persons ofdifferent sex and of reproductive age) disregards themanner in which society intervenes to redefine whatis natural in humans. To give an example, the age atwhich it is physiologically possible to have childrendoes not necessarily correspond to the age at whichit is considered socially acceptable to have them. Aphysician would probably not offer assisted concep-tion to an infertile adolescent couple. The biologicalnorms of reproductive capacity are always reassessed
in the light of social norms defining the aptitude tobecome a parent. Even a distinction as biologicallyevident as morphological sex differences can turn outto be an ambiguous criterion, in the rare cases in whicha person has an anomaly of the sexual organs or hasundergone hormonal and/or surgical transformationof his/her sex. Sexuality itself is reduced, in thisperspective, to its species-oriented function: repro-duction.
Legislation thus conceived aims to exclude allnormative options that might define assisted concep-tion as anything other than an exceptional venturingaway from the “normal” ways of founding a family.The use of reproductive technology as a procreativealternative to sexuality is perceived as too radical anoption, with unknown social consequences. And yetthe very notion of what constitutes a family hasalready been profoundly affected by the increase indivorce and remarriage, by the growing number ofnon-married couples and of same-sex unions. RecentUSA census data (6) indicate that less than a quarterof the households are made up of married couples withchildren, whereas the number of families with childrenbut no spouse present are increasing, a trend whichis now much advanced and well established inEuropean countries. Procreative plans and behaviourhave also undergone considerable change with accessto earlier forms of reproductive technology, such ascontraception and abortion. And single women, gaysand lesbians did not wait for reproductive assistanceto have children: many made special sexual arrange-ments to achieve their purposes and invented newforms of parental relationships with their children (7) .Of course, DI has contributed in making theseprocreative possibilities seem more attractive, parti-cularly to those who wished to dispense withopportunistic sexual relations. And some procreativeoptions were not possible as long as conception tookplace entirely within the body. Indeed, IVF now allowsfor heretofore unimaginable dissociations of thereproductive process: the possibility for two separateforms of biological motherhood (8), the separategestation and birth of embryos conceived at the sametime, reproduction with only one or with three sourcesof gametes (9,10) . But many changes in thecontemporary family cannot be attributed to theseprocreative innovations.
The family has never been a natural unit; nor canit be considered the social expression of the biologyof reproduction. Family forms have varied consider-ably through time and space, and, in many societies,
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socially and legally sanctioned kinship relationshipsdo not necessarily reflect the biological ties betweenpersons. In many contemporary societies, it is truethat the legal ties binding the spouses in a marriageusually carry with them the expectation that thespouses will also be the genitors of the children bornto that marriage. This expectation has for centuriesrested on the moral value of sexual fidelity. But whatinstitutes the parental tie is a legal act, and not abiological one: even when a society decides to giveprecedence to biological ties in establishing parent-hood, this is a social decision with its correspondingjustifications and not an imposition on society of anincontrovertible biological fact (11) . Of course, asknowledge accumulates about the facts of reproduc-tion and heredity, our own societies may be attributingan increasing importance to biology in their thinkingabout the family. The tendency is then to confusescientific truths about conception and heredity withthe social and legal organization of family ties and theemotional and physical experiences underlying thequest for children. As biological metaphors andmetonymies for kinship relationships flourish,evolving from the outmoded notion of blood ties tothe more scientifically modern notion of genetic ties,we forget that these expressions only signify a morecomplex whole.
Given that humanity has known so many familyforms and been so inventive in finding solutions tothe lack of descendants, it is difficult to give credenceto the idea that the “traditional” family is in danger.The traditional family may simply be a normative idealthat uses the nuclear family as a landmark to providesocial bearings in times of disquieting change. Thedisadvantage with this approach to innovation is thatit defines outright all novelty as unethical or unsafe,while disregarding what may be morally questionablein familiar circumstances. Even if unprecedentedoptions disrupt our usual social and symbolic land-marks in thinking about procreation and the family,they do not, for that reason, threaten our humanity.They do make it vital to rethink the anthropologicalfoundations of procreation in the light of new options.
Whether science and technology represent athreat to family relationships and to social stabilitymay have more to do with our reasons for imple-menting these new techniques than with the idea thatwe may, unwittingly, be destabilizing natural humanphenomena. The risk of interfering with and destabi-lizing biological mechanisms is real and should not beminimized, but it is a scientific issue in its own right,
related but separate from the issue concerning the waya society deals with limitations imposed to humanaspirations by the body and by the environment. Thebest way to approach the ethical issues concerningthe effects of reproductive technology on children andtheir families may be to examine, not hypotheticaloptions, but those already available and consideredacceptable, with the unforeseen problems they raise.We may not have sufficiently explored and understoodthe novelty of familiar situations and, in particular, therole medicalization plays in that novelty. Some of theseissues may have an effect on the family and onprocreation that is more profound than is immediatelyevident: in fact, we may have already gone beyondthe controversial issue of whether or not persons inunconventional family situations should usereproductive technology to have offspring. The waydecisions are being made about current difficultiesmay give us clues to underlying trends, and thus tothe social choices we are really making.
At first glance, occasions for conflict in situationswhere the persons being treated are an infertileheterosexual couple appear to be less frequent andless radical. There are nonetheless numerous examplesillustrating that, even in the most conventionalindications, unforeseen incidents can create difficultethical dilemmas. I speak of dilemmas purposely, in thatmany of these situations seem to have no bestsolution: they either open a choice between twoequally unknown possibilities, or offer an optionbetween familiar but inadequate normative referencesand novel references whose normative pertinence isas yet unknown.
Not all issues underlying decision-making in thisarea can be handled within the confines of thetherapeutic relationship. Some may ultimately call fordiscussion and decision-making at a political level, theresults of which will be diversely affected by thepertinent social, cultural and economic context inwhich a reproductive procedure is being introduced.In other words, at the heart of the moral issue thatinvolves choosing the best solution for all theprotagonists involved, is the social issue of decidingwhat is the best framework for ensuring the desiredoutcome.
Avoiding harm and taking risks
No matter how conventional the familial situation ofthose who request procreative assistance, reproduc-
Changing conceptions of reproductive choice 325
tive technology involves would-be parents in un-precedented ways of engaging their sexuated bodiesin a procreative relationship. Reproductive experienceis dismembered and extended in time and space,especially when conception is externalized. Thismultiplies the number of reproductive events callingfor decision-making, and thus the occasions forunforeseen incidents and conflict. The personsdirectly involved in the conception of a human beingare also more numerous: they are not only the would-be parents, but also the professionals technicallycompetent in reproduction and eventually the donorsof reproductive cells. If all the protagonists share amoral obligation to act rightly with respect to them-selves and to others, those intervening as specialistshave an added obligation to provide care meeting thestandards of the profession.
Ensuring the quality of medical attention providedto patients requires a translation of this generalprinciple into concrete technical choices. In strictlydefined therapeutic situations, these choices usuallyreflect a consensually defined approach to diseaseprevention, in harmony with professional standardsand guidelines for a particular act; they also ideallyreflect the medical staff’s basic ethical stance ofbeneficent action in caring for patients. In the case ofreproductive technology, physicians additionallycontrol access to essential technical and biologicalresources that make fertilization possible in a medicalsetting; they thus exercise discretionary powers inbasic reproductive decisions, in particular in caseswhere procedures require choosing an appropriatereproductive partner—an egg or a sperm donor. Thereis still much discussion among physicians concerningthe criteria on which these choices should be basedand the responsibility associated with the conse-quences of these choices.
Concretely, questions about medical responsibi-lity usually arise in situations which involve risk-taking, and in which the protagonists hold differingviews of what constitutes an acceptable risk in thelight of expected benefits (12–14). In reproductiveprocedures, eventual risks first concern the woman’shealth, as she is the primary patient. As such, manyquestions raised by conflict between conceptions ofprofessional responsibility and of patient autonomydo not differ essentially from those raised in atraditional therapeutic situation. But as mentionedearlier, infertility is not a life-threatening disease, noris assisted conception treatment for infertility. Failureto intervene cannot be said to endanger the woman’s
health, as might be the case in some routine therapeu-tic circumstances, whereas there may be importantrisks in undertaking the procedure. Many forms ofassisted conception are physically and emotionallytrying experiences for women; they do not alwaysresult in a live birth, or may do so only after repeatedattempts. Many women may, nonetheless, feel thatnot having access to the procedure at all couldprovoke personal distress that is just as serious.
What makes matters even more complicated is thefact that medical concern with risk-taking in reproduc-tive procedures tends to include an, as yet, non-existent third party, the unconceived child. Shouldprofessional responsibility for the competent manage-ment of a reproductive procedure be guided by theendeavour to do anything more than simply avoidprocedures harmful to the woman’s health and life?The question is raised acutely in cases where there isa risk that the child will be born with a serious disorder.When such a risk is inherent to the procedure, it is inmost cases relatively uncontroversial to stop provid-ing it. But when the risk for harm derives from themedical and the social background of the genitors, themedical stance considered most appropriate is far fromconsensual.
Establishing a medically appropriate response toa person’s request for assistance with conception maybe approached either as a question regarding legallydefined medical responsibility or as a broader concernwith moral responsibility. From a legal perspective, aphysician in normal therapeutic circumstances isobliged to propose the necessary means to restorehealth, but is not held responsible for the outcome oftreatment, if the procedure has been performedcorrectly. In certain situations, physicians occasion-ally experience these minimal legal requirements asinsufficient from a moral perspective. In the case ofassisted conception, physicians may even feel thatthe reverse relationship is true: physicians should notbe obliged to propose systematically the means ofconceiving, but may be held responsible for theoutcome (12–15).
In both perspectives, the fundamental questionremains the same: in so far as reproductive technologyis not, strictly speaking therapeutic, what criteriadefine the competent and responsible enactment of areproductive procedure? An answer to this questionrequires agreeing on what is the outcome of thatprocedure. The immediate objective is a viablepregnancy, for as long as this objective is not attained,the procedure will be repeated. There might however
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be a limit to the number of times a procedure may beattempted, without harm to the patient. But when theprocedure succeeds, does the physician’saccountability stop there? Or is the physicianultimately responsible for the state in which the childwill be born? If the latter is the case, to what extent isthis true? Quite obviously, different definitions of theoutcome of a procedure affect working conceptionsof appropriate action.
Three recurrent dilemmas are encountered byphysicians in routine practice. These dilemmas oftenoblige them to reconsider the assumptions on whichtheir practice is based. In many cases, the dilemma willfirst arise as a technical problem requiring a profes-sional response, but as physicians try to solve it, thesocial and ethical significance of the problem comesto the surface. In some cases, they become a sourceof conflict with patients. Their immediate solutiondoes not seem to involve finding a right answer, butreaching an agreement among all concerned as to howthe priorities in decision-making will be distributedthroughout the procedure. This implies identifying thepossible consequences on the child and the family ofeach solution and on whom the responsibility for theseparticular consequences will rest. The three dilemmasare as follows.
1. In what circumstances is the transition fromsexuality to assisted conception justified?
This problem arises in routine practice with both fertileand infertile couples. In the case of infertile couples,the question essentially involves deciding when oneshould consider that treatment of infertility has failedand that it is legitimate to go on to offer palliativesolutions, such as assisted conception. One exampleof such a dilemma is choosing whether or not to try acurative option such as microsurgery of blockedfallopian tubes, which may not succeed, or go on tothe palliative option, IVF. Another is whether or nottherapeutic action should be delayed, such as in casesof low fertility where there is a statistically significantchance that a couple might conceive. Medicalattitudes vary with respect to this problem: some willpersist in delaying treatment or attempting curativesolutions if the chances for success seem reasonable,on the basis that restored fertility and thus reproduc-
tive autonomy is the best solution for the couple.Others may feel that precious time, in particular withrespect to female fertility, may be lost with treatmentof uncertain benefit, thus diminishing the chances ofarriving at the essential objective, a live birth.
The problem also arises in the treatment ofcouples who request assisted conception with donorgametes to avoid transmitting a serious disease (suchas HIV) or a hereditary disorder to the child. Thecouple is not infertile and, in the case of recessivehereditary conditions, each partner would have beenable to conceive children without that particular riskhad they been with another partner who was a non-carrier of the same trait. Moreover, when the malepartner is the carrier, he must use some form ofcontraception during the period of insemination.Abstaining from using one’s procreative capacities isoften difficult to accept, even when one is perfectlyconscious of the risks involved; in fact, on occasion,the child born after DI is afflicted with the disease,because no contraception had been used. In the caseof a dominant hereditary condition, the problem issimpler to resolve: a vasectomy or tubal ligationpermanently avoids the risk of transmitting a geneti-cally determined condition. Assisted conception isthen more easily justified on the grounds of infertility.
In the situations I have observed, contrary to whatmight be expected, geneticists and physicians arequite reticent to push a couple into a situation in whichthey must abandon the idea of conceiving on theirown. They often prefer recommending geneticcounselling and prenatal diagnostic techniques. Theuse of donor gametes is proposed only when nogenetic testing for the condition is available, thegenetic condition under consideration is serious, andthe risk of transmission very high. They will alsoaccept requests from couples having had to terminateseveral pregnancies after amniocentesis.
In all of these situations, it is the high probabilityof not conceiving a child at all or of conceiving a childstricken by a serious or life-threatening healthcondition that justifies the move to assisted concep-tion. Physicians perceive the couple’s sexual rela-tions, even when the partners are fertile, as being, forall practical purposes, sterileii. This approach to theproblem validates medical interference in the intimaterealm of impregnation. It often also validates the
ii It is my view that a definition of infertility, not as an individual incapacity to conceive (and bear) a child, but as an incapacityto produce a healthy child, will play a major role in the way both reproductive technology and genetic diagnosis and therapywill evolve as medical practices in the future.
Changing conceptions of reproductive choice 327
exclusion of single women, lesbians, and womenhaving reached menopause.
But there are other unusual requests that do notfit so neatly into one of the slots of this dichotomy.For example, most physicians would not refuse to treatany person with a medically diagnosed infertilityproblem, no matter what their sexual and relationalpreferencesiii but many might balk at the idea ofextending their services to assisted conception.Another example: although most physicians refuse tooffer assisted conception to a menopausal women(who by definition cannot benefit from regular treat-ment for infertility), most physicians would find itunacceptable not to offer assisted conception to awoman whose premature menopause has beenmedically induced.
Some cases are highly controversial, even amongphysicians themselves. One interesting borderlinecase is the following: what if the persons requestingassisted conception are a couple in which the malepartner is a transsexual?iv Here, as in the case of pre-mature menopause, the infertility results from medicalintervention that amounts to castration: the endo-crinological and surgical transformation of a womaninto a man. Those who oppose treating such couplesfeel that, just as in the case of single women orlesbians, the new situation created is not a “natural”situation of heterosexual infertility. But others feel thatit is difficult to refuse a request coming from personswhose status as man and woman has been recognizedcivilly, sometimes even by marriage, and whoseinfertility is the result of recognized therapy for trans-sexualism.
Another example: is it a physician’s role to proposean alternative in circumstances that create obstaclesto heterosexual relations? When these obstacles arerelated to physical health (for example, the husbandis a paraplegic), physicians accept. But when thecircumstances are social, such as employment thatkeeps a couple apart for great lengths of time,physicians tend to refuse. On some rare occasions,the competent administrative authorities in Francehave asked physicians to inseminate the wife or partnerof a man serving a prison term, whose wife will havereached menopause at his release. Here the couple’ssterility is due to the social constraints placed on theheterosexual relationship, not only by the prison term,
but also by the fact that sexual relations are notallowed in French prisons.
The underlying dilemma in all these unusualsituations remains the same as in the conventionalsituations: when is it justified to abandon sexualityfor assisted conception? However, the question is nolonger framed in terms of real or effective infertility,either because fertility is not a problem (single women,lesbians, separated couple) or because infertility is anaccepted constitutional and socially recognized state(menopause, transsexualism). Most nonmedicallymotivated requests for assisted conception arefounded on the idea of nondiscrimination in accessto reproductive procedures. The question remains asto whether there are justifiable limits to free access.
If our societies decide to no longer restrictprocreative possibilities to heterosexual relations orto medically justified procedures using marital hetero-sexuality as a normative reference, two problems areraised. The first requires rethinking our kinshiprelationships in such a way that they take into accountall forms of procreation. The second requires review-ing a physician’s responsibility in situations where thedemand for professional competence is restricted toimplementation of a procedure, with practically nointervention in the area of diagnosis5 . We must notforget, however, that, in the background, a definitionof infertility, not as an individual incapacity to con-ceive and bear a child but as a conjugated incapacityto produce a healthy child, is probably playing a majorrole in extending the medical (and therefore apparentlynoncontroversial) indications for both reproductivetechnology and genetic diagnosis and therapy.
2. To what extent is a physicianÊs responsibilityinvolved when, in the context of assistedconception, there is a risk of harming eitherthe woman or the future child through theprocedure?
As mentioned earlier , many of the responsibilityissues in assisted conception are similar to those inany kind of treatment; they require an appropriatecontrol of professional negligence by members of theprofession through the setting of standards ofpractice. There is now relative consensus on how tohandle some of the major risk problems of assisted
iii They might refuse to treat persons with a serious disease or a mental health condition.
iv These requests were first made in France in the mid-eighties. They have become more frequent in the past few years.v This type of medical but nontherapeutic situation already exists with respect to contraception and abortion.
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conception, such as ovarian stimulation and thenumber of embryos to be transferred to the womb afterIVF (usually a maximum of three). But there is atendency to disregard these standards when bothphysician and patient fear that caution will only berewarded by the absence of a viable pregnancy.
Consensus is much more difficult to obtain whenthe risk involves transmitting a serious or life-threatening condition to the future child, because thisrisk is not immediately linked to the implementationof the procedure but to the medical history of itsgenitors (parents or donors). As we have just seen,physicians often perceive this risk as a justifiablemedical indication for assisted conception even infertile couples, as well as for screening donors toprevent the inadvertent transmission of disease. Thisscreening in some countries, notably France, includesgenetic screening of recipients, to avoid pairing adonor with a recipient who is a carrier of the samerecessive trait. Most preventive measures taken in theinterests both of the woman and the child are relativelyuncontroversial (HIV testing of donors, for example);but can a physician go too far in attempting to preventdisease in children born through assisted conception?The disquieting spectre of eugenics raises its head.
The birth of a healthy child can never be guaran-teed, no matter how many preventive measures aretaken. Medicine’s increased capacity to detect andeventually to prevent genetically determined condi-tions and malformations does not necessarily meanan increase in control over genetic parameters: theyare too numerous, and the relationships between themtoo complex to be totally under control, even in a singlespecific situation. Physicians do nonetheless feel that,over and beyond their concern for their immediatepatient, the woman, they can and must attempt tomaintain the risks incurred by the future child at a limitdefined as acceptable. However, the very task ofdefining such a limit in concrete terms is a complexand controversial process, even among physiciansthemselves. It is often quite easy for them to agree onthe objective data that characterize a particularcondition or a procedure, as well as on the objectivedata that describe the situation of the patient whosecase is being considered. But evaluating the serious-ness of a condition, the importance of the risk involved(is 5% or 10% a high or low risk?), and consequentlydeciding whether or not that condition justifiesmedical intervention (or on the contrary, refrainingfrom intervening), requires subjective appraisal ofobjective medical data. At this point, the varied
clinical experience of physicians with their patients aswell as their divergent professional and personalmoral views come into play, making consensus as towhat constitutes an “acceptable” risk, in some cases,an unattainable ideal.
For example, in the case of donor screening, manyphysicians feel that it is unacceptable to use the semenof a man certain or suspected of being a carrier of aserious genetic condition and, in the case of certainrecessive conditions, that can be found frequently inthe population, and for which there is a high risk oftransmission. When the genetic origin of a conditionhas not been clearly established (for example, in thecase of a donor who has been cured of cancer), theyalso feel that, in the absence of conclusive data, it isunacceptable for the physician to take the responsi-bility of accepting such a donor. Risk-taking hereconcerns someone else’s offspring.
But is a physician responsible in the same way forthe outcome of a pregnancy, when the risk of transmit-ting a genetically determined condition emanates fromthe parents’ family history? In some cases, physiciansdiscover that the woman, whose partner is infertile, isherself a carrier of a serious dominant condition, butwhich she only has in a minor form; this is often thereason why it was first overlooked. In other cases, shemight be a carrier of a serious dominant condition(such as polyposis of the colon) which is a late-onsetdisease of variable penetrance. A more recent problemconcerns the appropriateness of proposing ICSI tocouples in which male infertility is associated withbeing a carrier of a statistically frequent and seriousrecessive condition, cystic fibrosis. Contrary to thesituation in which it is decided to exclude a potentialdonor, because someone else’s offspring will beaffected, the decision to refuse assisted conceptionon the basis of the parents’ family history, even whenthis attitude seems medically justified, is experiencedby many physicians as a “questionable decision”.
Is there a dividing line, and if so where, betweenthe physician’s responsibility for controlling the medi-cal factors which intervene during a pregnancy andthe couple’s autonomy in decision-making regardingtheir reproductive lives? Does the fact that the birthof a handicapped child implies expensive medicaltreatment, usually paid for by the state, weigh as a validcounterargument against the fact that ultimately it isthe parents who assume responsibility for raising thechild? In other words, who assumes responsibility forthe consequences of risk-taking in childbearing andhow does this affect their right to decide?
Changing conceptions of reproductive choice 329
These questions are raised most acutely in caseswhere an at-risk pregnancy is monitored with prenataldiagnostic techniques. The probability of giving birthto a child with a serious disease or malformation canbe determined with certainty, but some anomalies ofthe karyotype may be detected whose consequencesfor the health of the child are unknown. When indoubt, physicians and parents may have differingattitudes about pursuing the pregnancy. After amnio-centesis, a physician may refuse to terminate apregnancy if this does not seem medically justified,but cannot force a woman to abort, even if from amedical viewpoint this seems acceptable. One couldimagine similar scenarios in the case of prenatalgenetic diagnosis (PGD), where a physician may refuseto initiate a pregnancy by not transferring affectedembryos, but cannot impose a transfer against thewoman’s will (4).
A patient may legitimately question professionalstandards, as well as a physician’s right to intervenein as personal a decision as whether or not to acceptthe birth of a child with a mental or physical deficiency.The physician him/herself may question this right tointervene. For in fact, medical and lay definitions ofan acceptable risk, which frequently pit patientsagainst physicians, also tend to overlap and even-tually to conflict even in the physician’s ownreasoning: a physician’s personal values with respectto the very sensitive problem of reproductive choices,also influence his/her professional attitudesvi (16).
What ultimately makes this problem such atroubling one is that, even if professionals are respon-sible for correctly establishing a probability of risk,once that risk is known, deciding what is an acceptablerisk becomes a joint moral issue for all the protagonistsinvolved. At length, it is also a social and policy issuebecause it requires deciding how far physicians mayinterfere in would-be parents’ procreative decisions,to maintain their professional standards of risk-taking.Physicians are, after all, the present gatekeepers ofreproductive technology.
3. To what extent is a physician accountablefor the social conditions in which a child willbe born?
Beyond concern with donor screening, most countries
still honour a tradition, stemming from almost acentury of practising DI, that allows parents—if theyso desire—to conceal from family, friends and eventhe child, the means by which the child was con-ceived. This requires a policy of donor anonymity, butalso selecting a donor whose physical traits matchthose of the would-be couple. Minimal matchinginvolves controlling for such traits as skin colour (andin some cases hair and eye colour), as well as bloodgroup. Proceeding in this manner makes it plausibleto the ordinary observer that the parents conceivedthe child.
However , some donors have hereditary traitsthat do not justify exclusion but that could becomemarkers revealing the parents’ recourse to a donorprocedure. Several genetic traits fall into this category,but each one poses different problems. A donor whois a known heterozygote for a recessive condition thatneither of the parents have, has a 1in 2 possibility oftransmitting this trait to the child. However, this traitis not visible, at least in the first generation: at most,the child will himself or herself be a heterozygote forthat condition and will therefore be healthy. A cleftpalate and a harelip are also hereditary malforma-tions; they are visible, but operable defects. But theydo not necessarily function as markers, becausesporadic (nongenetically determined) cases are alsopossible. On the other hand, a polydactyl donor(having more than the usual number of digits on thehands or feet) has a visible hereditary trait, which doesnot threaten the child’s health but which indisputablyacts as a marker of DI. Should such a donor beaccepted?
Acceptance of such donors raises, as in ourpreceding dilemma, questions about the extent andthe limits of genetic screening. Should physiciansavoid the deliberate transmission of any harmful oranomalous genes; or should they attempt only toprevent the most disabling hereditary conditions? Inthe latter case, it must not be forgotten that evaluatingthe seriousness of a condition is never a totallyobjective procedure. Accepting such donors alsopresupposes that would-be parents are aware of thecriteria that guide physician selection of donors ingood health, and that they are ready to surpass theneed for secrecy. And yet it has been this guaranteeof secrecy that has allowed the practice to thrive and
vi An interesting international comparative study, directed by D.Wertz and J. Fletcher of the attitudes of clinical geneticistsfrom 19 different countries confronted with a typical set of difficult cases, shows how values concerning medical decisionsrelated to genetics, which often imply reproductive choices, vary from one society to another, as well as among individualpractitioners, in particular according to their age, sex and religious practice.
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to become socially acceptable, at least to a certainextentvii.
In associating, for reproductive purposes, twopersons unknown to each other, who will not be recog-nized socially as the child’s parents, the physicianquite obviously plays a role that surpasses medicalresponsibility for correct implementation of aprocedure. Paradoxically, this role as mediator in amorally delicate situation has always seemed self-evident. In recent years however, the psychologicaland moral validity of donor anonymity and of secrecyabout the child’s origins has been questioned. Semenbanks in some countries offer nonidentifying informa-tion concerning donors and may even allow would-be parents to choose. Donated eggs are so difficultto obtain, that many physicians are now opting fornonanonymous donations, because women acceptmore willingly to undergo the risks of the procedureif the beneficiary is a friend or relative. These changesimply reconsidering the physician’s role in donorprocedures, as well as the criteria and purpose ofscreening and matching donors with recipients. Manyof what may seem self-evident decision-makingcriteria are implicit suppositions about stable familylife, child development, and concepts of health andnormality. These must ultimately be submitted to opensocial discussion and some aspects of donor matchingmay call for policy decisions.
Questions about the physician’s role and respon-sibility as mediator in a reproductive procedure alsoarise in nondonor procedures, in particular when anunforeseen incident changes the context in whichassisted conception is being offered. One example isthe unexpected death of the woman’s husband orpartner after treatment has been initiated (4). Some-times frozen semen or embryos are still in storage and,on several occasions, women have requested thetreatment be continued, alleging not only that this istheir last chance to conceive, but that they wish tohave the child of their deceased husband. Physicians’attitudes have varied and, in some cases, they havechosen to pursue treatment; but independently of thefinal action taken, concern has always been expressedabout purposely favouring the birth of a child whosefather is deceased. If the initial request was consideredacceptable, to what extent, if at all, are the social condi-tions of a child’s birth a physician’s responsibility?
Most physicians do not restrict their evaluationof a medical indication for treatment to the physicalsymptoms. The choice of the most adequate treatmentoften takes into consideration a patient’s finances,family surroundings, mental health, etc. In the caseof assisted conception, the social condition of thewould-be parents—married and in many countriescohabiting couples of acceptable procreative age—is part of the criteria defining the so-called medicalindication. In this sense, the refusal of physicians topursue treatment when the couple’s social conditionhas changed (death or illness of one of the partners,divorce) appears to be a logical sequel to the initialstance. In this sense, our last dilemma returns to thefirst, the difference being that what appears as asocially unacceptable context arises from an unfore-seen incident in a conventional situation, and not fromthe characteristics of the initial request.
Conclusion
What are the consequences for a society of havingchosen to develop a medically mediated form ofreproduction? The fact that would-be parents, what-ever their social status, are asking physicians toprovide the means of accomplishing what was oncean intimate act is hardly an anodyne fact. Whateverthe differences in technical variants, reproductivetechnology appears essentially to be “emancipating”procreation from the usual conditions of heterosexualcommerce. Artificial insemination has long sincedesexualized the act of conception. IVF has nowdisembodied conception, a trend that could beextended to the rest of pregnancy by creating theconditions for ectogenesis. The prospect of cloningnow augurs the emancipation of procreation from whatstill remains the fundamental requirement of sexualreproduction, the participation of sexually differen-tiated beings, and introduces the possibility of usingreproductive cells (embryonic stem cells) for non-reproductive therapeutic purposes. What seems to beat stake in the development of these practices is atransformation of the anthropological conditions ofprocreation.
Should these new ways of conceiving becomeavailable to all persons who express a desire for
vii The fact that secrecy is the most frequent attitude found among parents of children conceived with donor gametes belies thefact that this particular way of conceiving children and the kinship it establishes is not always perceived and experienced aslegitimate.
Changing conceptions of reproductive choice 331
children, or should they only be dispensed to personsin particular situations? Diverse variables affect boththe ways in which the question is raised and themanner in which a society explores the reasons it hasfor implementing these techniques. Generally speak-ing, some countries favour a rights approach to issuesof choice, giving more space to the political expressionof atypical requests; others prefer an approachestablishing the limits of what is socially permissible,devolving to physicians as professionals competentin reproduction the task of supervising the respect ofthese limits. However, the tendency to dissociateissues of reproductive freedom from the medicalcontexts in which they often arise tends to blind usto the constant interaction of issues of choice withmatters of medical responsibility, as well as to the factthat the contours of professional competence andresponsibility is a social and ethical issue in its ownright.
This paper comes to no major conclusion as to thebest way to proceed. How can it, when many of theseissues are still emotionally charged objects of moraland political dissent? It does, however, distinguishsome strong underlying trends in the development ofthese practices.
1. There seems to be a trend, even in conservativecountries like France, to increasing acceptance ofunconventional requests for assisted conception.This is happening, not through open politicaldebate about rights and discrimination, butthrough the constant redefinition of what consti-tutes acceptable conditions for access to treatment,in particular through extensive interpretations ofinfertility and disease prevention.
2. Issues related to changes in the family are basicallyexamined from the point of view of nonmedicallymotivated requests for assisted conception (singlewomen and lesbians, menopausal women). Lessattention is being given to the way medical reasonsand, in particular, motives for genetic screening anddiagnosis, are progressively shaping aspects ofindividual procreative choice. Mounting concernwith the transmission of genetically determinedconditions may have profound effects on the waypersons meet and decide to have or not to havechildren, as well as the type of health care theyseek. There may be significant differences betweenthose who decide to take preventive measures andthose who do not—differences that most certainlyreflect the way persons deal with the disability that
afflicts their family.3. These two trends are intimately linked to evolving
conceptions of medical responsibility, an aspect ofdevelopment in this area of medical practice that isfar from getting the attention it needs. In somecases, physicians seem to be offering new optionsto persons who had no hope of having children;but they are also creating new constraints onprocreative liberty. Some constraints imposed bya physician’s concern with taking appropriatemedical action may be based on valid arguments,pertinent to their field of competence (certain kindsof screening). Other constraints appear morequestionable (limiting assisted conception to casesof infertility), but may occasionally derive from asocial function attributed to physicians by societyas part of the responsible exercise of his/her profes-sion. All of these aspects merit close evaluationand, in the case of the latter, more open social andpolitical debate. For as expectations grow regardingtheir technical competence and as the scope of theirprofessional activity increases, physicians may,more often than not, be asked to make essentialreproductive choices, even by the “patients”themselves.
References
1. Becker G. The elusive embryo: how men and womenapproach new reproductive technology . Berkeley,University of California Press, 2000.
2. Nau J‚ “Un enfant a été créé par fécondation in vitropour soigner sa soeur leucémique aux Etats-Unis‚ LeMonde , 5 octobre, 2000.
3. Robertson J. Children of choice: freedom and the newreproductive technologies. Princeton, PrincetonUniversity Press, 1994.
4. Bateman S, Novaes S, Salem T. Embedding the embryo.In: Harris J, Holm S, eds. The future of humanreproduction : ethics, choice and regulation. OxfordUniversity Press, 1998:101–126.
5. Novaes S. Giving, receiving, repaying: gamete donorsand donor policies in Reproductive medicine. Interna-tional Journal for Technology Assessment in HealthCare , 1989, 5 :639–657.
6. Fields J, Casper LM. America’s families and livingarrangements: March 2000 . Current PopulationReports. Washington, DC, U.S. Census Bureau, 2001:20–537.
7. Hanscomb GE, Foster J. Rocking the cradle: lesbianmothers and the challenge in family living . London,Peter Owen, 1981.
8. Cohen C, ed. New ways of making babies: the case of
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egg donation. Bloomington, Indiana University Press,1996.
9. Kolata G. “Babies born in experiments have genes from3 People”. The New York Times, May 5, 2001.
10. Nau J-Y. “Des chercheurs américains sont accusésd’avoir conçu des enfants au patrimoine génétiquemodifié”. Le Monde, 7 mai, 2001.
11. Macklin R. Artificial means of reproduction and ourunderstanding of the family. Hastings Center Report,1991, 21:5–11.
12. Novaes S. Les passeurs de gamètes. Nancy, PressesUniversitaires de Nancy, 1994.
13. Novaes S. Beyond consensus about principles: decision-making by a Genetics Advisory Board in reproductivemedicine. In: Bayertz K, ed. The concept of moralconsensus: the case of technological interventions into
human reproduction. Dordrecht, Kluwer AcademicPublishers, 1994:207–221.
14. Novaes S. Making decisions about someone else’soffspring: geneticists and reproductive technology. In:Fortun M, Mendelsohn E., eds. The practices of humangenetics. Dordrecht, Kluwer Academic Publishers,1998:169–184.
15. Novaes S. Éthique et débat public: de la responsabilitémédicale en matière de procréation assistée. In:Cottereau A, Ladrière P (sous la direction de). Pouvoiret légitimité: figures de l’espace public. Paris, Éditionsde l’EHESS, 1992, 3 :155–176.
16. Wertz DC, Fletcher JC. Ethics and human genetics: across-cultural perspective. Berlin and Heidelberg,Springer-Verlag,1989.
Ethical issues arising from the use of assisted reproductivetechnologies
BERNARD M. DICKENS
Introduction
The purpose of this paper is to address ethical issuesarising from four aspects of the employment ofassisted reproductive technology (ART), namely:
• the principle of equity;• the establishment and change of social policies;• commercialization of human gametes and embryos;
and• conflicts of interest.
Issues will be considered in this sequence, butthey are not entirely separate from each other. Thereis unavoidable overlap among them, and some topicsmay fit as well under the headings of two or moreissues. Similarly, there is some overlap among issuesaddressed in this and the other background paperson ethical and social concerns in this publication.Accordingly, for the sake of convenient analysis,topics will be presented under headings and sub-headings, but they are not to be considered asdiscrete from each other. Some discussions will relateto others in different sections of the paper, and inother papers. Further, the thrust of some discussionsmay appear to vary from and even contradict that ofothers. This is because ethical analysis does notnecessarily lead to a self-determined conclusion;rather, it exposes considerations that require or
warrant attention, balance and prioritization. Balanceand prioritization may be achieved in different ways,depending upon the ethical orientations, principlesand levels of analysis that are brought to bear. Forinstance, deontological or principle-based orienta-tions may produce different outcomes from utilitarianor consequentialist orientations, ethical principlessuch as beneficence and justice may be ordered indifferent priorities, and interpersonal or microethicsmay justify different results from public or macro-ethics (1).
Different conclusions can be of equal ethical merit,related to the different factors that contribute toundertaking ethical reflection. For instance, muchconsideration of ART involves gamete and embryodonation, but in the Islamic tradition, where con-ceiving children and raising them in religious faith areparticularly important values, so too is the integrityof a family’s genetic lineage (2). Accordingly, in thiscontext, gamete and embryo donation from outside amarried couple is ethically unacceptable, but within amarriage artificial techniques may be employed toachieve pregnancy. In contrast, the Roman Catholicbranch of Christianity limits acceptable humanreproduction to natural intercourse between a marriedcouple (3) , but may tolerate transfer of a donatedovum to an infertile woman’s reproductive system fornatural insemination there by her husband. Artificialconception may therefore be ethically available to a
334 BERNARD M. DICKENS
Muslim but not an observant Roman Catholic couple,and ovum donation may be ethically available to aRoman Catholic but not an observant Muslim couple.
Within some religious faiths, ethical pluralism isrejected, and divergence from authoritative doctrinemay be deemed heresy. The modern practice of ethicsor bioethics is secular and pluralistic, however (4),recognizing that ethical reasoning on the same issuecan justify different conclusions. This is not to saythat every option is acceptable, but that adherents ofone preferred outcome may well acknowledge thatadherents of an alternative preferred outcome areapplying approaches that result in different ethical,but not unethical, conclusions.
The principle of equity
Equity and equality
Equity is distinguishable from equality, although thetwo often coincide. Equality requires the identicaltreatment of all despite their differences, whereasequity requires equally fair treatment of individualstaking account of ethically significant differencesamong them. The ethical principle of justice requiresthat like cases be treated alike (hence the legal pre-occupation with precedents) and that different casesbe treated in ways that acknowledge the differences,raising ethical concerns of likeness and difference. Forinstance, the private insurance industry in the USAhas long treated men and women as equals in coveringcontraceptive services for neither. However, womenbear the consequences of, particularly unplanned,pregnancy more directly and oppressively than men.The inequity of this equality became clear wheninsurance companies speedily extended their cover toinclude the new male potency drug Viagra (5), movingsome state legislatures to require coverage ofcontraception (6).
An initial issue of equity and equality concerningART is whether people with impaired fertility,including those who turn to ART because their naturalreproduction would expose their children to un-acceptable risks of harmful genetic inheritance, shouldbe as free to reproduce as people of usual fertility. Inmany countries and cultures, particularly of the westernworld, the latter are not subject to legal prohibitions,requirements of marriage or, for instance, medicalscreening on genetic or other grounds, although theyare subject to the regular law on their partners’ capable
consent and the prohibition of incest. The mature andresponsible are not privileged over the immature andirresponsible, nor the wealthy over the poor or thehealthy over the infected, but all rank equally asindividuals able to exercise choice of reproductivebehaviour according to their own preferences andinstincts.
In contrast to the capacity of usually fertileindividuals to undertake consensual reproductivebehaviour in private, is the public attention andregulation to which reproductively impaired indivi-duals are increasingly subject when they proposeresort to ART. Particularly in developed countrieswhere ART techniques have been pioneered, such asAustralia and the UK, state and national commissionswith distinguished memberships have proposedcriteria by which ART may become restrictivelyavailable to reproductively impaired people. Proposalsof many commissions have been enacted into laws oradopted as professional or clinical practices. These maylimit access to ART to legally married or cohabitingheterosexual couples in relationships of specificduration, require or facilitate their scrutiny accordingto medical, genetic and perhaps psychological stand-ards, or screen them by reference to other criteria suchas age, personality and criminal or childcare history.
An ethical concern is the extent, if any, to whichdifferent approaches towards reproductively impairedand unimpaired people, established in law or practice,can be justified. An important human rights provisionis nondiscrimination on grounds of physical andmental disability, according to which reproductivelydisabled people should be placed at no disadvantagein contrast to people of usual fertility. Another provi-sion is to ensure due protection of children, however,which allows, for instance, lawful removal from theirparents’ care of children exposed to or at serious riskof abuse or neglect. This provision may afford anethical justification of laws and practices that bar orscrutinize access to ART of people whose circum-stances or histories furnish credible apprehensionthat, even unintentionally and despite their good will,any children for whose care they became responsiblewould be at risk of serious disadvantage or neglect.The ethical principle of respect for persons balancesrights of autonomy against rights to protection ofvulnerable persons, of whom young, dependentchildren are obvious examples.
The goal of serving the best interests of prospec-tive children is sometimes invoked to justify limitingpeople’s access to ART, even though the consequence
Ethical issues arising from the use of assisted reproductive technologies 335
may be that the prospective children whose interestsare claimed to be protected are never conceived. Theinequality or inequity of controlling the reproductionof infertile people who are dependent on ART, whenthat of usually fertile people is not and perhaps cannotbe controlled, is sometimes explained on pragmatic orutilitarian grounds, and by recognition that, in manycountries, fertile people whose parenthood exposestheir children to undue risks will be subject to childprotective intervention that denies them childrearingopportunities. However, the children of fertile couplesare not legally removable from their care on the groundonly that public agencies believe that they can betterserve the children’s “best interests” by placing themelsewhere, and it appears inequitable to invoke a “bestinterests” criterion legally to deny ART to infertilecouples when there is little risk of their future childrenbeing abused or neglected.
Disability and pathology
Impairment of fertility may be due to a pathologicalcause, but it is ethically contentious to describe peopleseeking access to ART generically as unhealthy ordiseased people, or, indeed, apart from their impairedreproductive capacity, as disabled. Infertility itself isnot a disease, and alone it does not impair medicalhealth, although among those who want to have theirown genetically related children it may impair theirhealth in so far as the World Health Organizationrecognizes “health” as a state not only of physical well-being but also of mental and social well-being. On thisbasis, UN conferences have endorsed the definitionthat: “Reproductive health is a state of completephysical, mental and social well-being and not merelythe absence of disease or infirmity, in all matters relat-ing to the reproductive system and to its functionsand processes. Reproductive health therefore impliesthat people are able to have … the capability toreproduce and the freedom to decide if, when and howoften to do so. Implicit in this last condition are theright of men and women to be informed and to have… the right of access to appropriate health-careservices that will … provide couples with the bestchance of having a healthy infant” (7).
Infertility can deny mental or social well-being andbe a cause of acute affliction and anguish, evidencedby the extent of physical and financial cost individualsare willing to bear for its relief. However, manycountries that provide publicly funded health care formedically necessary services do not fund ART. They
usually fund diagnostic services, and may fund drugand surgical treatments, such as of diseased fallopiantubes, that restore fertility, but not ART that does notreverse the medical condition of infertility but over-comes it by artificial means of conception.
The ethical and related human rights principle ofnondiscrimination on grounds of disability raises thequestion of whether states should ethically do morethan to permit those with the personal means to availthemselves of accessible ART services to do so; thatis, whether ART should be allowed as luxury medi-cine, like, for instance, cosmetic surgery, available withminimum screening on social or moral grounds to thosewith the means of purchase, or whether the principleof equity requires some measure of public funding orsubsidy of ART services, such as by taxation relieffor its cost. States that provide publicly funded healthcare services to restore natural capacities, includingreproductive capacities, may claim that they satisfytheir duties of equity in treating all eligible recipientsof state medical services alike, and that they have nofurther ethical responsibilities to those that ordinarycare cannot assist. It may be that medical treatmentof pathological conditions that cause infertility, suchas premature menopause and fallopian tube blockage,discharges the duty of health care equity, and thatthere is no such duty to relieve remaining disability byprovision of costly ART services. Nevertheless, limitedaccess to ART services due to their high cost remainsa major equity issue raising questions about reproduc-tive rights of people with limited financial means.
Negative rights and positive rights
Considering impaired fertility as a reproductivedisability raises the concern of the appropriate publicor macroethical response to the rights of such disabledpersons to equitable treatment. Rights are oftencontrasted by reference to negative and positive rights.Negative rights amount to rights to be left alone,whereas positive rights require that holders be provi-ded, often by state agencies, with means to exercisesuch rights. Rights to luxury goods and services areusually considered only as negative rights. Byanalogy to transportation, governments may providelow-cost or subsidized public transit services by roadand rail to take people to and from work and betweenmajor population centres, but not maintain ruraltransit networks, provide subsidized airline services,or provide motorized vehicles for private use. Similarly,they may provide routine, low-cost treatment for
336 BERNARD M. DICKENS
pathological causes of infertility and limited higher-cost care for more resistant conditions, but not themore expensive forms of ART. They may explain thisin terms of health care economy, and also by referenceto cost-effectiveness considerations in the budgetingof public services.
The negative right to ART, meaning individuals’right to acquire access by their own resources,requires that state and other agencies forbear orrestrain themselves, or be restrained by judicial orother lawful means, from undue intervention by theircreation of barriers or obstacles to equitable access.Many of these barriers have been of a moral nature,prohibiting individuals from unfettered resort to bothpublicly funded and privately available ART services.Some initial reactions to novel means of conceptionhave exhibited what has been described as “moralpanic”‚ meaning an unreasoning fear of subversionof the moral order. It was noted in 1991 that “Whilethe past 40 years has seen the meltdown of the nuclearfamily and its surrounding myths and ideologies—inless than ten years half of all children born in theUnited Kingdom will be brought up outside the‘conventional’ family—new demons, chimeras andspirits have been summoned to haunt the new familieswhich technological and personal upheavals haveintroduced” (8).
For instance, unmarried individuals, includingsingle people and partners in same-sex relationships,have been barred from ART by laws or by institutionalor professional rules or practices. These have beenbased on or reinforced by claims that limits arecompelled or justified to protect children against birthsinto unstable or otherwise unconventional domesticsettings. These speculative claims may be un-supported by empirical data, however, such as isavailable of the harms suffered by children that livein violent homes. Comparable claims that have deniedrights to adoption of children are now yielding in manycountries to recognition that children are as well rearedin less conventional as in more conventional homeenvironments. It is increasingly recognized that morethan conservative orthodoxy and negative speculationbased on generic bias are required to deny a right ofprivately funded access to ART.
Preconceptions about the unsuitability andineligibility for access to ART of those affected bymental disorders may also require reconsideration ongrounds of equity. Mental disorder of a severe nature,although not requiring institutionalization, may justifyineligibility for a childrearing role, whether children
result from natural or medically assisted procreation,but many mental disorders are transient, of differentlevels of severity and amenable to treatment. It hasbeen observed that “The stigma suffered by thementally ill dates back to antiquity and has its originsin fear, lack of knowledge and ingrained moralisticviews. Though erroneous, these associations remainpervasive…. At times, the unusual and even un-founded nature of psychiatric theories and thepractitioners who uphold them has compounded theproblem” (9). Equity requires that particular appli-cants for ART be clinically assessed on their indivi-dual merits, and not be denied rights of access ongrounds of impersonal, collective stigmatization anddiscrimination.
ART applicants’ liability to exclusion on groundsof their physical health should similarly be clinicallyassessed. Their vulnerability to premature death ordisability, leaving young children at risk of orphanage,destitution or neglect, may properly weigh negativelyin the balance, but rights of access should not bedenied on the basis of negative stereotyping. TheBritish Medical Journal has recently observed, forinstance, that in view of the prolonged life expectancyof people who are HIV-positive and receiving treat-ment now available, particularly in developedcountries, there is no justification for denying infertil-ity treatment to patients who bear the infection. Itreported that “Judicious use of combination anti-retroviral therapy during pregnancy and labour,delivery by caesarean section, and avoidance ofbreastfeeding are proved measures which havereduced the risk of vertical transmission to less than2%” (10). Exclusion of HIV-positive applicants fromART programmes may be explained not by theirincapacities to be suitable parents, but by health carepractitioners’ inequitable reluctance to treat them aspatients (11) .
Although potential donors of gametes andsurplus embryos may be liable to comparable negativestigmatization, for instance when gay men are rejectedas sperm donors, it is doubtful that they have anethical or equitable right of donation. The question issometimes posed of, whether human tissue donors,for instance‚ of blood for transfusion or creation ofplasma products, have a general right or only aselective privilege of donation. Egalitarians tend tofavour the former in light of the humiliation and lossof self-esteem those whose altruistic offers ofdonation are rejected may suffer. The right/ privilegedistinction may be a false dichotomy, however, since
Ethical issues arising from the use of assisted reproductive technologies 337
donation may be neither a right nor a privilege, butonly a qualified opportunity; that is, an opportunityto offer to satisfy objectively, scientifically justifiedcriteria of eligibility. For instance, a couple may beadmitted to an ART programme as suitable, informedrecipients of the service, but not be eligible on geneticor other grounds to donate their gametes or surplusembryos to others. They have no ethical rights ofdonation, but only the right to offer to donate (seethe chapter on “Gamete and embryo donation” fordetails on the criteria of acceptability).
A related question is whether recipients of ARTservices can claim a right to choose specific gameteor embryo donors. With the exception‚ for instance‚of the wife of an infertile couple choosing her brotheras a sperm donor, couples may claim a right of choiceof donors who meet routine criteria, such as beingHIV-negative. It has been reported regarding ovumdonation, for instance, that “90 percent consideredusing a sister, 76 percent decided that a sister wouldbe the preferred donor, 70 percent asked a sister todonate, and 60 percent found a sister to be willing”(12). Ethicists and practitioners have raised theconcern that family relationships may become blurredor confused by the use of such known donors (13),and issues of blame or regret may arise if donation isfollowed by an adverse outcome. Allowing ARTpatients to recruit donors also raises concerns offinancial inducements, emotional coercion andexploitation of dependent relationships. The New YorkState Task Force on Life and the Law recommendedthat: “When known egg donors are used, informedconsent to donation should take place outside thepresence of the recipient. Physicians should attemptto determine whether known donors are motivated byundue pressure or coercion; in such cases, the physi-cian should decline to proceed with the donation. Whenapplicable, the informed consent process shouldinclude a discussion of the psychological and socialramifications of egg donation within families” (14).
Establishing and changing social policies
Policy evolution
The ethical conduct of a “social policy” suggestspursuit of a principled, deliberative public programmeof action designed to serve the interests of a givenorganized population or society, according to thescience of politics or statecraft. However, the concep-
tion and birth of children has customarily beenregarded as a private or family matter, regulated by theunpredictable chance of nature or as a divine mysteryoutside decisive human control. The principles offamily law within a community reflect its most historicaland customary or intuitive values, often embedded inreligious beliefs regarding private intimacy, associatedwith the transition between generations of familytraditions, identity and property.
The emergence of ART including gamete donationhas confused the genetic cohesion and integrity oftraditional family identity (15), and initially triggeredconservative responses. First reactions to whatreproductive technology shows to have becomepossible are often more instinctive or visceral thanintellectual, and policy responses have tended tofocus more on defence against perceived dangers totraditional values than on achieving potentials forhuman satisfaction and cultural enrichment throughnew applications of biotechnology. This was observedwith the early popularization of artificial insemination,when Kleegman and Kaufman noted in 1966 that:
Any change in custom or practice in thisemotionally charged area has always eliciteda response from established custom and lawof horrified negation at first; then negationwithout horror; then slow and gradualcuriosity, study, evaluation, and finally a veryslow but steady acceptance (16).
Societies progress through this transition atdifferent paces, and establish and change theirpolicies accordingly. Those most influenced byreligious concepts are in some ways slowest toprogress. For instance, since the Roman CatholicChurch adopted the concept of papal infallibility in1870, its teachings cannot contradict earlier papalpronouncements made ex cathedra, and much of itsscholarship is devoted to assertion of the authorityof conclusions reached in earlier times. Doctrinalreassessment within the church is severely compro-mised, because it has to be shown consistent withexisting authority. Social policies that reflect anyvariation from church doctrine, such as the doctrinethat artificial or “unnatural” means of achievinghuman conception are illicit, are considered a scandalor heresy, and strongly opposed. Indeed, it has beenexplained that the modern emergence of secular ,pluralistic western bioethics was strongly influencedby the Vatican’s intransigence in 1968 on doctrinal
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reform regarding artificial contraception (17) . Incontrast, although Islamic prohibition of gamete andembryo donation is firm, the use of ART to overcomeinfertility within marriage is accepted, often welcomeand even considered necessary (18).
Different popular religious attitudes to relationsbetween human beings and their perceived divinecreator can influence policy responses to ART. Inmany Christian communities, for instance, it isconsidered offensive and a condemnation that oneshould assume to “play God” with human conceptionand birth, as an impertinent human arrogation ofdivine power and authority. Accordingly, social policytreats the practice of ART conservatively as borderingon impropriety, and detracting from or tampering withthe awe and humility with which to face divineauthority. In other religious traditions, however, suchas Judaism, there is a perceived partnership betweenhumans and their divine creator, so that individuals’“God-given gifts” of skill and initiative are properlyemployed in scientific advance and in the cure orovercoming of medical impairments, including by ART.In this tradition, the divine creator is described asacting in ways of beneficence, mercy and compassion,and “the human being is required to imitate God in thisrespect” (19). Social policy in Israel, for instance, isstrongly pro-natalist (20), and encourages ARTwithin marriage, provided that ovum donors to Jewishcouples are Jewish, in accordance with the firstdirection given to Adam and Eve in the biblical Bookof Genesis, chapter 1, verse 28, to “be fruitful andmultiply, and fill the earth,” reinforced perhaps bydemographic and geopolitical incentives.
Problematic and constricting though religiouslyconditioned social policy may be, it has the ethicaladvantage over purely secular policy development ofinvoking profound and enduring principles. Incontrast, secular policy-making is more pluralistic butmay seem to defy the ethical principle of justice inproducing quite different responses to the samecircumstance, influenced by idiosyncratic values andpriorities and introduced as a consequence of politicalpower rather than of any transcending ethical principleor even conscious tolerance of ethical pluralism. Whensurrogate motherhood rose to public visibility, forinstance, and women were recognized as potentiallywilling to gestate and surrender children to serve otherfamilies, diametrically opposed responses appeared.Some urged and enacted policies that prohibited anywoman from undertaking surrogate gestation who hadnot previously delivered a child, on the principle that
truly informed consent to gestation and childbirthcould not be given by a woman lacking this experi-ence. Others were fearful of the psychological harm ayoung child might suffer from recognizing that itsmother is willing to give away her child to others, andurged that women with dependent children beprohibited from surrogate gestation (21).
Policy (reform) commissions
Nevertheless, the advent of surrogate motherhoodillustrated an ethically defensible process to establishsocial policy, to evaluate whether existing policy isdysfunctional or inadequate to address new technicalpossibilities, such as arise from ART, and to changeit if necessary. From the late 1970s, many countriesand states and provinces such as those of Australia,Canada and the USA, established governmental orother official enquiries into ART, to propose socialpolicy responses to limit, accommodate and/ormonitor effects of these new biotechnologicalcapacities on human reproduction and the foundingof genetically diverse families (12,21–29). Theytended to be composed of members of mixed social,academic, philosophical, religious and other back-grounds who were experienced in development ofsocial policy. They received representations fromcommunity groups and individuals, solicited informa-tion and opinions they considered necessary orappropriate to fulfil their mandates, and consulted withspecialists in technical areas and on social and ethicalimplications of policy options. They tended notexplicitly to invoke the language or categories ofethical discussion, speaking instead of the socialvalues and pragmatic considerations they consideredsignificant, but their discussions and conclusionswere amenable to ethical analysis.
The conclusions and array of recommendationsthat these commissions produced did not always winfavour with ethical analysts, and were often greetedwith dismay both by libertarians and by many whoassessed them from conservative religious perspec-tives. This was because they tended to recommendacceptance of some practices, such as unpaid gameteand surplus embryo donations, prohibition of others,such as commercial transactions including surrogatemotherhood agreements, and, for instance, setting ofconditions and time limits by which preserved gametesand embryos had to be let perish.
The commissions contributed to ethical socialpolicy development, in that they opened issues to
Ethical issues arising from the use of assisted reproductive technologies 339
public debate, either through their own processes orthrough generation of public discussion of theirconclusions, and sometimes both. They wererespectful of those who made oral or written represen-tations to them, although at that time organizedreligious institutions were better equipped to advancetheir views than bodies claiming to represent infertilepeople, they beneficially added to public under-standing of the issues and response options raisedby ART, and they attempted to justify their balancingof the competing principles and pragmatic considera-tions that conditioned their conclusions andrecommendations. They had different levels ofsuccess in having their recommendations enacted inlaw, but tended to be well respected by medical andrelated professional associations whose memberswere practitioners of ART.
The ethical character of these commissions wasbased more on the transparency and integrity of theirprocesses than on the substance of their conclusionsand recommendations, many of which were conten-tious among ethical analysts and commentators.Many received information and opinions, and formedtheir own conclusions, before the present emphasison evidence-based medicine arose. In light of thisnewer perspective, some of the information they weregiven and the scientific conclusions they reachedmight now appear questionable. Further, and perhapsmore significantly, they made no approach to advanceor consider founding the social policies they explicitlyor implicitly adopted on empirical evidence. Theyalmost invariably accepted as true, for instance, thatchildren are better reared in legally married unions thanin unmarried unions, and that heterosexual parent-hood provides a superior rearing environment to stablesame-sex unions. Many uncritically accepted conven-tional stereotypes of family life and functioning,without seeking or reviewing evidence, for instance,of the incidence and nature of marriage breakdownand family dysfunction within their societies, and theeffects on children’s well-being. This deficit in thesestudies raises ethical concerns about the adequacyof this method of establishing, changing or decliningto reconsider social policy.
The burden of proof
Commissions of enquiry often include members fromthe legal profession or judiciary, sometimes as theirleaders, and some indeed have been conducted withinlaw reform commissions (21,26). This may provide
means to address, though not necessarily to resolveto uniform satisfaction, a key ethical issue of wherethe burden of proof lies to preserve or change prevail-ing social policies. The evidence and policy implica-tions arising from individuals’ access to ART servicesand from operation of ART programmes are rarelyunequivocably favourable or unfavourable. It isuncertain, for instance, whether treatment that resultsin an infertile couple having a new family of two orthree prematurely born children that suffer respiratoryand/or neurological impairments is to be consideredsuccessful or unsuccessful, or whether treatment thatprovides an infertile couple with one or two healthychildren following a multiple pregnancy that was“selectively reduced” by ending the lives in utero ofseveral embryos or fetuses is to be celebrated ordeplored. When a country’s social policy is un-accommodating of equivocal new technology, theethical question is whether potential users can claiman ethical right to policy change to accommodate it,so that opponents have to make the case to preservethe status quo, or whether the burden lies onsupporters of the new technology to make the casefor policy change. Similarly, when a governmentproposes a new law to restrict access to a newlydeveloped service, the question is whether thegovernment has to make an ethical case (30), orwhether the ethical burden of resistance is on politicalopponents; the policy is not ethical simply because agovernment can implement it in law.
When the need for, or desirability of, policy reformis equivocal, and there is as much to be said againstpolicy change as for, and vice versa, the question ofwhether supporters or opponents of policy changebear the burden of making their case is decisive.Neither case may be made persuasively, and the sidebearing the burden will fail to discharge it. Conserva-tive or risk-averse forces will claim that a long-standingand adequate social policy should be changed onlywhen advocates of innovation present a convincingargument in favour, and those of a reformist or sociallyexperimental disposition will claim that prima facieevidence of advantage from innovation should besufficient to propel policy reform, and that those resis-tant to reform bear the burden of establishing the caseagainst it. In contrast, however, when a new practiceappears to threaten conventional values, such assurrogate motherhood or human cloning, conserva-tive forces want to speed restrictive provisions, andreformists urge caution and time for balancedreflection against precipitate prohibitions (31).
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Both conservative and reformist preferences maybe based on ethical principles, and often on variantsor counterpoints to the same principles. The principleof beneficence may support reform to accommodatethe advantages attributable to a new technology, butthe duty to do no harm, nonmaleficence, may supportits rejection. Supporters of reform may claim thatdenying a policy that would accommodate the newtechnology does harm to those it may benefit, andthat reform is required by the principle of justice, sincethe new but excluded practice is like one alreadyaccommodated. However, opponents may identify afeature or consequence of the new practice thatrenders it distinguishable. For instance, advocates ofcloning by embryo-splitting may claim that it onlysimulates natural or spontaneous identical twinning,and so should be allowed, while opponents may claimthat it accommodates multiplication by successivetwinning of an embryo twinned in vitro and, unlikenatural twinning, allows identical twins to be gestatedand born years apart. A social policy compromise maybe to limit induced twinning to a single occasion, andrequire concurrent implantation of successfullydivided embryos. Ethics may provide no self-evidentor clear outcome on the merits of a particular case, butprovide protagonists of different outcomes with thelanguage and concepts of their advocacy.
Commercialization of gametes/embryos
Ethical arguments against commercialization
Ethical arguments against commercialization includereference to dangers of exploitation of vulnerablepeople, such as those who are impoverished, and tothe more abstract concept of human dignity (32). Aprincipal argument against allowing human gametesand embryos to be the subject of commercial or profit-earning exchange stems from the ethical principle ofrespect for persons, which is sometimes consideredanalogous to the concept of human dignity as appliedin Europe. Neither gametes nor embryos are persons,but both may be considered potential persons andwhat philosophers describe as “the argument frompotential” (33) requires that they be treated with therespect and dignity due to the persons they have thepotential to become. Since abolition of slavery, theconcept advanced by the German secular philosopherImmanuel Kant (1724–1804) has prevailed, that people,and by implication potential people, should not be
treated as objects, nor only as means to ends. As endsin themselves, individuals have inherent worth andvalue, not simply the instrumental or utilitarian valueascribed to objects, which are valued only for whatcan be done with them. Accordingly, it is inconsistentwith their inherent worth that human gametes andembryos should become the subject of commercialvalue, barter and trade.
This ethical reasoning is supported from a varietyof extraneous perspectives. A religious view, adoptedby the Roman Catholic Church in 1869, displacingearlier concepts of ensoulment that determined whenthe soul enters the body, is that human life begins atconception or fertilization (34). This view requires thatan embryo be afforded the same respect and protec-tion as a born person, although the application of thisview to sperm and ova appears more difficult toestablish (35). A view from philosophy and politicalscience is that some interests, objects and functions,such as motherhood, should not be amenable to markettransactions because of the damage that would resultto human values, community and dignity. MargaretRadin, for example, condemns paid surrogate mother-hood as devaluing women in general, mothers inparticular, and children universally by making them“completely monetizable and fungible objects ofexchange”‚ meaning that any one may be replaced byany other and has no individual value in itself, soleading to “an inferior conception of human flourish-ing” (36).
The ethical argument against commercialization ofgametes and embryos is not simply the pragmatic harmthis may do to the spirit and practice of altruism. Noris it the inducement payment affords sellers to concealand misrepresent reasons why the material they pro-pose to sell may be tainted and harmful to recipients,advanced in a modern classic text opposing paiddonation of blood for transfusion (37), and indirectlyadvocating the moral and practical superiority of (UK)socialized medicine over (USA) market-directed healthcare. Rather, the argument is that commercializationthrough commodification damages important ethicalvalues in that it raises functional utility over inherenthuman worth, invites competitive bidding for superiorover inferior products, in the case of gametes andembryos‚ perhaps because of offensive distinctionsin genetic pedigree and racial or ethnic properties, andimposes a monetary tariff on all means by whichchildren are conceived and born. That is, a man’sloving act by which his wife conceives their childbecomes reduced to his transfer of sperm of a given
Ethical issues arising from the use of assisted reproductive technologies 341
market value, and her gestation becomes a service,even when unpaid, that is known to be commerciallymarketable at an employment rate per month or lesserperiod.
This impoverishes the quality of human and familylife, because it devalues and impersonalizes aprofound act of personal commitment and dedication.The social fracture in relationships is comparable tothat done by a guest invited to a friend’s home fordinner who strips the invitation of its personalcharacter by equating enjoyment of the company andthe meal to a restaurant service, and expressesappreciation by placing the assessed money value onthe table in cash. A more obvious analogy may be inequating reproduction to prostitution. This descrip-tion is now often redeemed or mitigated, acknowledg-ing the vulnerability and oppression that direct youngpersons into this occupation, by being termed“commercial sex work”‚ but its original descriptionimplies shameful and immoral debasement, or sacrificeof self-respect for financial gain.
This analogy contributes to another pragmaticreason to oppose commerce in human gametes andembryos; that it would be liable to be exploitive ofthose vulnerable through poverty who have no othermeans of earning. Gamete selling is more oppressiveof women than is sperm selling of men, since ovarecovery, perhaps following superovulation inducedby hormonal or other drug treatment, would beconsiderably more physically invasive and un-comfortable or risk-laden. Similarly, experience showsthat infertile couples may be induced to trade a numberof their cryopreserved embryos created in vitro inexchange for a further treatment cycle, when theycannot afford its financial costs. This payment in kind,in exchange for services rendered, would not be askedor invited of couples that request further treatment ona regular fee-for-service basis.
Ethical arguments allowing commercialization
Few arguments urge commerce or trafficking in humangametes or embryos as positively desirable in itself(38,39), and some who find payments defensiblerecognize that there is something unsavoury inindividuals selling their gametes (40). However, manyfind that exchange for value may be tolerable, andanalogous to practices societies have already accept-ed. Invoking the ethical principle of justice, that likecases be treated alike, they equate giving andreceiving commercial rewards for rendering the service
of donation with other payments for products andservices that are reputable and tolerated in materialisticand capitalistic or market-based economies. They findcontradiction and even hypocrisy in social toleranceand sometimes admiration of some forms of commercein the overcoming of infertility that accompaniescondemnation of giving and receiving commercialrewards for supply of the gametes and embryos thatmay make treatment possible. For instance, medicalpractitioners earn professional fees or salaries for theirservices (41), infertility clinics organize diagnosis andtreatment on a for-profit basis, particularly sincepublicly-funded health services tend not to coverART services adequately or at all, in some countriessperm banks provide samples for payment, labora-tories charge for testing gametes, genetic and othercounsellors earn livelihoods by their availability and,for instance, drug companies and equipment manu-facturers sell their products for care of infertilepatients. The demand or expectation that only thosewho supply their own sperm, ova or embryos for thesame purpose should be altruistic, appears unjust.
Even where the admonition of Richard Titmussagainst commercial purchase of blood for transfusion(37) is taken seriously, laws often allow payment forwhole blood or plasma donation, as an exception fromtheir general prohibition of commerce in humantissues, on pragmatic grounds. The social need for anadequate supply of transfusible blood and bloodproducts overwhelms objections of principle tocommercial transactions. The physical dangers towhich people are exposed from infertility are less thanthose posed by loss of blood and by anaemia, butwhere the claims of infertile patients to have childrenare respected, commercial incentives to donation,where necessary, may be ethically tolerable. Accord-ingly, the UK Human Fertilisation and EmbryologyAuthority (HFEA) has suspended its plan to prohibitpayment to sperm and ova donors of a modest fee andreasonable expenses (42). Allowance may serve theethical goal of beneficence, and the burden may fallon those who argue that, on the contrary, commercial-ization violates the ethic of nonmaleficence, that is theethic to do no harm, to make their case persuasively.In utilitarian terms, they must show that the harm ofsociety enduring relievable childlessness, andimposing it on those who seek to have children, is lessthan the harms that would arise from commercialtransactions in human gametes and embryos.
The case that would-be sellers might suppressinformation that would expose their genetic material
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and embryos as unsuitable for use is considerablyweakened where modern means of genetic diagnosisare available, since they make reliance on theproposed seller’s disclosure of personal and familyhistory less necessary. More persuasive may be theclaim that payment would induce poor people toundertake what people of means refrain from doing,that is‚ to make their genetic material and embryosavailable to strangers. The special emotional burdenof donation of extra embryos created in infertilitytreatment is that the gamete donors may remainchildless, while knowing or suspecting that a strangecouple have borne and are rearing their child. The riskthat impoverished people will become liable toexploitation arises from many sources. These includeexperience in tissue donation, for instance, when fourpoor Turkish workers were paid to fly to a Londonhospital for removal of kidneys for transplantationinto wealthy recipients, in documentation of eye andkidney sales in the Republic of Korea under recession(43), and in surrogate motherhood transactions whenthere are significant wealth differences betweencommissioning couples and gestational mothers,raising concerns about “how such practices might fur-ther oppress poor and disadvantaged women” (44).
Against this, however, it is argued that in order tosustain prohibitions of apparently exploitive practiceson ethical grounds, “we need better reasons than ourown feelings of disgust” (45). “Protecting” willing,intellectually competent vendors of their gametes andembryos against “exploitation” may disrespectfullydeny them their ethical claim to autonomy, and holdthem within a paternalistic confine that is itself anoppressive exercise of power over less powerfulmembers of society. They may consider such a saleto be the best option open to them, so that their posi-tion is worsened when the option is removed.
The argument that poor people cannot exerciseintelligent choice, such as the choice of a healthy,fertile woman to donate ova or of a healthy, athleticman to undertake professional high-risk contact sportsuch as boxing, is patronizing and insulting. Theargument that their choice is not freely made becauseof the pressure of poverty scarcely provides an ethicaljustification for further denying their choice. The claimthat their choice may not be adequately informed, forinstance‚ because they have not been able to consideror gain access to feasible options, provides a basisfor affording them additional, realistic information oropportunities rather than denying them the choice ofacting on the information they possess. The objection
that ovum sales may involve women in medicallyunnecessary, invasive and risk-bearing treatments hassubstance, but the procedures are the same forcommercial as for altruistic donors, and although thelatter may be willing so to serve only for familymembers and friends rather than for strangers, theexchange of money does not itself affect the natureof the procedures, and should not affect the careoffered by those who counsel or conduct them.
The objection that commercialization of donationunfairly attracts poor people to serve as vendors, andunfairly privileges rich people as purchasers, may befactually correct. However, this does not distinguishgamete and embryo sales from the attraction poorpeople may feel to sell their labour in low-paying,unpleasant or above-average risk employment, or fromthe capacity of rich people to purchase superiorconsumer products and services, including privatehealth care. Where legal prohibitions exclude thecapacity of affluent people to purchase the productsand services they desire in their jurisdictions ofresidence, they are allowed to seek them elsewhere,including as “reproductive tourists”. In any event, theunjust privileges available to people of means do notprovide ethical grounds to deny poor people theopportunity to obtain benefits as they perceive them.
An ethical middle ground·regulation
Even where gametes themselves cannot legally be soldor purchased, donors often receive payments that maynot be unlawful. Prohibition of commercial commodi-fication of gametes has not prevented payments frombeing made to donors, not for their genetic materialitself but for the service of making it available. Thatis, they receive payment not in a commodity transac-tion but under a service transaction. Men are not paid,for instance, for the genetic properties or volume oftheir ejaculate, but for the service of offering itsavailability. In principle, they should receive thescheduled payment even if their sperm are found onanalysis to be unsuitable for use in reproduction due,for instance, to a genetic deficiency or viral infection.In the same way that health care professionals areethically entitled to charge conscionable fees for theirservices, gamete and embryo donors may claim that itis not unlawful or unethical that they should receivepayments that are proportionate to their inconven-ience in donation. For instance, in the UK, the HumanOrgan Transplants Act 1989 provides in section 1 (1)that a person commits an offence if (s)he “makes or
Ethical issues arising from the use of assisted reproductive technologies 343
receives any payment for the supply of, or for an offerto supply, an organ”‚ but section 1 (3) states that“payment” means “payment in money or money’sworth but does not include any payment for defrayingor reimbursing … (b) any expenses or loss of earningsincurred by a person so far as reasonably and directlyattributable to his supplying an organ from his body”(46). Organs cannot be traded, but those supplyingthem can recover the reasonable costs of that service.Ethical concern that it is inconsistent to allowpayment for the service of donation but not for thedonated product may be addressed, in part, byrecognition that service costs are more measurable inequitable market terms, and less open to the chargeof people turning their bodies into “things”.
Rates for the supply of gametes and embryoscould be independently set or approved underregulations of an appropriate public or publiclyaccountable agency. This would unlink buying fromselling, preclude private barter, and prevent wealthierpatients from outbidding less wealthy applicants forinfertility treatment. Payments could be made by anindependent agency rather than by, for instance, a for-profit clinic, and donations be allocated among clinicsaccording to an equitable formula. This would addressan ethical objection to commodification of gametesand embryos, namely‚ that it unfairly privileges thewealthy through their superior means of purchase.
Both banning commerce in gametes and embryosand permitting their availability according to marketprinciples are ethically problematic. Bans risk exclusionof legitimate benefits, and injustice in light of what elsesocieties permit to be traded, and free operation ofmarket forces risks indignity and indefensibleexploitation. In principle, markets may be believed tosolve problems of inadequate and surplus supply and,for instance, of quality control, but these conceptsseem inappropriate and offensive to commonsentiment where human reproduction is concerned.Even in the USA, where supply of health services iswidely believed best undertaken through privateagencies, there are legal prohibitions of commerce inorgans, children and, for instance, surrogate mother-hood services (47) . The logical virtues of marketdiscipline are subordinated to moral repugnance (48).Nevertheless, the ethics committee of the AmericanSociety for Reproductive Medicine has recommendedlimiting payment to the last few years’ “marketplacenorm” of US$ 5000 per completed cycle for donatedova (49).
Between the ethical hazards of a prohibited market
and an entirely free market is the ethical preference ofa regulated market. This is shown in the UK, wherethe HFEA monitors ART developments, licenses ARTcentres according to their capacities of equipment andpersonnel, enforces a Code of Practice, gathersrelevant data and informs the public in general andprospective users of services in particular of wherethey may receive treatment and how successfullyparticular treatments, and treatment centres, work. TheHFEA monitors research initiatives, storage anddisposal of embryos, and compliance with legalrequirements. The Authority also determines whichpayments are acceptable and which are not, decidingin 1998, for instance, that it is tolerable for a patient’sin vitro fertilization (IVF) treatment to be subsidizedin return for the donation of some of her ova (50).
The HFEA’s observance of the law has also castillumination on “reproductive tourism”. This is oftendiscredited by association with sex tourism, thecondemned practice of people, overwhelmingly men,going to usually poor foreign countries to have sexualencounters with local residents that are unlawful intheir own countries, such as with legal minors. In 1997,the English Court of Appeal ruled that the HFEAcorrectly applied legislation of 1990 in denying awidow permission to be inseminated with spermrecovered without his consent from her comatosedying husband (51). The Court noted, however, thatthe widow was entitled to seek lawful services incountries of the European Community that wereunlawful in the UK, and she subsequently wassuccessfully inseminated in Belgium. Accordingly, so-called reproductive tourism need not be regarded onlyas a devious way to avoid the restrictions of nationallaws, but may be an ethical means to achieve personalreproductive goals compatibly with the differentstandards of one’s own country and of another whereservices are lawfully available. Instead of using thepejorative description of “reproductive tourism”‚ withits implications of flawed morality or leisure-timetriviality, it may pay ethical respect to those who seekto have children to employ a description such asresort to “transnational services”.
Conflicts of interest
Conflict in reality or in appearance
In ethics as in law, conflicts of interest clearly arisewhen those who induce others to depend on their
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integrity and good faith place their own interestsabove those of such dependants. Accountability forconflict of interest goes far beyond this, however,because it also arises when those in whom others areencouraged to trust are in a position to favour theirown interests, whether or not they actually succumbto the temptation of self-interest. Practitioners inhealth care professions, on whose specializedknowledge and training lay people must necessarilydepend for the services they feel they need, are almostinvariably enmeshed in multiple functions andcommitments that require an exercise of choice amongoptions, some of which might appear more favourableto themselves than others, and some of which mightappear less favourable to the interests of patients towhom they have conscientious duties. Conflict ofinterest arises not just from the actual prioritizationof self-interest, but also from an appearance that self-interest might be indulged at the cost of a reliantpatient. For many reproductive health care practi-tioners, in publicly funded facilities as well as inprivate, for-profit centres, conflict of interest createdby the appearance of conflict of interest, is in-escapable.
Conflict is more obvious in some cases, of course,than in others. Professional fee-splitting is consideredconflictual because it risks dissipation of the practi-tioner’s allegiance to the patient (52). Practitionerswho are also owners or financial shareholders in for-profit clinics, who advise clinic patients to take morecostly or prolonged treatments than appear indicated,are vulnerable to the suspicion of conflict. So equally,however, are practitioners on fixed salaries in publiclyfunded services, who advise patients whose carewould be costly of material resources and/or care-givers’ time that their prospects of successfultreatment are poor, and that they should reconcilethemselves to clinical failure and perhaps pursue analternative such as adoption. When practitionersserving fee-paying patients with the same medicalcharacteristics advise them that further treatment isworthwhile because it may succeed, it may appear thatthe former practitioners are unethically serving goalsof institutional economy, contrary to their patients’interests, that the latter practitioners are unethicallyprofiteering or serving futile extravagance, at theirpatients’ cost, or both.
Practitioners therefore need not be employed infor-profit clinics to fall under suspicion of being in aconflict of interest. Private clinics that genuinely canpresent themselves as non-profit institutions, for
instance, may pay staff members, who may also beproprietors, inflated salaries, and function to covertheir costs, which are boosted by paying such salaries.Although these clinics may accordingly be non-profit,they may be sources of considerable personalenrichment to their practitioners.
Conflicts may appear in the options and advicethat practitioners offer patients on preservation anddisposal of their gametes and embryos. If clinics makeprofits from storage, or storage fees contribute to paythe costs of storage facilities, clinic personnel mayhave an apparent interest to recommend or offerpreservation, reinforced by the incentive this may givedonors to remain in treatment programmes. It has beenreported, for instance, that a facility in New Yorkcharges $ 500 for three months’ storage of embryos(53). As against this, however, patients’ compliancewith requests or recommendations that patientsshould make surplus ova and/or embryos available fordonation to other patients, may provide clinics withaccess to scarce materials through which treatmentscan be offered to additional patients, and withincentives to super-ovulate women patients in waysthat may be contrary to their health interests andreproductive options. The HFEA in the UK acceptedtransfer of ova for fees or as part-payment in kind forinfertility treatment late in 1998 (50), and has nowallowed similar donation of embryos (42) . Practi-tioners’ interests in preserving and employingpatients’ gametes and embryos in these ways are notnecessarily contrary to patients’ interests, butopportunities for clinics’ and practitioners’ ownadvantage exist from which conflict may appear.
The definition of „infertility‰ and „genetic risk‰
Particular difficulty arises from different, legitimatedefinitions of what constitutes infertility, and fromwhat outcomes of natural reproduction presentprospective children with genetic risks. In Canada, forinstance, the Royal Commission on New ReproductiveTechnologies, following the practice of the WorldHealth Organization, conservatively defined infertilityas a failure to conceive following 24 months of normallyfrequent unprotected sexual intercourse (29) ,whereas clinics often admit applicants on the basis of12 months’ failure. Clearly, more couples are infertileby a 12-month test than by a 24-month test. This raisesthe concern of whether clinics are being aggressivelyentrepreneurial and self-serving in admitting appli-cants of normal fertility or slight subfertility, claiming
Ethical issues arising from the use of assisted reproductive technologies 345
credit for pregnancies during the following 12 monthsthat occurred or would have occurred naturally, oreven applying procedures that obstruct pregnanciesthat would have happened without their interventions.
Clinics may justify a 12-month test, however, onrational and compassionate grounds. Their clients, orpatients, tend not to be young, newly married couples,but couples in which the female partners are approach-ing, at or a little beyond so-described advancedmaternal age, meaning about 35 years of age or above.They may be in second or later marriages, perhapshaving had children in earlier relationships but wantingto have families in their new marriages. Whenwomen’s capacity to achieve pregnancy is in naturaldecline, clinics are reluctant to require that they waita further year or more to become eligible for treatment.Further, with a rising risk of abnormality in a later-conceived child, particularly Down syndrome, delayin access to ART may be clinically contraindicated.Accordingly, clinics’ apparent haste in admittingapplicants to treatment on an assessment of theirinfertility may not be clinically suspect or unethical.
Assessments of genetic or dysgenic risks tofuture children that may induce couples to forgonatural reproduction and turn to gamete or embryodonation, or to IVF with their own gametes andpreimplantation genetic diagnosis (PGD), may becomemore refined with advances in genetic understanding.However, questions are likely to remain of calculationsof genetic risk, how prospective children’s pre-dispositions or susceptibilities to illness or injury dueto genetic inheritance are explained to prospectiveparents, and what inherited conditions or abnormali-ties render a child’s nonexistence preferable to itsexistence, in its own interests, those of its prospectiveparents or those of others such as existing childrenof the family. A background concern is the qualifica-tion a practitioner or counsellor has to undertakegenetic counselling of ill-informed and perhapsapprehensive applicants for ART. Considerable roomexists, by choice of language, emphasis, nuance,contrast or analogy, which may be deliberate orunconscious, to control or influence patients’decisions. Eugenic and aesthetic themes may infiltratediscussions, on practitioners’ or counsellors’ initia-tives. Their preferences for children of particularstature, appearance and propensity can distortprospective parents’ exercise of the choices that,ethically, they should be informed and empowered tomake. Practitioners and genetic counsellors mustshow that they can be relied upon to be self-conscious
of their own values and biases, and to exercise the self-restraint to suppress any tendencies to impose theirown preferences that may be in conflict with those oftheir patients.
Resolution of conflicts of interest
In an idealized clinical setting for ART, conflicts ofinterest would be avoided. Although real settings arefrequently far from ideal, the ethical principles ofbeneficence, nonmaleficence and perhaps justicecompel practitioners’ efforts to minimize the incidenceand extent of conflicts. For instance, clinicians shouldnot ask their patients to volunteer to be subjects ofresearch studies of which they are the principalinvestigators, lest they unethically abuse theirpatients’ dependency on them for their own interests(54) . Similarly, clinicians should not accept or berequired to be gatekeepers of departmental or othercollective resources on which treatment of theirindividual patients must draw, lest they may favourtheir patients to the disadvantage of colleagues’patients, or violate their ethical duty of allegiance bysacrificing their patients’ interests to a perception ofdepartmental, institutional or other extraneouspriorities. As departmental or institutional gate-keepers, they are unethically compromised indischarge of duties owed to individual patients whorely on their disinterested judgment, clinical integrityand capacity for supportive advocacy of theirinterests. In many legal systems, these ethicalresponsibilities to patients are reinforced by the law.
Because conflicts of interest consist in appearanceas well as reality, they are frequently inescapable. Theymay then be ethically resolved by due disclosure.Disclosures should be to those at risk of sufferingdisadvantage from a conflicted exercise of choice, orat least to a superior officer whose duty is to ensureethical management of conflicts, and that those thatconsist in appearance do not evolve to consist inreality too; that is, that an apparent conflict is confinedto the superficial level of mere appearance. In thedoctor–patient setting, the doctor’s conflict shouldin principle be disclosed to the patient. For instance,doctors with financial interests in the profits of drugcompanies whose products they are inclined toprescribe, or for instance‚ in clinical laboratories towhich they propose to refer their patients for thetesting of their biological samples, should so informthe patients, and provide them with alternative drugor laboratory options in which they are disinterested.
346 BERNARD M. DICKENS
Physicians’ interests in these regards are notnecessarily unethical. They may be based on agenuine conviction that these companies or labora-tories provide superior products and services or, forinstance, on the conviction that, as interest-holders,the physicians can ensure maintenance or improve-ment of their products or standards. If these convic-tions are sincerely held, indeed, it may be unethicalfor a physician to seek to avoid the appearance ofconflict of interest by prescribing inferior products orreferring patients to inferior services; disclosure maybe the ethical ideal for patients’ informed choice.
It has been seen that a conflict arises when aperson who wants therapeutic care from a clinician isasked by that clinician, or by a colleague on his or herbehalf, to consider entering a study that the clinicianis proposing to conduct. The proposal requires thatthe person be clearly informed that treatment underthe study is not intended primarily as therapy, andthat, if the study design includes randomizationbetween an unproven intervention and a placebo, itmay include no proven medical treatment at all.Disclosure to the person seeking care is ethicallynecessary, but not sufficient, because those askingphysicians for care often accept the so-called“therapeutic fallacy” that the medical treatment theyare offered in research studies is intended for theirpersonal well-being. Accordingly, proposed investi-gators must also submit their study designs, includingdetails of how subjects are to be recruited andinformed, to independent ethics review committees.These committees will address how adequatelyprospective subjects are informed that the studies areprimarily intended to advance scientific knowledgerather than their personal therapy, and how capablesuch subjects are to decline involvement in studiesand instead to obtain the therapy they seek.
A modern classic of unethically resolved conflictof interest arose in the much-discussed legal case ofMoore versus Regents of the University of California(55). A patient whose cells were found to haveunusually valuable genetic properties was asked toprovide additional tissues so that investigators,presenting themselves only as his therapists, couldpatent and trade in a cell line they biotechnologicallydeveloped from them. The Supreme Court of Californiadismissed his claims based on his property interest inhis cells or the cell-line, but allowed it to proceed forhis lack of informed consent and the investigators’breach of the fiduciary duty they owed him. This isthe way courts may reinforce the ethical duty of more
powerful parties not to benefit themselves at the costof those they induce to depend on their superiorknowledge (56).
A particular conflict that may affect ART clinicsis how they report and advertise their treatmentoutcome data. Independent monitoring systems, suchas in Sweden‚ may provide the public with reliabledata. Similarly, governmental agencies in, for instance,the UK and USA, require clinics to submit annualreports of their practices, including numbers ofpatients and conditions treated, procedures under-taken and results. The Centers for Disease Control andPrevention (CDC) in the USA (57), and the HFEA inthe UK (58,59) publish quite detailed aggregatedannual data reports, and include warning that the datado not allow reliable comparisons among clinics, forinstance‚ because they will have treated differenttypes of patients with different severities of reproduc-tive disorders. Nevertheless, the news media have attimes publicized the data in the form of a table thatranks clinics in order of their performance, or, as theCDC report is entitled, their “success rates”.
The conflict of interest, arising at both micro-ethical and macroethical levels, is that clinics caninfluence their success rates by the choice of patientsthey accept and how they treat them. They can achievehigher success rates by accepting only patients belowcertain age levels, who are more subfertile thaninfertile, and whose conditions afford greatestprospects of successful treatment. Clinics that, as amatter of social justice and commitment, or of researchinterest to advance care, accept patients who haveless promise of success and who are more difficult totreat, are liable to appear lower in rankings of success.Clinics operated for profit, that promote their servicesby commercial advertisement, have an incentive toboost their competitive status by screening outapplicants with poorer prospects of reproductivesuccess, and admitting those of borderline infertility.Clinic success rates may be achieved at a loss of socialequity in access to services.
A more immediate ethical concern is whetherclinics recommend more traditional infertility treat-ments before recourse to ART, even when their usemight compromise later ART, or whether ART will befirst recommended when more traditional, lessexpensive procedures might succeed. Recommendedcare should be based on practitioners’ clinicaljudgement directed to each patient’s conscientiouslyassessed best interests. An incentive to achieve aclinic’s financial success or an impressive publishable
Ethical issues arising from the use of assisted reproductive technologies 347
success rate may present a practitioner with anunethical conflict of interest. Disclosure of the profit-seeking status and preferred practice of clinics toregulatory authorities, and indirectly or directly toprospective patients, may afford such patientsdesperate for reproductive success only limited meansto exercise independent choice. Professional ethicsand self-regulation have a significant role in monitor-ing the integrity of clinical practice and guarding thepublic and prospective patients against unethicalpractice.
References
1. Beauchamp TL, Childress JF. Principles of biomedicalethics, 4th ed. New York, Oxford University Press,1994.
2. Serour GI, ed. Ethical guidelines for human reproduc-tion research in the Muslim world. Cairo, InternationalIslamic Center for Population Studies and Research, Al-Azhar University, 1992.
3. Magisterium of the Catholic Church. Instruction onrespect for human life in its origin and on the dignityof procreation: replies to certain questions of the day(22 February 1987), Vatican City.
4. Habermas J. Moral consciousness and communicativeaction (translated by L. Lenhardt and S.W. Nicholsen).Cambridge, Polity Press, 1982.
5. Hayden LA. Gender discrimination within the reproduc-tive health care system: viagra v. birth control. Journalof Law and Health, 1999, 13:171–195.
6. Bycott SE. Controversy aroused: North Carolinamandates insurance coverage of contraceptives in thewake of viagra. North Carolina Law Review, 2001,79:779–811.
7. UN International Conference on Population andDevelopment (Cairo, 1994),Programme of Action, 7.2(U.N. Doc. A/CONF.171/13/Rev. 1).
8. Morgan D‚ Lee RG. Blackstone’s guide to the HumanFertilisation and Embryology Act 1990. London,Blackstone Press, 1991:4.
9. Garfinkel PE, Goldbloom DS. Mental health—gettingbeyond stigma and categories. Bulletin of the WorldHealth Organization, 2000, 78:503–505.
10. HIV and infertility: time to treat [Editorial]. BritishMedical Journal, 2001‚ 322:566–567.
11. Dickens BM. Health care practitioners and HIV: rights,duties and liabilities. In: Jayasuria DC, ed. HIV law, ethicsand human rights. New Delhi, UNDP Regional Projecton HIV and Development‚ 1995:66–98.
12. The New York State Task Force on Life and the Law.Assisted reproductive technologies: analysis andrecommendations for public policy . New York,NYSTFLL, 1998:242.
13. Cohen CB. Parents anonymous. In: Cohen CB, ed. New
ways of making babies: the case of egg donation.Bloomington, University of Indiana Press, 1996:89–91.
14. The New York State Task Force on Life and the Law.Assisted reproductive technologies: analysis andrecommendations for public policy . New York,NYSTFLL, 1998:282–283.
15. Dickens BM. Reproductive technology and the ‘new’family. In: Sutherland E, McCall Smith A, eds. Familyrights: family law and medical advance. Edinburgh,Edinburgh University Press, 1990:21–41.
16. Kleegman SJ, Kaufman SA. Infertility in women.Philadelphia, Davis FA, 1966:178.
17. Reich W. The ‘wider view’: André Hellegers’s passion-ate, integrating intellect and the creation of bioethics.Kennedy Institute of Ethics Journal, 1999:25–51.
18. Serour GI. Islam and the four principles. In: Gillon R,ed. Principles of health care ethics. Chichester, Wiley,1994:75–91
19. Steinberg A. A Jewish perspective on the four princi-ples. In: Gillon R, ed. Principles of health care ethics.Chichester, Wiley, 1994:65–73.
20. Glick J. Health policy-making in Israel. Religion,politics and cultural diversity. In: Bankowski Z, BryantJH, eds. Health policy, ethics and human values: aninternational dialogue. Geneva, Council for Interna-tional Organizations of Medical Sciences, 1985:71–77.
21. Ontario Law Reform Commission. Report on humanartificial reproduction and related matters. Toronto,Ministry of the Attorney General, 1985:240.
22. Committee to consider the social, ethical and legalissues arising from in vitro fertilization. Interim report,Victoria, Australia, Committee‚ 1982.
23. Committee to consider the social, ethical and legalissues arising from in vitro fertilization. Report ondonor gametes in in vitro fer tilization. Victoria,Australia, Committee. 1983.
24. Committee to consider the social, ethical and legalissues arising from in vitro fertilization. Report onsurrogate mothering . Victoria, Australia, Committee.1984.
25. Committee to consider the social, ethical and legalissues arising from in vitro fertilization. Report on thedisposition of embryos produced by in vitro fertilization.Victoria, Australia, Committee. 1984.
26. Law Reform Commission. Report on artificial concep-tion: human ar tificial insemination. New South Wales,Australia. 1986.
27. Law Reform Commission. Report on artificialconception: surrogate motherhood. New South Wales,Australia. 1988.
28. UK Department of Health and Social Security. Reportof the (Warnock) Committee of Inquiry into HumanFertilisation and Embryology, 1984.
29. Canadian Royal Commission on New ReproductiveTechnologies. Final Report, Proceed with Care, Ottawa,Minister of Government Services Canada, 1993:183.
30. Robertson JA. Procreative liberty and the State’s burdenof proof in regulating noncoital reproduction. In: Gostin
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L, ed. Surrogate motherhood. Bloomington, Universityof Indiana Press, 1990:24–42.
31. Brahams D. The hasty British ban on commercialsurrogacy. Hastings Center Report, 1987, 17(1):16–19.
32. Council of Europe: Convention for the Protection ofHuman Rights and Dignity of the Human Being withRegard to the Application of Biology and Medicine:Convention on Human Rights and Biomedicine, 1996,Article 21.
33. Steinbock B. Life before birth: the moral and legalstatus of embryos and fetuses. New York, OxfordUniversity Press, 1992:59–71.
34. McAllister J. Ethics with special application to themedical and nursing professions, 2nd ed. Philadephia,Saunders, 1955:223.
35. Harris J. The value of life: an introduction to medicalethics. London, Routledge and Kegan Paul, 1985:11–12.
36. Radin M. Market-inalienability. Harvard Law Review,1987, 100 :1849–1937.
37. Titmuss RM. The gift relationship: from human bloodto social policy. London, Allen and Unwin, 1971.
38. Andrews LB. New conceptions: a consumer’s guide tothe newest infertility treatments, including in vitrofertilization, artificial insemination, and surrogatemotherhood. New York, Ballantine, 1985.
39. Andrews LB. My body, my property. Hastings CenterReport,1986, 16(5):28–38.
40. Macklin R. What is wrong with commodification? In:Cohen CB, ed. New ways of making babies: the case ofegg donation. Bloomington, University of IndianaPress, 1996:106–121.
41. Gray BH. The profit motive and patient care: thechanging accountability of doctors and hospitals.Cambridge, Harvard University Press, 1991.
42. HFEA. Ninth Annual Report and Accounts. London,The Human Fertilisation And Embryology Authority.2000:28.
43. Lang A. What is the body? Exploring the law, philosophyand ethics of commerce in human tissue. Journal ofLaw and Medicine, 1999, 7:53–66.
44. Sherwin S. No longer patient: feminist ethics and health
care. Philadelphia, Temple University Press, 1992:90.45. Radcliffe-Richards J et al. The case for allowing kidney
sales. Lancet, 1998, 351:1950–1952.46. U.K. Statutes 1989, c. 31.47. Robertson JA. Children of choice: freedom and the new
reproductive technologies. Princeton, PrincetonUniversity Press, 1994:140–142.
48. Prichard JRS. A market for babies? University of TorontoLaw Journal 1984‚ 34:341–357.
49. Larkin M. Curb costs of egg donation, urge USspecialists. Lancet, 2000, 356:569.
50. HFEA Chairman’s Letter, 9th December 1998 and theresulting HFEA General Directions, D 1998/1.
51. R. v. Human Fertilisation and Embryology Authority,ex p. Blood, [1997] 2 All England Reports 687 (EnglishC.A.).
52. Spece RG, Shimm DS, Buchanan AE, eds. Conflicts ofinterest in clinical practice and research. New York,Oxford University Press, 1996.
53. Stolberg SG. Clinics full of frozen embryos offer a newroute to adoption. New York Times (Science Section),25 February 2001.
54. Levine RJ. Ethics and regulation of clinical research,2nd ed. Baltimore, Urban and Schwarzenberg, 1986:121–123.
55. Moore v. Regents of the University of California 1990,793 Pacific Reporter 2nd 479 (Cal. C. A.).
56. Dickens BM. Living tissue and organ donors andproperty law: more on Moore. Journal of Contem-porary Health Law and Policy , 1992, 8:73–93.
57. Centers for Disease Control and Prevention. 1998Assisted Reproductive Technology Success Rates:National Summary and Fertility Clinic Reports (USDepartment of Health and Human Services: CDC,December 2000)
58. HFEA. The patients’ guide to IVF clinics. London, TheHuman Fertilisation and Embryology Authority, 2000(at web site http://www.hfea.gov.uk/)
59. HFEA. The patient’s guide to D.I. [donor insemi-nation]. London, The Human Fertilisation andEmbryology Authority, 2000 (at web site http://www.hfea.gov.uk).
Section 6
National and international surveillance of assistedreproductive technologies and their outcomes
The Swedish experience of assisted reproductive technologiessurveillance
KARL NYGREN
Introduction
In addition to the standard peer review mechanismsthat exist in most countries, of scientific articles, semi-nars and national professional meetings, Sweden hasestablished two permanent and independent systemsto monitor assisted reproductive technology (ART)outcomes. Furthermore, several national ad hocresearch projects have been conducted using informa-tion from these two national databases.
Annual clinical summary reports oncohort data covering treatmentoutcomes
The first child born after in vitro fertilization (IVF)treatment in Sweden was delivered in 1982. Since1987, Swedish law has required all IVF clinics tosubmit annual summary reports on the results oftreatment. These summaries report on cohort datacovering treatments starting during a specific year andincluding the outcome of the resulting pregnancies.The data are usually available one year after the endof the treatment period. The reports are sent to theCentre for Epidemiology at the National Board ofHealth and Welfare. This Centre has expert statisti-cians and demographers who are responsible for thepreparation of an annual national report, in consulta-
tion with one of the practising IVF doctors in Swedenwho acts as a senior consultant to the Centre.
In 2001, for the first time, the report has beenexpanded to include trends in the data over the timeperiod 1991–1997 (1).
These annual reports have been widely used bythe medical profession, by couples seeking informa-tion, and also by the general public, usually throughthe media. The reports have not explicitly includedclinic-specific data, although by Swedish law suchinformation must be available. The reason foravoiding the publication of individual clinical data inthe reports is the awareness that the public would havegreat difficulties in interpreting these data and that thepublic could easily be misled. This position has beenstrengthened by negative experience in the UK andthe USA where the publication of results from indivi-dual centres has resulted in some confusion.
The summaries from each clinic contain thefollowing data:
• The number of IVF procedures, pregnancies anddeliveries by ART procedure including standardIVF, intracytoplasmic sperm injection (ICSI),frozen and thawed cycles and unstimulated cycles;
• The number of cycles started, number of ovumaspirations and number of embryo transfers;
• Abortions and ectopic pregnancies, reportedseparately;
352 KARL NYGREN
• Deliveries, reported as simplex, duplex, triplets orhigher order;
• The number of caesarean sections;• The number of liveborn children;• The proportion of deliveries per cycle, per ovum
aspiration and per embryo transfer;• The number of IVF treatments, reported by ART
procedure, the indications for treatment and thewomen’s age, in five-year intervals;
• The number of embryos replaced per procedure,related to pregnancy and pregnancy outcome;
• The proportion of children who are born with a lowbirth weight, i.e. below 2500 g.
Before embarking on this relatively simple andinexpensive system of surveillance, the Swedishauthorities discussed whether a system of directreporting of individual cycle data would be prefer-able. It was decided, however, that such a systemwould be very expensive and would probably necessi-tate a separate authority. It was also felt that a validationsystem for the clinical annual summaries could be setup by cross-linkage to other reporting systems andregisters already in operation in Sweden.
Therefore, this relatively simple approach worksvery reliably in Sweden and it is planned to continuewith this system. Each year, the forms for reportingare reviewed and often revised. This depends on thedynamics of developments in ART. Changes haveincluded data on the different types of ICSI that havebeen incorporated into clinical practice and the mostrecent change is the inclusion of information on
elective one-embryo transfers.Recent descriptions of time trends have shown an
increasing number of ART procedures in Sweden aswell as an increasing effectiveness reported asdelivery rates per procedure. In addition, there is adeclining multiple pregnancy rate. Ten years ago,triplets or higher-order pregnancies accounted for 5%of deliveries, whereas today it is close to zero;similarly, the twinning rate has gone down fromapproximately 28% to 22% over the same period(Figures 1–3).
Over recent years, the forms for reporting datahave also been adjusted to the norms that have beenadopted in Europe through the European Society forHuman Reproduction and Embryology (ESHRE).Therefore, today, each clinic reports its data only oncea year to the Centre of Epidemiology. Further, interna-tional reporting comes from the Centre itself. Theburden on the clinics to report data is, therefore,minimal.
Surveillance of children born after IVF
A separate surveillance system has been establishedto collect data concerning the health of children bornsince ART procedures were introduced in Sweden (2) .
This system operates through separate reportingfrom all clinics on all women who have delivered oneor more children after ART treatment. Each Swedishcitizen has a unique ten-digit identification number(PIN) and the clinic report includes each woman’s
Figure 1. Number of embryo transfers, by ART procedure, 1991–1998
1991 1992 1993 1994 1995 1996 1997 1998
0
2
4
6
8
Total
Standard IVF
Microinjection/ICSI
Frozen/thawed (Standard IVF och Microinjection/ICSI)
X 1000
The Swedish exper ience of assisted reproductive technologies surveillance 353
PIN. The Centre for Epidemiology has developed aspecific register covering all ART deliveries inSweden and reports have been produced covering twotime-periods, the first covering all ART children bornbetween 1982 and 1995, and the second covering theyears 1996–1997.
The ART delivery register is then cross-linkedwith the already existing Medical Birth Registry, theCancer Registry and the Registry for Malformations.These also use the same PINs and, therefore, eachwoman can be identified in all registers. The PIN forthe ART children is identified through the Medical
Birth Registry.The integrity of the individual’s data in each
registry is guaranteed and protected by law. Resultsfrom these registries may never be published showingan individual’s data.
All deliveries in Sweden are reported to theSwedish Medical Birth Registry, which has been inexistence since 1973. The registry contains informa-tion collected during pregnancy, delivery and theimmediate postpartum period and is based on standardmedical documents used in all Swedish antenatal carecentres, delivery and neonatal units. The registry also
Figure 2. Number of deliveries per embryo transfer (per cent), by ART procedure, 1991–1998
1991 1992 1993 1994 1995 1996 1997 1998
0
5
10
15
20
25
30
35
Total multiple births
Twin deliveries
Triplet deliveries
per cent of total deliveries
Figure 3. Multiple bir ths, rate of all deliveries, 1991–1998
1991 1992 1993 1994 1995 1996 1997 1998
0
5
10
15
20
25
30
Standard IVF
Microinjection/ICSI
Frozen/thawed (Standard IVF och Microinjection/ICSI)
per cent
354 KARL NYGREN
includes information about health and various socialconditions before and during pregnancy. Medical dataon the outcome of delivery and on neonates, such asbirth weight, duration of pregnancy and diagnosisduring the neonatal period, including malformations,are included. The quality of the registry has beenassessed and shows that the drop-out frequency isvery low.
The Swedish registers of congenital malformationand of cancer are also well established and the infor-mation from the first time period (1982–1995)includes approximately 6000 children born followingan ART procedure. They were compared to all otherchildren born during the same time-period, about 1.4million children. These results have been publishedrecently and constitute the largest follow-up of ARTchildren published worldwide (2). The main conclu-sion of the report was that the increased rate ofmultiple pregnancies, in this case mostly twins, carrieswith it an increased risk of prematurity and consequentincreases in perinatal mortality and morbidity. Thereport did not find that the ART technique itselfcaused problems. The report concluded that the highrate of multiple pregnancies (including twins) must bereduced or eliminated.
The Centre of Epidemiology at the Swedish Boardof Health and Welfare, together with the ART profes-sionals, have decided to continue this follow-up of theentire ART population, at timely intervals, toaccumulate even more powerful data, with thepossibility of describing time trends at a later stage.
Additional ad hoc projects
In addition to the two permanent surveillance systemsdescribed above, a number of ad hoc projects havebeen undertaken.
One of these has been the collection of data onneurological disturbances in children born after ARTtreatment. Again, this report has included all ARTchildren born compared to selected controls. Theresults show that the increased rate of prematuritycreates a subsequent increase in the risk of cerebralpalsy (3). Again, the conclusion is that the ARTtechnique itself does not cause these problems but thatthe increased rate of multiple pregnancies is to blame.
Another ad hoc national project covers theemotional and psychosocial development of ARTchildren at the age of approximately 8–10 years. Theresults are yet to be published.
Conclusions
The two independent surveillance systems, onecovering direct clinical results, the other coveringfollow-up of the health of IVF children, together givea valid and true picture of the situation in Sweden. Thetwo systems will continue to operate but will be modi-fied according to the dynamic situation in the area ofART.
References
1. The National Board of Health and Welfare, Statistics,Health and Disease. Assisted reproduction: results oftreatment 1994–1997. The National Board of Health andWelfare, Center for Epidemiology‚ Official Statistics ofSweden, 2000.
2. Berg T et al. Deliveries and children born after in vitrofertilization in Sweden 1982–95: a retrospective cohortstudy. Lancet , 1999, 354:1579–1585.
3. Strömberg B et al. Neurological sequelae in childrenborn after in vitro fertilisation: a population based study.Lancet, 2002, 359:461–465.
The Latin American Registry of Assisted Reproduction
FERNANDO ZEGERS-HOCHSCHILD
Introduction
Over the past few decades, remarkable progress hasbeen made in modern reproductive technology. LatinAmerica has not been untouched by these develop-ments‚ and a serious and systematic effort has beenmade in the transfer of technology and its applicationin the developing countries of Latin America. Incontrast to the introduction of new scientific develop-ments, these countries have been less effective ingenerating laws to regulate reproductive health and‚to date, no country in Latin America has adopted lawsregulating the practice of modern reproductivetechnologies. In addition, access to fertility treatmenthas not been part of the agenda of national healthauthorities and, furthermore, private health insurancecompanies do not cover expenses related to fertilitytreatment. For many legislators, procedures such asin vitro fertilization and embryo transfer (IVF-ET), areconsidered morally unacceptable and others considerthem to be a luxury that should not be supported withstate funds. An extreme example of this is Costa Ricawhere the high court has recently banned IVF-ET, byconsidering it morally unacceptable (1). These aresome of the conditions contributing to restricted andinequitable access to modern reproductive technol-ogy in Latin America. Today, more than 90% of thecentres in the area of assisted reproductive technol-ogy (ART) are private institutions which do not
receive university or government support, and restrictaccess almost exclusively to couples who can pay thehigh costs involved. Assuming a prevalence ofinfertility of 10% in women aged between 20 and 40years of age, 20% of whom will at some time requireART, and considering the number of ART cyclesperformed per country, the number of women withaccess to these therapies does not exceed 0.7%–2.8%of those who would theoretically benefit from thesetreatments (2).
Since 1984, when the birth of an IVF-ET baby wasfirst reported in Latin America (3), ART has spreadthroughout the entire region. Given the lack of nationalregulatory bodies and the reluctance to deal with con-troversial issues, very little is known about the numberand type of procedures performed by each countryup to 1990, when a multinational registry of assistedreproduction was initiated. This activity, known as theRegistro Latinoamericano de Reproducción Asistida(RLA) has been published annually since 1992 (report-ing cycles initiated during 1990 and births taking placeup to 1991). Today, it covers more than 90% of initiatedcycles in centres located from Mexico in the north toChile in the south (4).
From the very start, centres voluntarily agreed toadhere to a registration protocol and to provide theirdata to the registry, with the understanding that theresults of individual clinics or countries would not bedisclosed. Results were to be reported and published
356 FERNANDO ZEGERS-HOCHSCHILD
as summaries for Latin America as a whole, withpregnancy rates according to diagnostic category,age of female partner, etc. The outcome of clinicalpregnancies was also recorded together with gesta-tional age at delivery and perinatal mortality rates.
The Latin American Registry was initiated withthree objectives in mind: first, to create an educationaltool that, together with health professionals, wouldallow couples to evaluate the costs and benefits ofART procedures; second, to develop a comprehensive,regional database to serve as an external reference foreach centre’s self-evaluation; and finally‚ to have arobust database, allowing for epidemiologicalresearch to be conducted.
When the Registry started, very few centres hadprotocols for data collection, only one-third hadcomputerized registration and there was little experi-ence in participating in multicentre trials. Over theyears, the Registry has served as an educationalinstrument, contributing in the development of ARTin centres that otherwise would have never beeninvolved in data registration and research.
After four years of continuous publication of theresults from the Registry, it was decided that the timehad come to undertake further tasks. It was then thatthe “Red Latinoamericana de Reproducción Asistida”(Latin American Network of Assisted Reproduction)was born. Latin America was divided in five sub-regions and a board of regional directors was electedto represent and coordinate subregional activities.Apart from continuing the Registry, the LatinAmerican Network has focused most of its efforts oneducation and multinational research. The major efforthas been in the area of quality control of IVF labora-tories, training health professionals and the transferof new technology. A continuous accreditationprocess has also been established, in which standardconditions are required for centres to participate in theNetwork and to have their results published in theRegistry. The accreditation process is carried out byteams, consisting of a biologist and a clinician,belonging to centres located in a different subregion.The centre that is being evaluated voluntarily agreesto open its records to the accreditation team, whichchecks for consistencies between the data reportedin the Registry and the actual files and laboratory data.The referees also check for the existence of: qualitycontrol protocols for laboratory facilities, air purity,culture media, incubators, etc.; clinical and laboratoryprocedures such as ovulation induction, ovum pick-up, fertilization and preimplantation development and
manipulation, etc.; the follow-up of pregnancies;signed consent forms, and consistencies in the resultsreported to the Registry. The centre needs to report aminimum of 20 cycles per year and the results must beat least one standard deviation below the mean forLatin America.
Methodology
Selection of centres
During the first five years, the policy was to allow asmany centres as possible to be part of the Registry. Itwas assumed that, because individual results were notdisclosed, centres would see no benefit in manipula-ting their results. However, after some time, it wasobvious that inconsistencies found in the dataprovided by a few centres were not only the result ofinvoluntary errors; some of these centres were in factmanipulating their results to fit the computer programdeveloped to check for inconsistencies. Some centreswere consistently under the minimum efficiencyrequired and were not participating in the educationalactivities developed by the Network. These were thetwo major reasons why eight out of 101 centres wereexcluded from the Registry in 1999. Presently, once anew centre expresses its willingness to be part of theNetwork, it receives the computer software and sub-mits its results which are checked for consistencies.It is then visited by an accreditation team and‚ ifaccepted, the centre is included as part of the Registryand the Network. When the Registry started in 1990,19 centres in eight countries reported 2460 cycles, in1999, 93 centres in eleven countries initiated morethan 14 763 cycles.
Type of software and distribution
The computer program is sent to the participatingcentres in the form of three 3.5" floppy disks, or viaemail. Each centre is given a security code accordingto the country of origin and name of the centre. Thedata produced by each centre are entered in tableswhich have an inbuilt validation system and once allthe information has been completed, the centregenerates a file which is sent to the central office. TheRegistry central office double-checks for inconsis-tencies before the data are included in the report.
The Latin American Registry of Assisted Reproduction 357
Figure 1
Type of information produced
The following information is obtained for each ARTprocedure:
• Number of initiated cycles, follicular aspirationsand transfer cycles;
• Pregnancy, delivery and live-birth rates byfollicular aspiration and by transfer cycles;
• Pregnancy, implantation and multiple gestationrates according to the age of the female partner,and/or number of transferred embryos, and/or stageof development at the time of ET;
• Outcome of clinical pregnancies, includingspontaneous and induced abortion, ectopic preg-nancies, stillbirths, live births and early neonataldeaths;
• Gestational age at delivery, birth weight, majormalformations and cytogenetic analysis of abortionmaterial (where available).
Figure 1 provides an example of the forms usedfor data recording by the clinics for pregnancy,implantation and multiple gestation rates, and Figure2 is an example of the forms used for data recordingon outcome of clinical pregnancies, birth weights, etc.
Surveillance system
There are two levels of surveillance. One is inbuilt inthe computer software and includes a program whichchecks for inconsistencies. It does not allow theoperator to continue with the program if there isinconsistency between the numerical informationentered in a certain table and the numerical informationavailable in previous tables. The program advises theoperator on the source of the inconsistency. If theoperator wishes to continue running the program, heneeds to correct the conflicting figures. The questionarises as to whether this “correction” of numbers doesin fact reflect the truth. The second level of surveil-lance checks the consistency in the centre, betweenthe reported numbers and actual numbers that shouldbe present in the patients’ files and/or in the specificprotocols for clinical and laboratory proceduresperformed by each centre. These data are checked bythe accreditation teams. This process was conductedin all clinics between December 1999 and March 2000and it is expected that every participating clinic willbe reassessed every three years.
358 FERNANDO ZEGERS-HOCHSCHILD
Figure 3. Clinical pregnancy rate according to the number of transferred embryos in women >40 years of age (IVF).(Source: 1998 Latin American Registry)
Figure 2
Results
The Registry is an educational tool for both couplesand centres. To inform infertile couples, each centreshould use their own data together with an externalregistry. In this way, couples or individuals canexamine their chances of success and, at the same time,evaluate the relative performance of that centre inrelation with other centres or with a region as anexternal reference.
The way the data are processed in the RLA makesit possible to address some of the questions that ariseroutinely when examining costs and benefits of ART
procedures. Much of this information should be partof the documents used to prepare couples for aparticular therapy. The following are examples offrequently asked questions from infertile couples:
I am 40 years old. What are the chances ofbecoming pregnant transferring only two orthree embryos? The answer can be found inFigure 3.
Indeed‚ this question can also be addressed as thechances of delivering a normal child. It is also possibleto stratify the answer according to the day of ET.
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The Latin American Registry of Assisted Reproduction 359
Latin American Registry have changed in the past tenyears, the main body of information has remainedunchanged, allowing for longitudinal analyses.
Figure 4 shows how ART in Latin America hasgrown over the years. Between 1990 and 1998, 27 859transfer cycles produced 6952 clinical pregnancies,5239 deliveries with live births and 6480 live births. In1990, 21 centres produced almost 2500 cycles. In 1998,84 centres produced 12 274 cycles. In terms of thenumber of initiated cycles, the major contributors areBrazil (42.9%), Argentina (22.7%), Mexico (11.1%),Colombia (5.9%) and Chile (5.7%).
Figure 5 shows how the age of the female partnerhas changed. In 1990, 65.6% of the population wasunder 35 and only 8.7% were 40 years or more in age.In 1998, only 50% were under 35 and the proportionof women aged 40 years of age or more increased to14%. The age median increased from 33 in 1990 to 35in 1998. These factors need to be considered whenperforming longitudinal analyses on pregnancy anddelivery rates in the region.
Figure 6 shows that, in spite of the increase in thewomen’s age, between 1990 and 1998, the clinicalpregnancy rates and delivery rates increased signifi-cantly. The years in which the changes were moredramatic coincided with the initiation of continuouseducation programmes by the Network (1995–1996).
Figure 7 shows how technology transfer haschanged over the years. It took five years from thebirth of Louise Brown in Great Britain to the birth ofthe first IVF baby in Latin America, but it took only
Table 1. Multiple gestation according to the age of thefemale partner and the number of transferred embryos(IVF)
Number of Age Number Overall High-orderembryos (years) of multiple multipletransferred pregnancies gestation gestation
(%) (%)
1 <35 27 7.4 0.035–39 22 4.5 0.0>39 9 11.1 0.0Sub-total 58 6.9 0.0
2 <35 55 10.9 0.035–39 41 24.4 0.0>39 15 6.7 0.0Sub-total 111 15.3 0.0
3 <35 143 31.5 4.935–39 75 16.0 2.7>39 4 0.0 0.0Sub-total 222 25.7 4.1
4 <35 216 38.0 14.835–39 114 26.3 7.0>39 17 23.5 7.9Sub-total 347 33.4 11.8
5 <35 73 53.4 20.535–39 75 30.7 8.0>39 10 40.0 0.0Sub-total 158 41.8 13.3
6 <35 36 27.8 11.135–39 30 26.7 10.0>39 11 36.4 27.3Sub-total 77 28.6 13.0
Total 973 29.0 8.3
Source: 1998 Latin American Registry
Table 3. Malformation rate in ART
Year Number of live births Malformationobserved %
1996 1711 0.71997 1343 1.21998 807 2.0
Source: 1998 Latin American Registry
Table 2. Outcome of clinical pregnancies
IVF ICSI OD (fresh)
Clinical pregnancy 973 1124 333Spontaneous abortion 18.5% 20.9% 18.6%Ectopic pregnancy 2.6% 1.2% 2.1%Stillbirth 1.0% 1.3% 0.9%Deliveries with >1 live birth 77.9% 76.6% 78.4%
Source: 1998 Latin American Registry
I am 32 years old. What are my chances ofhaving a multiple pregnancy if you transferthree embryos? The answer can be found inTable 1.
This question can also address the chances ofhaving a triplet or a twin pregnancy.
If I get pregnant, what are my chances ofdelivering a normal child? The answer canbe found in the outcome of pregnancy (Table2) and the risk of major malformations (Table3).
The Registry can be used as a database for epi-demiological studies. Although the forms used in the
360 FERNANDO ZEGERS-HOCHSCHILD
Figure 4. Centres reporting data
Figure 5. Age of women receiving IVF
Figure 6. (A) Pregnancy rate per transfer in IVF
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The Latin American Registry of Assisted Reproduction 361
Figure 6. (B) Delivery rate per transfer in IVF
Figure 7. Percentage of the total number of attempted oocyte retrievals according to procedure
Figure 8. Multiple gestation rate in ART
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362 FERNANDO ZEGERS-HOCHSCHILD
one year to transfer the technology of ICSI fromEurope to Latin America. Today, ICSI is performed by88.2% of centres and represents almost 67% of theART procedures undertaken in Latin America.Although this technique has opened the possibilityof becoming a parent to otherwise azoospermic orseverely oligozoospermic men, it is surprising howmuch ICSI has spread, considering that male factorsdo not appear to be increasing in the region.
Multiple gestation deserves special attention‚considering that selective fetal reduction and thera-peutic termination of pregnancy are illegal proceduresin Latin American countries. Over the past four years,the average number of embryos transferred has been3.2 and the rate of multiple gestation has remainedabove 28%, which is unacceptably high. However,what gives most cause for concern is the proportionof higher-order multiple gestations (triplets and more)(Figure 8).
Table 1 shows the overall and higher-ordermultiple gestation rates according to the number ofembryos transferred and the woman’s age. The rateof multiple gestation in women under 35 years of ageis similar when three or when four embryos aretransferred (31.5% and 38%, respectively). However,the rate for triplets and higher-order pregnanciesincreases from 4.9% to 14.8% for three and fourtransferred embryos, respectively, and reached 20.5%when five embryos are transferred. The high rates ofstillbirth and perinatal mortality are strongly relatedto low birth weight associated with multiple gestation(Table 4).
Conclusions
One of the great achievements of the Latin AmericanRegistry and the Latin American Network of AssistedReproduction has been to provide scientists andclinicians responsible for ART centres with a common
objective. This started with the Registry and laterevolved into continuous education and multinationalresearch. The Registry has provided centres with arecording system which, using a common languageto register results and compare success rates, allowsfor better and more fluent interaction between profes-sionals in the region. Furthermore, it has providedinfertile couples with an educational instrument that,when used properly, helps in their decision-makingprocess.
Different from the recently formed Europeanregistry, which is mostly a scientific compilation ofnational registries, the Registry consists of individualcentres located in twelve countries. In fact, the fewnational registries in the region (Argentina, Brazil,Chile and Mexico), have been created from informa-tion provided by the Registry. In Latin America, thereare no national bodies responsible for regulating ART.Therefore, without these regulatory bodies, all thesurveillance programmes, the transfer of technologyand voluntary regulations have been generated by thescientific community associated with the LatinAmerican Network of Assisted Reproduction. Theactivities of the ART community in Latin America canbe found on the web site www.redlara.com.
References
1. Supreme Court of Costa Rica—15 March 2000.2. Zegers-Hochschild F. Attitudes towards reproduction in
Latin America. Teachings from the use of modernreproductive technologies. Human ReproductionUpdate, 1999, 1:21–25.
3. Costoya A et al. Pregnancy obtained by in vitrofertilization and embryo transfer. Revista Chilena deObstetricia y Ginecología, 1984, 49:206–216.
4. Zegers-Hochschild F, Galdames V, Balmaceda J, eds.Registro Latinoamericano de Reproducción Asistida1998. Santiago, Latin American Network for AssistedReproduction, 2000.
Table 4. Per inatal outcome according to the order of gestation (IVF + ICSI)
Single Double Triple >QUAD
n % n % n % n %
Total births 1172 100 707 100 277 100 52 100
Stillbirths 13 1.1 17 2.4 27 9.7 4 7.7
Live births 1159 98.9 690 97.6 250 90.3 48 92.3
Neonatal deaths 8 0.7 11 1.6 6 2.2 5 9.6
Source: 1998 Latin American Registry
Assessment of outcomes for assisted reproductivetechnology: overview of issues and the US experience inestablishing a surveillance system
LAURA A. SCHIEVE, LYNNE S. WILCOX, JOYCE ZEITZ, GARY JENG, DAVID HOFFMAN,ROBERT BRZYSKI, JAMES TONER, DAVID GRAINGER, LILY TATHAM, BENJAMIN YOUNGER
Introduction
Every year, infertility affects millions of couples whodesire children. In the USA, the latest population-based estimates of infertility are derived from the 1995National Survey of Family Growth (1). The estimatesvary, depending on the question asked, but eachsuggest a substantial disease burden. Among womenof reproductive age, 10% of those surveyed (represent-ing 6.1 million women) reported they had difficultyconceiving or carrying a pregnancy to term, 2%(representing 1.2 million women) reported they had aninfertility health care visit in the past year and 15%(representing 9.3 million women) reported they had aninfertility visit at some point in the past. Infertilityvisits were defined to include medical advice, diagnos-tic tests, drugs, surgery or other treatments. Amongmarried couples in which the woman was of reproduc-tive age, 7% (representing 2.1 million couples) reportedthey had not conceived after twelve or more monthsof unprotected intercourse.
In the USA, as elsewhere, couples have increas-ingly turned to technological advances such asassisted reproductive technology (ART) proceduresto overcome their infertility. The first infant conceivedwith ART in the USA was born in 1981. In 1998, morethan 80 000 ART procedures were performed in theUSA, and more than 28 000 infants were born as aresult of these procedures (2).
As the use of ART increased throughout the1980s, there was a growing concern over the informa-tion infertility patients were receiving. Many clinicsoffering ART began tabulating and reporting theirsuccess rates, both directly to patients and sometimesthrough paid advertisements. These rates usedvarious definitions for numerators and denominators,resulting in confusing and often exaggerateddepictions of clinics’ successes. In response to thisconcern, Congress enacted the Fertility Clinic SuccessRate and Certification Act (FCSRCA) in 1992, mandat-ing that all ART clinics report success rate data to thegovernment in a standardized fashion (3). ART wasdefined to include all fertility treatments in which bothovum and sperm are handled. Thus assisted insemina-tion (also known as intrauterine insemination [IUI] orartificial insemination) is not considered ART in theUSA surveillance system; nor are treatments in whichovarian stimulation medications are given but thereis no intention of retrieving ova. The Centers forDisease Control and Prevention (CDC) was chargedwith implementing FCSRCA and it published the firstreport under the law in 1997 (4) . That report was basedon ART procedures initiated in 1995. The medicalprofessional organizations, the American Society forReproductive Medicine (ASRM) and the Society forAssisted Reproductive Technology (SART) support-ed this legislation and along with the patientadvocacy association, RESOLVE, they have support-
364 LAURA A. SCHIEVE et al.
ed CDC’s activities in implementing the law.In this report, methodological issues in defining
ART success rates and collecting success rate dataare discussed, the USA programme for reporting ARTsuccess rates is described, lessons learned arereviewed and future directions are discussed.
Defining ART success rates
How do you count a success?
In defining and reporting success rates, the first issueto consider is the numerator. Although seeminglystraightforward, many options exist for definingsuccess. These can be considered sequentially frompositive pregnancy test to healthy, thriving child.Each option must be considered in light of both therelevance to the intended audience (consumer,scientist, physician, policy-maker) and the feasibilityof accurately collecting the data.
At a fundamental level, the goal of ART is toovercome a couple’s infertility and achieve pregnancy.To the ART physician, then, a reasonable measurementof success is pregnancy. To the couple undergoingthe ART procedure, the goal is not just pregnancy,but the birth of a healthy child. This is not to suggestthat physicians do not also desire that their patientshave a live birth of a healthy child. Rather, from ascientific and clinical standpoint, the ART physicianintervenes to bring about the fertilization of oocytesand subsequent implantation of embryos. Thus, whenassessing medical practice and advances in ARTtechnology, it is appropriate and even preferable attimes to define success in terms of the most proximateoutcome—pregnancy. Indeed for many physiciansand laboratory personnel, when developing andtesting new in vitro culture techniques and treatmentprotocols, an even more explicit evaluation is oftenfavoured, such as assessing the percentage of ovathat were successfully fertilized (i.e. fertilization rate)or assessing the number of embryos that successfullyimplanted among all those that were transferred intothe uterus (i.e. implantation rate). Such measuresprovide useful information that cannot be gleaned bymerely calculating the live-birth rate, a compositemeasure that encompasses factors not only related tosuccessful fertilization and implantation, but also tofactors associated with the maintenance of pregnancy.
The numerator of any success rate, then, must beconsistent with the objective the success rate indica-
tor is intended to serve. If the objective is to comparediffering treatment approaches, the more proximateoutcome, pregnancy, gives a better indication of thedirect treatment effect and is thus preferable. Con-current evaluation of the more distal outcome, livebirth, might also be useful in such assessments, asthis measure may provide insight into additionalindirect effects of the treatment. If the objective indefining a success rate is to present scientific data toprospective patients such that they can make aninformed choice about whether to undergo ART treat-ment, the best single measure is the more distal out-come, live birth. This measure is closer to the patient’sgoal of becoming a parent, rather than just achievingpregnancy.
The complexity of defining the numerator extendsbeyond the decision as to whether the outcome ofchoice for a given objective or audience is pregnancyor live birth. Within each of these broad categories,further definition is desirable to ensure comparabilityacross rates. For the purposes of ART, pregnancy ismost reasonably defined as the presence of a gesta-tional sac, visible sonographically, in the uterus. Thisreflects evidence of implantation and coincides withthe time a pregnancy becomes recognizable clinically.This definition would exclude apparent “chemical”pregnancies (i.e. transient increases in human chori-onic gonadotrophin [hCG] in the woman’s serumwithout evidence of a gestational sac). Live birth istypically defined as the birth of one or more infantsthat show signs of life. This definition is acceptable,but does not disentangle the infant’s health status atbirth. Rather, both singleton and multiple-birthdeliveries are included in the definition and normal-birth-weight‚ healthy infants born at term with a highprobability of surviving the infant period are notdistinguished from infants born with morbidities thatput them at risk for infant death. The ability tosubdivide live-birth deliveries into more meaningfulsubgroups is hampered by the difficulties in collectingdata on ART outcomes.
As the numerator moves along the continuumfrom pregnancy to healthy child, it becomes increas-ingly difficult to collect complete and accurate dataat the population level. The paramount barrier is thatin many countries, including the USA, medical care isoften not coordinated among infertility, obstetric andpediatric providers. In the USA, the responsibility forreporting ART success-rate data rests with the infertil-ity clinic that provided the ART treatment. Theseclinics do not typically provide care for patients
Assessment of outcomes for ART 365
beyond the first trimester of pregnancy. Thus clinicpersonnel must work to track patients once they arereleased from the clinic’s care to ascertain the outcomeof each pregnancy. The scope of this follow-up islimited by the feasibility of collecting various medicaldata. In the USA, data collection extends only to thepoint of birth and is limited to data that can be reliablycollected from either parents or obstetric providers,such as birth occurrence, number of infants liveborn,date of birth and birth weight(s). Information on birthdefects and other anomalies present at or shortly afterbirth, other medical complications and healthconditions diagnosed during infancy, and infantdeaths cannot be reliably ascertained with the currentsystem. Thus the USA live-birth rate can be furthersubdivided into singleton and multiple-birth rates anda general assessment of low birth weight is feasible,but it is not possible to address specific infant healthoutcomes.
Who should count in the denominator?
In addition to accurately defining, collecting andreporting numerator data, it is important to carefullyconsider which patients and procedures should beincluded in the denominator of each success rate andto adhere to standard criteria when collecting denomi-nator data. Much of the confusion in defining thedenominator stems from the fact that an ART proce-dure is not really a procedure at a single point in time,but rather ART is more appropriately considered as acycle of treatment. A typical ART procedure or cyclebegins with ovarian stimulation and monitoring,progresses to ovum retrieval, fertilization (generallyin vitro), embryo transfer (ET), and hopefullyimplantation, pregnancy and live-birth delivery. A
cycle may be discontinued at any of these steps, forclinical reasons such as unsuccessful ovum retrievalor ET, because of medical complications (e.g. ovarianhyperstimulation syndrome [OHSS]) that arise duringthe cycle, or because the couple chooses to withdrawfrom treatment. Thus, the success rate that is calcula-ted may be highly variable depending on whichprocedures are included in the denominators. Figure1 depicts how fresh, nondonor ART cycles (i.e.excluding those cycles using embryos that werepreviously frozen or ova or embryos donated fromother women) progressed in 1998. As can be seen, thedenominators (and thus the rates) will be quitedifferent depending on the stage of treatment chosen.
FCSRCA specifies that live-birth success rates forUSA clinics must be based on “...the number ofovarian stimulation procedures attempted” (3). Thisis the rate that is perhaps most informative to consu-mers because it represents the average chance ofhaving a liveborn infant among couples that beginART treatment. At the time a couple is consideringART, they, of course, do not know whether and whenthey will withdraw from treatment; thus using thenumber of women who undergo ovarian stimulationwith the intent of ART (i.e. cycle starts) as thedenominator provides the most realistic picture of thesuccess rate. Presentation of supplemental rates basedon other denominators (e.g. cycles that progress toovum retrieval, cycles that progress to ET) providesadditional information on the likelihood of progress-ing from one stage to the next, once the cycle isinitiated. Such rates may also be more informativewhen presenting data related to specific ART treatmenteffects. For example, we have consistently found thatamong couples diagnosed with male factor infertility,the live-birth rate, considering cycles in which one or
Figure 1. Outcome of ART cycles using fresh, nondonor eggs or embryos, by stage, 1998
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366 LAURA A. SCHIEVE et al.
more ova were retrieved (live birth per retrieval rate),was slightly higher when intracytoplasmic sperminjection (ICSI) was used, indicating that ICSI mayimprove the chances of fertilization among suchcouples (2). However, when we limited analysis of thelive-birth rate to those cycles that progressed to ET(live birth per transfer rate), we found no differencebetween ICSI and non-ICSI cycles. This findingsuggests that ICSI does not have an additional impacton the success rate once fertilization is achieved.
A separate issue in defining denominators iswhether rates should be calculated based on ARTprocedures or based on women who undergo ARTprocedures. Because it is possible and in fact notuncommon for a woman to undergo more than oneART cycle in a given year, the number of ARTtreatment cycles is not equal to the number of womenundergoing ART. Currently, success-rate data in theUSA and elsewhere are collected according to cycles,and it is not yet possible to reliably link cycles for thesame woman. This, of course, presents a number ofmethodological problems. Whether or not a womanundergoes multiple cycles is likely to be related to theprobability that a given cycle will be successful. Firstit is possible to undergo multiple cycles in the sameyear if pregnancy is not achieved, presenting a biastoward couples who are less successful. On the otherhand, the decision of whether or not to undergo asecond, third or more, cycles of treatment may in partbe driven by assessment of various intermediatepoints in the previous cycle, such as the response toovarian stimulation. Thus it is possible that amongpatients with one unsuccessful cycle, those with amore optimistic prognosis for success disproportiona-tely choose to undergo further cycles. Additionally,for some patients the chance of success may actuallyimprove with each successive cycle of treatmentbecause the provider may adjust the treatment protocolon the basis of an assessment of the previous cycle.Thus cycles are not independent events and statis-tical comparisons of rates must be made cautiously.
Further issues in defining and interpretingsuccess rates
In addition to developing standard definitions fornumerators and denominators, success rates must beconsidered in light of the populations from which theywere drawn and a host of patient and treatment factorsassociated with success. As previously discussed,both national and within-clinic success rates are based
on a population of couples who chose to undergo ARTwithin a given year (and in some cases chose toundergo multiple cycles of ART). Thus, even whencollecting and reporting population-based data, thesuccess rate does not necessarily represent the theo-retical target population of interest—all potential ARTusers. It is important to collect as much informationas is feasible to describe the population and to adjustor stratify success rates on key variables known toinfluence success.
First, because ART encompasses a variety of treat-ment approaches, success rates should be presentedseparately by ART procedure. At a minimum, successrates should be subdivided according to (i) whetherembryos were fertilized as part of the current proce-dure (fresh) or had been fertilized during a priorprocedure and frozen until the current procedure(frozen); and (ii) whether the source of ova was thepatient (nondonor) or a woman serving as an ovumor embryo donor (donor). If the sample size allows, itis desirable to also examine success rates separatelyaccording to the method of embryo transfer, includingin vitro fertilization (IVF) and transcervical ET (IVF-ET), gamete intrafallopian transfer (GIFT) or zygoteintrafallopian transfer (ZIFT). Other treatment factorsthat should be examined include the number of embryos(or ova, in the case of GIFT) transferred, and specificprocedures used, such as ICSI or assisted hatching.
Consideration of patient factors should, at a mini-mum, include the age of the woman undergoing ART.Age has been shown in numerous studies to be oneof the strongest predictors of ART success amongwomen who use their own ova (2,5,6). Other patientfactors that should be considered for evaluationinclude infertility diagnosis, patient history includingprevious pregnancies and births, infertility treatmenthistory, and clinical factors such as follicle stimulatinghormone (FSH) levels.
Evaluation of both treatment and patient factorsis limited by the feasibility of collecting detailedclinical data on a population level and by the smallsample sizes within clinics and even within certainsubgroups on a national level. At a minimum, presen-tation of clinic-specific success rates should addressdifferences across clinic patient populations in distri-butions of patient age and the general categories ofART treatment including fresh-nondonor, frozen-nondonor, fresh-donor, frozen-donor. A comprehen-sive evaluation of other factors is also recommended,but is generally limited by sample size to national-leveldata only.
Assessment of outcomes for ART 367
In addition to stratification or adjustment forpotential confounding factors, clinic-level statisticsshould incorporate a measure of the variance or un-certainty of key statistics attributable to small samplesizes. Even though the data within each clinic are‚ inone sense‚ population-based, presentation of confi-dence limits in addition to rates is preferred becauseit is important to convey the limitations inherent incomparing rates based on too few observations.
A final consideration in presenting ART successrates is the delay associated with data collection andreporting. To collect live-birth outcome data, a mini-mum lag time of nine months from cycle start isrequired. Additional time must be allowed for datacompilation and review, analysis, report preparationand publication. The USA process is described in thefollowing section. At best, there is an approximatetwo-year delay between when ART cycles wereperformed and when success rates are reported. Thisis not unusual for a public health surveillance system.However, because ART is still a relatively new tech-nology that continues to advance rapidly, reportedsuccess rates in this field do not always representcurrent clinical practices.
Collecting and reporting ART success ratedata in the USA
Overview
As previously discussed, medical centres in the USAthat perform ART are required to report annually toCDC data on every ART procedure initiated. FCSRCAwas enacted in 1992; however, since this mandate wasnot funded, implementation was delayed until 1997.To date, CDC has published reports for ART cyclesinitiated in 1995, 1996, 1997 and 1998 and the prepara-tion of the 1999 report is currently under way.
CDC’s primary objective in developing the ARTreporting process was to produce an annual reportthat provided accurate information about ART and wasaccessible to the public. To fulfil this objective, CDCentered into partnership with ASRM, ASRM’saffiliate, SART, and RESOLVE‚ the National InfertilityAssociation. ASRM and SART are medical profes-sional societies representing reproductive healthprofessionals and clinics that perform ART in the USA.RESOLVE is a national consumer organization repre-senting persons experiencing infertility. CDC meetsregularly with these organizations to review and revise
the reporting process, and the format and content ofthe published reports.
The ART reporting process includes data collec-tion, validation, analysis, writing, editing and review,and publication. Table 1 presents the steps in thisprocess with a time-line for the data flow. Altogether,there is an approximate two-year lag from when thelast ART cycle of a given reporting year is performedto the publication of the annual ART report. A detaileddescription of the reporting process is providedbelow.
Data collection
SART had been collecting data from its member clinicsand publishing annual reports on pregnancy successrates in its peer-reviewed journal, Fertility andSterility, since 1989. Rather than duplicate SART’sreporting system, and thereby burden ART clinics,CDC contracted with SART to obtain annually a copyof their clinic-specific database. All USA clinics thatperform ART are now asked to submit data to SARTfor inclusion in its database. Both SART and non-SART member clinics are now eligible to participatein SART’s data system. All clinics that submit theirdata to this CDC-supported SART system are consi-dered to be in compliance with FCSRCA.
SART maintains an index of ART clinics knownto be in operation in each year and tracks clinicreorganizations and closings. It is the responsibilityof the practice director of each clinic to notify SARTof the clinic’s existence and any changes in address,location or key staff. This requirement, along with allthe ART reporting requirements, was published in theFederal Register of the United States (7). SART alsofollows up reports of ART physicians or clinics noton its list. These reports generally originate fromconsumers looking for a particular clinic in the annualART report. Most often follow-up reveals that theclinic has only recently opened (and thus was noteligible for inclusion in the previous ART report).
Each year, SART distributes a database-manage-ment software system and instructions to all ARTclinics. Clinics abstract data from clinic records for allART cycles they initiated in a given reporting year, 1January to 31 December, and enter their data using theSART software. An ART cycle is considered to beginwhen a woman begins taking ovarian stimulatorydrugs or starts ovarian monitoring with the intent ofhaving embryos transferred. The data file is organizedwith one record per cycle. Multiple cycles from a single
368 LAURA A. SCHIEVE et al.
patient are not linked. Data collected include patientdemographics, medical history and infertility diag-noses, clinical information pertaining to the ARTprocedure, and information on resultant pregnanciesand births.
The medical director of each clinic is required tosubmit the clinic’s data file to SART by an establisheddeadline and to verify, by signature, that the datareported are accurate. The current deadline for datasubmission is in December, one year subsequent tothe reporting year in question. (For example, thedeadline to report data on cycles initiated in 1999 was15 December 2000.) This allows sufficient time for allpregnancies conceived in 1999 to have reachedcompletion and for clinic personnel to compile thesedata. All clinics known to be in operation throughouta given reporting year that fail to submit the requiredmaterials to SART by the required deadline areconsidered to not be in compliance with the federalreporting requirements of FCSRCA. These clinics are
notified by both SART and CDC that they will be listedas nonreporting clinics in the annual ART report.
Beginning with the reporting year 2000 data-collection cycle, SART asked clinics to submit aportion of their data for each ART cycle within threedays of the cycle start (i.e. before the outcome of thecycle was known). SART developed an internet-basedsystem to process these submissions. These prospec-tively reported data will be linked with the full datasetsubmitted at the end of the data-collection period.The feasibility of this system is still being evaluatedbut, in time, prospective reporting may become arequirement.
After the reporting deadline, SART compiles theindividual clinic data files and submits the national datafile to CDC. CDC and SART then work together toreview the data and identify inconsistencies and logicerrors. Clinics with errors for key data elements areasked to reconcile the discrepancies and submitupdates to SART. SART then compiles and submits
Table 1. Activities in ART repor ting process and usual time line
Activity Usual time line
ART cycles are performed January–December, Year 0*Data collection
SART distributes data collection materials to clinics January, Year 0SART distributes any updates to the data system to clinics by September, Year 1Clinics submit data to SART December, Year 1SART compiles clinic data and submits to CDC February, Year 2SART and CDC review data and ask clinics to reconcile errors February–March, Year 2SART submits final national dataset to CDC (cycle-level data) April, Year 2SART submits final clinic tables dataset to CDC (aggregate data) June , Year 2
Data validationCDC selects sample of reporting clinics for validation March, Year 2SART teams conduct site visits for all selected clinics April–June, Year 2SART and CDC review validation data June , Year 2
Data analysis and publicationCDC conducts analysis, develops graphics and text April–July, Year 2CDC, Division of Reproductive Health conducts initial proof of numbers in each clinic table June–July, Year 2CDC, ASRM, SART, RESOLVE participants review drafts of the report July–August, Year 2CDC editorial staff review and edit national report, format clinic tables and appendices July–September, Year 2
and conduct editorial proof for entire reportDesktop publisher lays out report for CDC September–October, Year 2Desktop version of report proofed by CDC editorial staff (corrections made by desktop October–November, Year 2 publisher if necessary)Report cleared for publication by CDC science director November, Year 2Files forwarded to printer and CDC web site team November, Year 2Report published, printed version and on CDC web site December, Year 2Final proof of web site against printed publication December, Year 2
Report release and dissemination January, Year 3
*Year 0 refers to reporting year , Years 1–3 refer to the 1–3 years subsequent to the repor ting year .
Assessment of outcomes for ART 369
the final national dataset to CDC.In addition to data entry for each ART cycle,
SART’s database software system includes program-ming that uses the cycle-level data to calculate keyART statistics for each clinic. Each year, SART refinesthis program in conjunction with CDC to ensure thatthese clinic-level statistics meet the needs of thefertility clinic tables section of the annual CDC ARTreport (see below—Data analysis and publication).Once the national dataset of individual ART cycles isfinalized, SART additionally compiles an aggregate-level dataset of clinic statistics (clinic tables dataset)and submits this file to CDC.
Data validation
Once all the data have been reported, reviewed andcorrected, a sample of reporting clinics (generally 8%–10%) are chosen for data-validation site visits. SARTand CDC jointly decide upon the criteria for clinicselection each year in advance of data collection (thusensuring that the criteria are not influenced by reviewof any clinic’s data). In general, most of the clinics arechosen using a simple random sampling scheme withweighting to reduce the likelihood that a clinicpreviously validated will be chosen again. Addition-ally, clinics with a statistical value above a pre-designated target level for a key indicator, such as live-birth rate, may be automatically selected. For eachclinic selected, a proportion of ART cycles (usually50) are sampled using a stratified random samplingscheme such that cycles in which a live birth occurredand cycles in which no live birth occurred are selectedproportionate to the total live birth per cycle rate. Two-person teams from the SART Validation Committeeconduct the data validation visits. (A representativefrom at least one non-SART member clinic sits on thiscommittee.) A CDC representative attends a portionof the visits to observe the process. During the visits,the validation teams compare data that were reportedto SART with clinic records. They note discrepancieson paper data validation forms and these forms arethen forwarded to CDC for data entry and analysis.CDC calculates error rates within and across clinicsand for each data item validated. SART and CDCreview these findings.
The data-validation process is meant to be pri-marily educational and to identify particular problemareas in the data-collection process such that theymay be corrected in subsequent data-collectioncycles. Within this context, SART may institute global
changes to their data-collection software or processon the basis of the validation findings and maycontact individual clinics after validation to reviewspecific problems identified. In nearly all instances,validation results are not expected to affect a clinic’sstatus in the annual ART report. However, in rareinstances, validation may reveal an unacceptable errorrate. The prevailing consideration in deciding if aclinic’s data are unacceptable is whether or not thevalidation findings suggest that publication of theclinic’s data, as reported, present a misleading accountof that clinic’s “true” success rate. If such a situationarises, SART and CDC may work with the clinic andallow for corrections in time for the publication of theannual report. If timely corrections are not possible,the clinic may opt to remove its data from the annualreport and be listed as a nonreporter. To date, errorrates for all clinics validated have been within accept-able limits. Moreover, the majority of errors identifiedhave been minor, e.g. date misrecorded by one or twodays, and the impact of errors on the success ratesreported has been estimated to be minimal.
Data analysis and publication
CDC holds the primary responsibility for data analysisand for writing and publishing the annual ARTsuccess rates report. The report is co-authored byASRM, SART and RESOLVE. Both printed and website versions of the report are published. Over the fouryears that CDC has been involved in this process,requests for printed reports have declined while hitsto the ART Report web site have increased dramatically.
The report is laid out in three main sections. Thenational report presents the overall US success ratesand provides some analyses of how patient andtreatment factors affect the rates.
The fertility clinic tables section provides onepage of key statistics for each clinic. The format andcontent of the most current clinic table is shown inFigure 2. As can be seen, the table is actually dividedinto three subsections: (i) an ART cycle profile thatprovides information on the various types of ARTperformed at the clinic and the distribution of patientinfertility diagnoses being treated; (ii) a pregnancysuccess rates section that provides several key preg-nancy and live-birth success rates, confidence limitsaround the live birth per cycle success rate, data onthe number of embryos transferred, and statisticsrelated to multiple births; and (iii) a current clinicservices section that provides various data on patient
370 LAURA A. SCHIEVE et al.
a Reflects patient and treatment characteristics of ART cycles performed in 1998 using fresh, nondonor eggs or embryos.b When fewer than 20 cycles are reported in an age category, rates are shown as a fraction. Calculating percentagesfrom fractions may be misleading and is not encouraged.c A multiple-infant birth is counted as one live birth.d Among women >40, rates change with every year of age. Refer to Figure 10 for average chances of success by yearof age.
Figure 2.Figure 2.Figure 2.Figure 2.Figure 2. Clinic table format, 1998 Assisted Reproductive Technology Success Rates Repor t
CURRENT CLINIC SERVICES AND PROFILE (as of 1/15/2000)
Current name: Clinic XServices offered: Clinic profile:Donor egg? SART member?Donor embryo? Verified laboratory accreditation?Single women?Gestational carriers? Additional information on laboratory accreditation isCryopreservation? available in Appendix C
1998 PREGNANCY SUCCESS RATES Data verified by Dr XY Zee
Age of womanType of cycle <35 35–37 38–40 >40d
Fresh embryos from nondonor eggsNumber of cyclesPercentage of cycles resulting in pregnanciesb
Percentage of cycles resulting in live birthsb,c
(reliability range)Percentage of retrievals resulting in live birthsb,c
Percentage of transfers resulting in live birthsb,c
Percentage of cancellationsb
Average number of embryos transferredPercentage of pregnancies with twinsb
Percentage of pregnancies with triplets or moreb
Percentage of live births having multiple infantsb,c
Forzen embryos from nondonor eggsNumber of transfersPercentage of transfers resulting in live birthsb,c
Average number of embryos transferredDonor eggsNumber of fresh embryo transfersPercentage of fresh transfers resulting in live birthsb,c
Average number of fresh embryos transferredNumber of frozen embryo transfersPercentage of forzen transfers resulting in live birthsb,c
Average number of frozen embryos transferred
Clinic XCity, State
1998 ART CYCLE PROFILE
Type of ARTa Patient diagnosis
IVF Procedural factors: Tubal factor Uterine factorGIFT With ICSI Male factor Other factorsZIFT Unstimulated Ovulatory dysfunction UnexplainedCombination Endometriosis
Assessment of outcomes for ART 371
services, such as whether donor ova and embryos areavailable, and clinic information, such as whether thelaboratory used is accredited. Of note is that the statis-tics presented in this table are stratified according tothe patient’s age and the general cycle type (i.e. freshversus frozen embryos and nondonor versus donorova or embryos). Finally, several appendices areprovided in the report. These include a glossary ofkey terms, an explanation of confidence limits and howto interpret the data using confidence limits, contactinformation for all clinics included in the report, and alisting of all clinics that were required to report underFCSRCA, but did not submit data. (Being listed as anonreporter is the only sanction for not reporting dataas required under FCSRCA; however, this appears tobe a fairly strong incentive for reporting as clinics havevoiced concern about the business implications ofbeing included on such a nonreporter list.)
Once CDC receives the final dataset from SART,data analyses for the national report begins concurrentwith data validation. The CDC scientific staff in theDivision of Reproductive Health conduct the analysesand develop the graphics and text to present keyfindings. Because the primary audience for this reportis current and prospective ART patients, the data mustbe presented in a simple and straightforward manner.Thus, in general, only univariable or bivariableanalyses are presented. However, for each findingpresented, additional descriptive analyses and statis-tical adjustments or stratifications are often alsoconducted and reviewed. If these additional analyseshave an impact on the final result, the presentation ofthe data or the text are adapted to provide a more accu-rate interpretation than the unadjusted data suggest.ASRM, SART and RESOLVE co-authors also reviewthe draft versions of the report and comment on thecontent and presentation of the data.
During this stage of the process, CDC staff alsoconduct an initial check of the numbers in each clinictable: (i) to ensure consistency between the two data-sets compiled from the clinic submissions (thenational dataset and the clinic tables dataset); and (ii)to ensure consistency between the final electronicversion of each clinic table and the correspondingprinted versions of the tables that each clinic medicaldirector was required to sign as verification of dataaccuracy.
All data and text files for the report are nextforwarded to the CDC editorial staff. They review andedit the national report, develop the final format forthe clinic tables and appendices, and proofread the
entire report. They then forward the report to adesktop publishing contractor for layout. Once thedesktop version is proofread and approved by CDC,the desktop publisher prepares files that are forwardedconcurrently to a printer for publication of hard-copyreports and to the Division of Reproductive Healthweb site team. As a final check, all text and data areproofread once more to ensure that the Web site andprinted versions agree. The report is then released anddisseminated.
Key findings
Since CDC began tracking ART success rates, therehas been a marked increase in both the number ofclinics performing ART and the number of ART cyclesreported to CDC (Table 2). This, coupled with a modestrise in success rates each year, has led to a corres-ponding increase in the number of live-birth deliveriesand infants conceived through the use of ART. Over28 500 infants were born as a result of ART cyclesperformed in 1998. Some clinics (5%–7% of those inoperation) did not report data, despite the federalmandate. Most of these are believed to be fairly smallpractices and it is thus estimated that more than 95%of all ART cycles have been reported each year.
Each year, the majority of cycles were classifiedas fresh-nondonor and in 1998, 76.5% of the cyclescarried out were of this type. Cycles are furthersubdivided as IVF with transcervical ET, GIFT or ZIFT.As seen in Figure 3, the vast majority of cycles werefresh-nondonor IVF.
In each report, a series of success rates are
Table 2. Use of assisted reproductive technology in theUnited States, 1995–1998
1995 1996 1997 1998
ART clinics in the – 315 359 390United States
ART clinics that 281 300 335 360submitted data
ART cycles reported 59 142 64 036 71 826 80 634Live-birth deliveries 11 609 14 388 17 054 19 891
resulting from ART cyclesLiveborn infants 16 520 20 659 24 582 28 500
resulting from ART cycles
Notes:Total number of ART clinics was not tracked for 1995Because more than one infant may be born during a live-birth
delivery, the number of live-birth deliveries and liveborn infantsare not equivalent.
372 LAURA A. SCHIEVE et al.
presented to provide a complete picture of a woman’schances of pregnancy and live-birth delivery atvarious stages of the ART cycle. Figure 4 showssuccess-rate data for fresh-nondonor cycles in 1998.While over 30% of cycles started resulted in apregnancy, only 24.9% resulted in a live-birth delivery.As expected, the live-birth rate varied according to thedenominator used. Among cycles that progressed toET, 30.8% resulted in a live-birth delivery. Successrates were lower for cycles that used frozen embryos(19.3% live births per transfer for frozen-nondonorcycles in 1998) and higher for cycles that used donorembryos (41.0% and 23.2% live births per transfer forfresh and frozen-donor cycles, respectively).
We have consistently found that the age of thefemale patient is one of the strongest predictors forsuccess among nondonor cycles; success rates
decline steadily from the mid-thirties onward. Incontrast, age has had little impact on the success ofcycles that used donor ova, suggesting that the ageof the woman who was the source of the ova is ofprimary importance (Figure 5).
In each report, we also have examined the effectsof several other patient and treatment factors on ARTsuccess. These include infertility diagnosis, previousbirths, number of embryos transferred, ART type (IVF,GIFT, ZIFT), use of ICSI and clinic size. The findingshave been fairly consistent over the years. Havingpreviously given birth has been associated withincreased success rates in all age groups. Transfer ofthree or more embryos has also been generally associ-ated with increased success (however, this finding wasvariable by age and was limited in that embryoavailability and patient choice drive decisions on ET).
Figure 3. Types of ART procedures·United States, 1998
Figure 4. Success rates for ART cycles using fresh, nondonor eggs or embryos, by different measures, 1998
Frozen nondonor 13.9%
Frozen donor 2.4%
Fresh donor 7.2%
Fresh nondonor ZIFT* 1.4%
Fresh nondonor GIFT* 1.8%
Fresh nondonor IVF* 73.3%
*IVF, ZIFT, and GIFT cycles using donor eggs or frozen embryosare included in “donor” or “frozen” categories.
0
10
20
30
40
50
60
70
80
90
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30.5
24.9
Pregnancies
cycleLive births
cycle
Live births
Retrieval
Live births
Transfer
28.930.8
Assessment of outcomes for ART 373
ICSI was associated with slightly higher success ratesamong couples diagnosed with male-factor infertility.Finally, larger clinics tended to have higher successrates. There has been little variation in success ratesacross infertility diagnosis or ART type categories.However, to date, diagnostic criteria have been poorlydefined. Beginning with the collection of the 1999 ARTdata, infertility diagnostic criteria have been moreexplicitly defined to standardize this data element andto allow for analyses of couples diagnosed withmultiple causes of infertility.
In each report, limited data on adverse pregnancyoutcomes such as spontaneous abortion and ectopicpregnancy, and data on infant outcomes such asmultiple birth have also been presented. Treatmentfactors on ART success are also examined. Theproportion of multiple-gestation pregnancies and
multiple-infant births associated with ART hasremained fairly constant over the past four years. In1998, 39% of pregnancies had more than one fetus(defined by the number of fetal hearts observed onultrasound) and 38% of live-birth deliveries includedmore than one infant (Figure 6). This compares with amultiple-birth rate of less than 3% in the generalpopulation (8).
Lessons learned
Like all large-scale surveillance projects, implementa-tion of FCSRCA has presented a series of challenges.During the past four years, a number of issues havearisen that have prompted both SART and CDC toreview and refine various phases of the reporting
Figure 5. Live births per transfer for fresh embryos from own and donor eggs, by age of patient, 1998
Figure 6. Risk of having multiple-fetus pregnancy and multiple-infant live birth from ART cycles using fresh, nondonoreggs or embryos, 1998
28%Twins
11%Triplets +
18 800 pregnancies
61%Singletons
Total multiple-fetus pregnancies
32%Twins
6%Triplets +
15 367 live births
62%Singletons
Total multiple-infant live births
0
10
20
30
40
50
60
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Age
Per
cen
t
Own eggs Donor eggs
374 LAURA A. SCHIEVE et al.
process. We believe such refinements have led to moreefficient data collection and processing and improve-ments in data quality and data presentation. Like allsurveillance systems, the ART data system is notstatic; indeed it is a particular challenge to keep ARTdata collection current with the ever-evolving innova-tions in the field.
The challenges can be divided into two generalcategories: data-collection and data-reporting issues.The challenges with data collection generally stemfrom the large number of individual ART clinics inoperation. This makes coordination of the data flowquite cumbersome. To proceed in both a timely, fairand impartial manner, both SART and CDC recognizedearly on that explicit deadlines and guidelines for datasubmission were needed. Additionally, with such alarge number of clinics now performing ART, clinicalpractice is increasingly variable across clinics; thus,relatively soon it became apparent that some dataelements had been ambiguously defined. For example,clinics were asked to select the primary infertilitydiagnosis (tubal factor, male factor, ovulatory dys-function, endometriosis, uterine factor, other factorsand unexplained infertility) for each cycle reported.During a joint SART–CDC review, two issuesemerged. Diagnostic protocols were fairly variablebetween clinics, and forcing selection of a primarydiagnosis among couples with multiple diagnosesoften resulted in an arbitrary decision by clinicpersonnel. In response, more explicit criteria weredeveloped on how to classify each diagnosis for thepurposes of the ART surveillance system and a dataentry scheme was developed that allows for entry ofmultiple diagnoses.
The other major challenge that has been faced isthe presentation of these complex data and ideas in asimple and clear manner that is informative to thegeneral public. To help us assess whether the reportswere fulfilling their objectives, two series of focusgroups with current and prospective ART patientswere undertaken. The latest of these was conductedin 1999 and was based on an evaluation of the 1996ART Report. The groups were generally satisfied withboth the content and the format of the report. Someareas of confusion were noted, however. Many of thefocus-group participants had trouble understandingsome of the more clinical and statistical terms andconcepts used in the report. Some of the most difficultincluded age-adjusted rate, 95% confidence intervalsand multiple-gestation pregnancy. To a lesser extent,even the basic indicators presented caused confusion.
For example, some participants could not understandthe differences between the live birth per cycle, livebirth per retrieval and live birth per transfer rates. Inresponse to these problem areas, adjusted rates are nolonger given and instead the focus in the clinic tablesis on rates stratified by patient age and cycle type.Confidence intervals are still included because we canfind no simpler way to provide a sense of the oftenlarge variance measures inherent in data from smallclinic samples, but we have expanded our explanationof how to understand and interpret a confidenceinterval. We altered some of the report terminology toprovide more familiar descriptions for certainindicators; for example, we now refer to multiple-fetuspregnancies rather than multiple gestations. Weexpanded the national report to provide a clearerpicture of the overall concepts of rates, why rates withdifferent denominators are presented, and how tointerpret the various rates presented. Finally, we add-ed a section to the report that include answers to manycommonly asked questions about the report processand content.
In addition to the focus groups, feedback isreceived each year from various individuals in thepublic domain as well as ART providers. We reviewtheir comments with SART and RESOLVE andconsider revisions and additions to data presentation.A particularly challenging issue that has arisen is howto present, fairly, data for clinics that were in operationduring a given reporting year but have undergonereorganization by the time of report publication.Reorganization can include a change of key staff(medical, practice and/or laboratory directors) or achange in clinic ownership or affiliation. Althoughonly a handful of such reorganizations occur eachyear, they have required a great deal of attention, aseach party involved is understandably concerned thatthe ART report represent their situation accurately. Inresponse to these concerns, a policy has been deve-loped to present each clinic according to the clinicname at the time of data collection (e.g. all clinics inthe 1998 report are presented according to their 1998clinic names). Changes in clinic names and any clinicreorganizations that have occurred after the reportingyear are noted.
Future directions
As the field of ART continues to evolve, the ARTsurveillance system will also evolve. SART, with
Assessment of outcomes for ART 375
support from CDC and RESOLVE, continues to reviewand revise its reporting system. As previously noted,SART has already made several important changes.It has clarified many case definitions and addressedseveral ambiguities in classifying ART cycle type andoutcome. This includes developing more explicitcriteria for documenting live-birth deliveries in clinicrecords and adding a provision for reporting thesource of information for each live birth. Additionally,SART has added several data elements to the systemto capture better patient and treatment differences thatmight be affecting success rates. These include dataon clinical indices such as the patient’s hormonelevels, and improved data on pregnancy history,infertility history and the history of previous infertilitytreatment. Several data items have been streamlinedor discarded because they were not deemed useful.The revised reporting system was instituted inthe1999 ART data-reporting cycle and CDC plans toassess the accuracy and completeness of the newdata items and incorporate analyses of these factorsin future reports.
CDC and SART are also investigating the feasibi-lity of various mechanisms that will allow the linkageof data from ART cycles performed on the samepatient. Such a system will permit the evaluation ofART usage patterns within and between clinics andover time‚ and the assessment of cumulative patientsuccess rates. As previously mentioned, SART is alsoworking on the development of systems to improvedata quality, such as adapting its data system to allowfor prospective reporting.
Finally CDC, ASRM, SART and RESOLVE continueto struggle with various “nonmethodological” issuesinherent in this surveillance system. ART, like othermedical specialties, is increasingly conducted inindependent clinics that must consider cost and profitissues to remain viable. Since this surveillance systemis clinic-based, there is often concern about theimpact that the ART report may have on clinicbusiness practices. Thus, it is especially importantthat success-rate data are collected in a fair andimpartial matter, that erroneous data are corrected tothe fullest extent possible and that all success ratesare presented in the appropriate context with fulldisclosure of the limitations in interpreting and com-paring success rates. Various concerns related to thisissue have been addressed already. The challenge isto meet the requirements specified in the nationallegislative mandate, to provide a report that is fair toclinics, but also to present these data in a meaningful
way at a level that is appropriate for the general public.ART use continues to grow in the USA and
throughout the world. The USA ART surveillancesystem and the annual reports published from thissystem provide standardized information on ARTsuccess rates for patients as well as for the medical andpublic health communities. These data are being usedby patients and providers to make informed choicesabout ART. CDC, ASRM, SART and RESOLVE havemade a great deal of progress in developing thecurrent surveillance system and will continue to colla-borate on this increasingly important public healthissue.
Appendix
To obtain a printed version of the most recent Assistedreproductive technology success rates report, callCDC’s Division of Reproductive Health, info line: 1-770-488-5372. For immediate electronic access to anyof the published reports, connect to the CDC web site:www.cdc.gov/nccdphp/drh/art.htm.
Acknowledgements
We are grateful to the many individuals at the Societyfor Assisted Reproductive Technology (SART), theAmerican Society for Reproductive Medicine (ASRM),and RESOLVE, The National Infertility Associationwho have contributed to the development andcontinued review of the assisted reproductive tech-nology reporting system in the USA and the annualAssisted reproductive technology success ratesreports.
References
1. Abma J et al. Fertility, family planning, and women’shealth: new data from the 1995 National Survey ofFamily Growth. Hyattsville, Maryland: National Centerfor Health Statistics. Vital Health Statistics, 1997:23(19)
2. CDC, American Society for Reproductive Medicine,Society for Assisted Reproductive Technology,RESOLVE. 1998 Assisted reproductive technologysuccess rates: national summary and fertility clinicreports. CDC‚ Atlanta, 2000.
3. Fertility Clinic Success Rate and Certification Act of1992 (FCSRCA), Public Law 1992:102–493.
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4. CDC, American Society for Reproductive Medicine,Society for Assisted Reproductive Technology,RESOLVE. 1995 Assisted reproductive technologysuccess rates: national summary and fertility clinicreports. CDC‚ Atlanta, 1997.
5. Feichtinger W. Results and complications of IVFtherapy. Current Opinion in Obstetrics and Gynecology,1994, 6 :190–197.
6. Winston RML, Handyside AH. New challenges in humanin vitro fertilization. Science, 1993, 260 :932–936.
7. CDC. Reporting of pregnancy success rates from assistedreproductive technology programs. Federal Register,2000, 65:53310–53316.
8. Ventura SJ et al . Births: final data for 1998. Nationalvital statistics reports. 2000: Vol. 48‚ No. 3. Hyattsville‚Maryland, National Center for Health Statistics, 48.
International registries of assisted reproductive technologies
KARL NYGREN
Introduction
International data collection and reporting of assistedreproductive technology (ART) results are still verymuch in their infancy. The same is true for nationalreporting systems; however, there are large differ-ences between countries. Many countries have noreporting systems at all while others do‚ although withdifferent levels of completeness, working definitionsand validation.
The degree of complexity of ART data reportingescalates from case reports via clinic reports throughnational reporting systems and regional reporting toworld reports. As the reporting widens and includesmore and more treatment cycles, the data tend tobecome more incomplete and originate from differentvalidation systems and definitions. However, thissituation is a very dynamic one. More and morecountries are now establishing national reportingsystems, on which regional and world reporting rely.
A commonly adopted strategy, at least amongthose responsible for national and internationalregistration of data, is that each clinic should reporttheir results only once. National bodies, be theygovernmental or nongovernmental, either on anobligatory or a voluntary basis, should collect, auditand publish national data, preferably on an annualbasis, in their own country. They should also reporttheir national data to regional bodies, where such
bodies exist. At present‚ four regional bodies reportdata annually: Australia and New Zealand (1), LatinAmerica (2), USA and Canada (3) and Europe (4).Regional bodies are also under preparation in South-East Asia.
The International Working Group for Registers onAssisted Reproduction, which is now a Task Forceunder the International Federation of Fertility Society(IFFS), has so far produced five world reports. Themost recent report was published in 2001(5).
Why register?
ART is a very dynamic field and will possibly remaindynamic for a long time. The dynamics includesmedical improvements, new treatment modalities,ethical issues, cost–benefit analyses for allocation ofresources and national legislation. Infertile couples,ART professionals, the industry, media, politicians,legislators and the public at large all need relevantinformation on results and outcomes of ART. Theyneed data from an individual clinic or an individualcountry and also international data, so that they canmake relevant comparisons to elucidate the character-istics of ART in their own setting. Therefore, thedifferent levels of reporting complement each other.
378 KARL NYGREN
How to register?
When a national registration on ART is established,there are two basic options to choose from. First‚ eachclinic in the country is asked to prepare an annualreport covering items decided by the registratingbody of that country. The data should ideally be cohortdata covering treatments starting over a period of oneyear and the outcome of those treatments, whichmeans that data usually cannot be collected until theend of the second year.
The second option is to collect data from eachcycle individually, preferably in a direct system wheredetails are reported before the outcome of eachtreatment is known.
The annual reporting system has, for example,been chosen by the Scandinavian countries. Thesystem is simple and cheap but it has a potentialproblem with data validation.
The individual cycle reporting system has beenchosen, for example, in Germany and the UK (4). It ismuch more expensive and complicated to follow buthas advantages as regards validation of the data.
The collection of national data must then befollowed by a process of auditing and publishing. Topublish only crude data is not acceptable to the consu-mers of the reports. The data have to be audited,important time-trends have to be highlighted and—avery controversial issue—the reporting of “successrate” per clinic has to be handled with care. (This lastissue is difficult indeed and is highlighted by theproblems created in the UK, where the authority triedto construct one simple measurement of success inART treatments. Despite the good intention‚ thisresulted in a distortion of available data so that coupleswere misled and clinics started to adopt proceduresthat were not necessarily medically indicated.)(Personal communication with Professor AllanTempleton)
The publication of national data should ideally beonce a year. The experience from several countries isthat such publication gets good coverage in the mediaso that the public can share the results. Internationally,the four regional reports in existence collect data fromtheir region and publish annual reports along the samelines as the national reports.
It is hoped that in the future the world reports willbe published on a biannual basis.
What should be reported?
Ultimately, each country should report the results ofdirect treatment (pregnancy rates, etc.), pregnancyoutcome (deliveries and children born), child develop-ment and primary or secondary side-effects for thewomen.
Each of these reporting areas need differentstrategies for data collection. Most registries todayonly deal with the first of these categories, reportingthe immediate results of ART treatments including theproportion of pregnancies, abortions, ectopic preg-nancies and deliveries (single or multiples) in relationto started cycles, ovum pick-up rates and the numberof embryo transfers. Different modalities of treatmentare reported separately (standard in vitro fertilization[IVF], intracytoplasmic sperm injection [ICSI], frozenand thawed embryo transfers, etc.). This category ofreporting sometimes, but not always, also includesinformation on the type of delivery (normal, forceps,vacuum extraction, caesarean section) and possiblythe birth weight and the gestational week of delivery.
The immediate outcome of the deliveries regardingthe health of the babies born (detailed information onbirth weight, week of delivery, malformations, perinataldeath rates, etc.) usually requires a quite differentstrategy of data collection and is much more complexto organize. In many countries specific reporting sys-tems have to be set up and they are difficult to managenationwide. Therefore, monitoring of the outcome forthe children from individual clinics is usually easierto perform. One exception is the Nordic countrieswhere national medical birth registries have been inexistence for some time and data are collected on allchildren born in the country. By cross-linkage tospecific ART registers it is much easier to have a com-plete and correct information of the outcomes for theART children and compare these and national data(6).
Later child development follow-up focuses notonly on psychosocial but also on late medical prob-lems such as neurological sequelae. In this case, datacollection is usually even more cumbersome andnecessitates much smaller samples of individuals.Reports in this category are still scarce.
Which ART categories?
The reporting systems described so far usually coverdifferent types of IVF but not other medical treat-
International registries of assisted reproductive technologies 379
ments, such as induction of ovulation. One of the mainmedical problems with ART treatment is the persistentoccurrence of high levels of multiple pregnancies.However, it may well be that this problem is of the sameor even higher magnitude after ovarian stimulationwithout ART. In this field, so far, only clinic reportshave appeared in the literature and there have beenno systematic national efforts at data collection. It isclear that this gap has to be filled and in Swedenefforts are under way to do so.
Where to go from here?
For future refinement of ART reporting, three areasappear to be the most important.
Definitions
Each country has its own working definitions coveringimportant determinants such as “When does a treat-ment cycle actually start?”, “What is a biochemicalpregnancy?”, “Where is the dividing line between alate abortion and a birth?”, “What is a major malforma-tion?” This situation has not come about by chancebut is the result of different cultures, different ethicalviews on ART, legislation on legal abortion, etc.Nevertheless, for the sake of comparison, a harmoniza-tion of definitions would be highly desirable and theInternational Working Group is preparing a list ofdefinitions used in ART.
Validation of register data
The possibility of validating data nationally andensuring that they are complete is rapidly improvingin many countries. One mechanism is through theprocess of accreditation, based on inspections ofclinics. Another possibility is to cross-link data fromdifferent registries. Today, some countries havehighly sophisticated validation systems although thedata are not complete. Examples of this include Germanyand the USA where reporting is not obligatory.
Again, the situation is dynamic and improving inmany countries. The driving force behind the changeis most probably that potential consumers of thisinformation in each country realize the importance ofthe data being both valid and complete.
Guidelines
The International Working Group for Registers onAssisted Reproduction has taken, as one of its tasks,the formulation of guidelines for the establishment ofnational registries on ART. The Group realizes thatsuch guidelines must recognize different ways indifferent countries of reaching the same goal, namelycomplete and valid data.
Summary of available data
Pregnancy rates, usually expressed as the proportionof pregnancies per embryo transfer, differ immenselybetween countries. There are three reasons for thesevery large differences. One may be differences in skillsin different countries. The most powerful reason,however, is the very different policies concerning thenumber of embryos transferred at each procedure.These numbers vary amongst countries from four ormore (examples are Eastern and Southern Europe, LatinAmerica and also partly in the USA) down to one ortwo embryos per transfer as in the Nordic countries.A third reason is the very varied practice of fetalreduction (the technique to reduce the number offetuses to transform a high-order multiple pregnancyto a low-order multiple pregnancy). This procedure isvery controversial in some countries but it is practisedfrequently in France and the USA but very rarely inthe Nordic countries (6).
Spontaneous abortions are heavily age dependent(increasing with the age of the woman) but the averageafter ART is not increased from the normal rate and isusually recorded as around 18% of pregnancies.
Ectopic pregnancies are fewer today compared tothe early days of ART treatment. This shift dependson the fact that women with tubal damage dominatedthe early years of ART treatment, whereas today theyform only a relatively smaller part of the indicationsfor treatment. Whereas ectopic pregnancy ratesformerly were reported as 3%–5% per embryo transfer,most countries today report an incidence of about1%–2%, which is not significantly higher than thenational rates in the population as a whole (1–5).
Multiple pregnancy rates are very different indifferent countries. Characteristically, they are low innorthern Europe and Australasia and high in LatinAmerica, the USA and Southern and Eastern Europe.The USA reports a multiple pregnancy rate of 37%while Europe reports a corresponding rate of 29% (3,4).
380 KARL NYGREN
Epidemiology
Today about one million children have been bornworldwide after IVF treatments per se and the numberof children born after other forms of ART is veryuncertain but is possibly about the same. Therefore‚around 2 million children have been born after assistedreproduction.
Availability
The availability of ART services differs widely amongcountries. One extreme example is the Nordic countries,where there are 1000 to 1500 treatments per millioninhabitants. In contrast, the availability in the USA isabout 200 treatments per million inhabitants. In severaldeveloping countries, including China and India, theavailability is certainly extremely low (5).
References
1. Hurst T, Shafir E, Lancaster P. Assisted conception,Australia and New Zealand. AIHW National PerinatalStatistics Unit. Sydney, 1996.
2. Zegers-Hochschild F, Galdames IV, eds. RegistroLatinoamericano de Reproduccion Asistida 1997. RedLatinoamericana de Reproduccion Asistida, 1999.
3. Society for Assisted Reproductive Technology. TheAmerican Society for Reproductive Medicine. Assistedreproductive technology in the United States: 1996results generated from the American Society forReproductive Medicine/Society for Assisted Reproduc-tive Technology Registry. Fertility and Sterility, 1999,71:798–807.
4. The European IVF-monitoring programme (EIM), forthe European Society of Human Reproduction andEmbryology (ESHRE) (2001). Assisted reproductivetechnology in Europe, 1997. Results generated fromEuropean registers by ESHRE. Human Reproduction,2001, 16:384–391.
5. Adamson D et al. International Working Group forRegisters on Assisted Reproduction. World collaborativereport on assisted reproductive technology, 1998.. In:Healey DL et al. eds. Reproductive medicine in thetwenty-first century. Proceedings of the 17th WorldCongress on Fertility and Sterility, Melbourne, Australia.New York, Parthenon, 2002:209–219.
6. Bergh T et al. Deliveries and children born after in vitrofertilisation in Sweden 1982–95: a retrospective cohortstudy. Lancet, 1999, 354 :1579–1585.
Recommendations
The meeting participants agreed upon the following recommendations which are grouped under theheadings of the various topics that were discussed. While in most cases it is self-evident as to whom therecommendation is directed, some recommendations specify the group or entity that would be expectedto take the appropriate action.
Section 1: Infertility and assisted reproductive technologies in the developing world
Papers
Infertility and social suffering: the case of ART in developing countries (Abdallah S. Daar, Zara Merali)ART in developing countries with particular reference to sub-Saharan Africa (Osato F. Giwa-Osagie)
Despite infertility being a universal health problem, infertile couples—especially in developing countries—have limited access to infertility services. Infertility has been argued to be relatively unimportant in low-resource settings where fatal and infectious diseases remain uncontrolled. While inadequate access toassisted reproductive technology (ART) is a worldwide issue, it is particularly pronounced in resource-poor settings. Improved access depends on a number of factors, including increased recognition ofinfertility as a public health problem by policy-makers, the development of simplified management schemesfor infertility and reduction in the cost of ART to the consumer.
Recommendations
• Infertility should be recognized as a public health issue worldwide, including developing countries.• Research is needed on innovative, low-cost ART procedures that provide safe, effective, acceptable
and affordable treatment for infertility.
384 Recommendations
Section 2: Infertility and assisted reproductive technologies from a regional perspective
Papers
Assisted reproductive technology in Latin America: some ethical and sociocultural issues (Florencia Luna)Attitudes and cultural perspective on infertility and its alleviation in the Middle East area (Gamal I.
Serour)Social and ethical aspects of assisted conception in anglophone sub-Saharan Africa (Osato F. Giwa-
Osagie)ART and African sociocultural practices: worldview, belief and value systems with particular reference
to francophone Africa (Godfrey B. Tangwa)Sociocultural attitudes towards infertility and assisted reproduction in India (Anjali Widge)Sociocultural dimensions of infertility and assisted reproduction in the Far East (Ren-Zong Qiu)
Cultural perspectives regarding infertility and ART are as diverse as the societies in which they exist.However, one common theme is that infertility is perceived universally by the infertile as a stigma. Inmany cultures infertility is usually blamed on the female partner. As a result, the burden of infertility isheavier for women, especially in societies that define womanhood through motherhood. The feeling ofstigmatization exacerbated by family, peer and media pressure leads to psychological, marital and socialproblems. The infertile couple, but more often the female partner, seeks assistance and advice frommembers of the family, traditional healers, primary health care providers or directly from infertilityspecialists. Often the infertile couple is especially vulnerable to chicanery by both traditional andconventional health care providers.
ART is practised in many countries and a wide range of perceptions exists, depending on the particularculture and society. Such perceptions are often influenced by religious views and traditional cultural values.Although in some societies ART may not be perceived with a positive attitude, the number of clinics thatoffer ART services is on the rise. The media are often responsible for creating a very promising image ofART and of what it can offer to the infertile couple. However, it is well known that in many countries thepublic lacks basic knowledge about infertility, its causes and its prevention, as well as accurate informationabout realistic possibilities for infertility treatment.
Recommendations
• Policy-makers and health staff should give attention to infertility and the needs of infertile patients.• Governments should improve education in infertility and reproductive health for the general public
and health care professionals.• A gender perspective needs to be applied by health care providers to infertility management and treatment.• Infertility management should be integrated into national reproductive health education programmes
and services.• Physicians should provide adequate investigation facilities and treatment for the infertile couple in a
culturally sensitive and ethically acceptable manner.• Where appropriate, traditional healers should be included in the dialogue between patients and health
care providers concerning the treatment of infertility.• Where public funding is insufficient, alternative sources of funding for public sector ART programmes
should be sought.
Recommendations 385
• Cost-effective options, including the establishment of national networks of satellite clinics to screenand refer appropriate couples to specialist centres, should be examined as a means of improving accessto ART.
• ART should be complementary to other ethically acceptable, social and cultural solutions to infertility.• Public awareness of infertility and its causes should be increased to improve preventative behaviour
and to diminish the stigmatization and social exclusion of infertile men and women.• The dissemination of public information on the options for treatment of infertility, including adoption
and the ethical and legal issues involved, should be improved.
386 Recommendations
Section 3: Recent medical developments and unresolved issues in ART
a. Gamete source, manipulation and disposition
Papers
Gamete source and manipulation (Herman Tournaye)Ovarian stimulation for assisted reproductive technologies (Jean-Noel Hugues)ICSI: technical aspects (Henry E. Malter, Jacques Cohen)ICSI: micromanipulation in assisted fertilization (André Van Steirteghem)Cryopreservation of oocytes and ovarian tissue (Helen M. Picton, Roger G. Gosden, Stanley P. Leibo)Cryopreservation of human spermatozoa (Stanley P. Leibo, Helen M. Picton, Roger G. Gosden)Gamete and embryo donation (Claudia Borrero)
Intracytoplasmic sperm injection (ICSI) has now become a widely used procedure and is indicated forthe treatment of male infertility; however, it should not be considered as an alternative to routine in vitrofertilization (IVF). The current methods of sperm selection for ICSI are unable to prevent the injection ofaneuploidic spermatozoa. As a result, the health of ICSI offspring has been of considerable concern. Todate, available evidence on the short-term health of ICSI children appears to be reassuring.
A possible factor in the failure of implantation is nonrupture of the zona pellucida. Recently, techniqueshave been developed to assist in the hatching of the embryo through the zona pellucida. These includedrilling with an acidified medium, zona slitting, zona thinning and, most recently, laser assisted hatching.Few randomized studies have been conducted; however, retrospective analysis has yielded equivocalresults comparing implantation and pregnancy rates from assisted hatching and control embryos.
The purpose of ovarian stimulation is the accelerated development of oocytes suitable for fertilizationeither in conjunction with in vivo insemination (donor insemination/artificial insemination from husband[DI/AIH]) or IVF–ICSI. In the past decade, there have been considerable advances in the understandingof ovarian follicular physiology together with the development and introduction of more specific drugsfor ovarian stimulation.
One of the major issues in ART is the high frequency of multiple pregnancy, and the associated prematurebirths and neonatal morbidity and mortality. Whereas the incidence of multiple births following IVF/embryotransfer (ET) or ICSI is determined by the number of embryos transferred, there is far less control overthe number of oocytes fertilized following ovarian stimulation and DI/AIH. In clinics where both proceduresare carried out and whether two to three embryos are transferred after IVF/ET or ICSI, high-order multiplepregnancies are almost exclusively the result of multiple in vivo fertilizations following ovarian stimulation.
Common to all methods of ovarian stimulation is the potential for ovarian hyperstimulation syndrome(OHSS). In the past decade, prevention of OHSS has been improved by the identification of high-riskpatients and closer monitoring of induced folliculogenesis, including serial serum estradiol estimationsand ultrasound assessment of the cohort of growing follicles. The prognosis of ART in older women isconsistently poor. In that respect, couples should be informed about the high risk of stimulation cyclecancellation and counselling should be provided on alternative solutions.
Concerns remain over possible associations between induced folliculogenesis and uterine and ovariancancer. However, concerns about breast cancer would seem to have been allayed.
Recommendations 387
Cryopreservation of male and female gametes has been a critical issue in the development of ART.Cryopreserved/thawed sperm and oocytes increase the flexibility of ART services, while they also allowpatients who might become infertile after medical interventions to restore fertility. Despite the clear evidenceof individual patient variation in the success of sperm cryopreservation, the methodology for sperm freezinghas changed little over the past 20 years.
In recent years, the prospect of ovarian tissue cryopreservation has attracted the attention of the medicalcommunity as well as the media. Despite sensational reports on the implications of such options for theconservation of future fertility, limited information is available on the optimal cryopreservation techniquesfor immature oocytes that would be recovered from unstimulated ovaries or ovarian cortical tissue.Although cryopreserved ovarian cortical tissue may be used as the source of immature female gametesand ovarian cortex autografting has the potential to restore reproductive function, long-term viability andsafety data are not yet available.
One of the reasons advocated for retrieval of immature oocytes from unstimulated ovaries has been thelimited availability of oocyte donors. Egg-sharing has been considered as a way of overcoming this problem.While the first presents significant technical difficulties, the latter poses complex psychological and ethicalquestions.
Recommendations
• Existing data on the efficacy, safety and outcome of ICSI should be analysed as a matter of high priority.• The effect of ICSI treatment on the risk of congenital malformation should continue to be monitored.• Further animal studies are needed to evaluate the safety of the following procedures currently being
investigated or proposed for the treatment of infertility:—ICSI using round spermatids—in vitro spermatogenesis—spermatogonial stem-cell maturation—in vitro growth and maturation of oocytes—cytoplasmic transfer—haploidization of diploid somatic cell nuclei.All of these procedures should be considered experimental.
• Nonobstructive azoospermia should be defined by clinical, biochemical and histological features priorto selection for ICSI.
• Methods need to be developed to detect aneuploidic spermatozoa so that these can be excluded fromsperm preparations to be used for ICSI.
• Because of the risk of aneuploidy in testicular spermatozoa, it is important to combine ICSI withpreimplantation genetic diagnosis (PGD) to prevent aneuploidy in offspring.
• Further research is needed on the outcome of pregnancies resulting from the use of nonejaculatedsperm.
• Research is needed on the role of prenatal testing during ICSI pregnancy.• Sensitive test systems (e.g. micro-array probes [gene chips]) need to be developed for screening ICSI
candidates for known genetic traits that can be transmitted to subsequent generations.
388 Recommendations
• Low-dose ovarian stimulation protocols should be used so that fewer follicles develop.• To reduce high-order pregnancies following ovarian hyperstimulation for non-IVF/ICSI-ET, if the
number of preovulatory follicles is more than two, the cycle should be converted to IVF/ICSI-ET, orif access to IVF/ICSI is not available, the cycle should be cancelled.
• Further research is needed on the efficacy of ovarian stimulation regimens in which exogenousrecombinant-follicle stimulating hormone (rFSH) or r-luteinizing hormone (rLH) are administered.
• Research is needed on the optimal regimen for oral contraceptives in programming gonadotrophin-releasing hormone (GnRH) antagonist cycles.
• Further research is needed on noninvasive measurement of ovarian blood flow for monitoring theinduction of ovulation.
• Research is needed on uterine receptivity using ultrasonographic measurement of peristaltic uterinecontractions.
• Research is needed on the efficacy of the vaginal route of administration of progesterone administration(particularly sustained-release formulations) compared with intramuscular injection for luteal support.
• Studies need to be conducted on the use of progesterone and/or estradiol for luteal phase support withor without human chorionic gonadotrophin (hCG) administration as regards implantation andmiscarriage rates.
• Further research is needed on the application of freeze-drying for human gamete cryopreservation.• Protocols for the cryopreservation of human gametes, embryos and gonadal tissues need to be
optimized.• Protocols for the cryopreservation of sperm need to be improved to reduce the observed variation in
sperm survival.• Sperm donors need to be screened for hereditary as well as infectious diseases.• Procedures for the separation of X- and Y-bearing spermatozoa should be used for preventing the
transmission of sex-linked diseases.• Further scientific and ethical research is needed on the application and use of spermatozoa retrieved
postmortem or from patients in a persistent vegetative state.• Clear guidelines need to be established for the optimal stage of oocyte maturation for cryopreservation
that maximizes gamete survival and developmental potential but which minimizes the risk of aneuploidy.• More research is needed on aneuploidy screening of oocytes after cryopreservation and of embryos
generated following ovum cryopreservation.• More research is needed on autotransplantation of frozen-thawed human ovarian tissue.• There is a need for long-term viability and safety data on the restoration of reproductive function
following ovarian autografting or the in vitro growth of oocytes.• Data are needed on the short-term and long-term medical and psychological issues related to oocyte
“sharing”, with a particular focus on the donor.• Long-term psychological follow-up is needed of gamete donors and recipients and of the resulting
offspring.
Recommendations 389
b. Embryo selection methods and criteria
Papers
Embryo culture, assessment, selection and transfer (Gayle M. Jones et al.)Preimplantation genetic diagnosis (Luca Gianaroli et al.)
Following fertilization, the zygote needs to mature to a stage that is suitable for uterine implantation. Thisprocess (which involves the transition from the zygote to the morula and then to the blastocyst) normallyoccurs in the fallopian tube and uterus, but can be induced in the laboratory. This in vitro process ofearly embryo development—termed embryo culture—has become a highly sophisticated set of laboratoryprocedures involving culture media and culture conditions, selection of embryos for transfer, techniquesand timing of ET, assessment of endometrial receptivity and luteal phase support in the postimplantationperiod. None of these procedures has been fully optimized and they are under constant refinement andimprovement.
The transmission of genetic disorders remains a major problem in reproductive medicine. Until recently,couples have been screened mainly by using maternal age or family history. Invasive procedures such asamniocentesis and chorionic villus sampling have been extensively used in high-risk populations. However,the detection of a genetic abnormality implies a decision to be made by the woman as to whether or notthe pregnancy should be terminated. In many countries this option is not available. PGD provides thepossibility for screening for chromosomal and genetic disorders prior to implantation; and if suchabnormalities are detected, the ET need not proceed. PGD is now an established technique for the detectionof genetic and chromosomal abnormalities in preimplantation embryos and may be used for detection ofchromosomal or monogenic diseases in high-risk couples.
Recommendations
• The optimal in vitro culture environment for human embryos needs to be established and refined andtested by randomized controlled trials of sufficient power.
• Research is needed to determine the cleavage stage of the zygote or blastocyst that is optimum fortransfer in terms of pregnancy outcome.
• The criteria for uterine receptivity in relation to implantation and continuing pregnancy need to be betterdefined.
• More specific criteria for predicting the developmental potential of the embryo need to be developed.• Research is needed on embryo morphology and growth rate including:
—the regulation of cell cycles in the preimplantation embryo—the aetiology of cell fragmentation in the preimplantation embryo—determination of the role of cytoplasmic and nuclear polarity in the viability of preimplantation embryos—relationship of embryo viability with follicular and oocyte parameters both within an ovulatory cycle
cohort and between cycles and patients.• Further research is needed on the sensitivity, specificity and predictive value of PGD alone for the
detection of aneuploidy. At present, amniocentesis or chorionic villus sampling are recommended afterPGD.
390 Recommendations
• Techniques need to be developed for the simultaneous screening for fetal single-gene disorders andchromosome aneuploidies using multiple markers.
c. Multiple pregnancies and multiple births
Papers
Multiple pregnancy in assisted reproduction techniques (Ozkan Ozturk, Allan Templeton)Outcome of multiple pregnancy following ART: the effect on the child (Orvar Finnstroem)Multiple birth children and their families following ART (Jane Denton, Elizabeth Bryan)
The number of embryos transferred is the major factor determining multiple pregnancy rates in ART.Elective single embryo transfer reduces the risk of multiple pregnancy and may result in a comparablepregnancy rate to that obtained with two embryo transfers. It has been shown that successive singlefrozen-thawed embryo transfers can achieve good cumulative conception rates while minimizing the riskof multiple pregnancy. In turn, this will reduce the excess maternal morbidity and mortality associatedwith multiple pregnancy.
The high percentage of multiple births following ART is mainly responsible for the high rate of pretermbirths, neonatal complications and congenital anomalies. The increasing numbers of preterm babies,especially from high-order pregnancies, have resulted in an exponential increase in the cost of neonatalcare. As a result of the increased health risks and costs, fetal reduction may be offered as an option inorder that some of the adverse effects of a triplet or higher-order pregnancy may be reduced. However,there are considerable ethical and legal implications of this technique. What strategies should be implementedto reduce multiple pregnancies associated with ART remains an unresolved issue.
Recommendations
• Prior to treatment, health personnel should provide patients with full information about ovarian stimulationand the risks and implications of multiple pregnancy.
• In view of the maternal and fetal risks of multiple pregnancy, no more than two embryos should betransferred per cycle.
• To encourage single embryo transfer, any additional spare embryos should be cryopreserved forsubsequent treatment cycles—if needed, and where it is not illegal to do so.
• Prospective studies are needed to compare the outcomes of elective single embryo transfers with twoembryo transfers.
• Methods need to be developed and tested for the selection of embryos for elective one- or two-embryotransfers.
• Ovarian stimulation protocols need to be optimized to reduce the likelihood of multiple pregnancy asa result of treatment with gonadotrophins followed by intrauterine insemination (IUI).
• The efficacy, side-effects, patient acceptability and costs of IVF, versus ovarian stimulation and IUI,need to be compared in patients deemed suitable for either treatment (unexplained infertility, mildendometriosis, and mild male factor infertility).
• More data are required on malformation rates following ART, especially in twin pregnancies.• As monozygous multiple pregnancies have a much higher perinatal mortality rate than dizygous
Recommendations 391
pregnancies, ART specialists and obstetricians should determine zygosity by assessing whether thereare one or two chorionic membranes (chorionicity). This can be defined by ultrasound scan prior to14 weeks’ gestation as the chorion is optimally seen in early pregnancy. It is particularly important inART multiple pregnancies in which the risk of monozygosity may be increased.
• The incidence and possible causes of monozygotic twinning in pregnancies resulting from ART needto be determined.
392 Recommendations
Section 4: Social and psychological issues in infertility and ART
Papers
Consumer perspectives (Sandra Dill)Gender, infertility and ART (Ellen Hardy, Maria Yolanda Macuch)Family networks and support to infertile couples (Pimpawun Boonmongkon)Parenting and the psychological development of the child in ART families (Susan Golombok)
Consumers have a key role in improving the availability and quality of infertility services especially throughlocal and national support groups. A crucial issue in the management of infertility, including ART, is thatinfertile couples need to have sufficient information so that they may make informed choices as to whereand how they will be diagnosed and treated.
Since the early days of ART more than two decades ago, there have been concerns about the health andpsychological well-being of ART offspring. As it is now possible to have up to five parents (an oocytedonor, a sperm donor, a surrogate mother and two social parents), many questions have been raised aboutthe consequences of such possibilities for psychological development through childhood and into adultlife. Additional concerns have been raised regarding the functioning of the ART family as a whole. Howthe relationships and dynamics in an ART family are affected by the partial or complete absence of geneticlinks between the child and the parents in cases of gamete donation, or by the secrecy or disclosure ofthe circumstances of conception to the child, are questions of critical importance especially with theever-growing number of people resorting to ART for solving their infertility problem.
Existing studies have shown that singleton ART children born at term do not appear to differ fromspontaneously conceived children with respect to psychological well-being or the quality of their relationshipwith their parents. Although data are limited, and research in this area lags behind the fast developmentsand advances in ART, there is no evidence of developmental delay among singleton ART children.
In many societies infertility problems are blamed on women irrespective of the diagnosis. As a result,traditionally, the burden of infertility has been heavier for women. ART has improved the chances ofinfertile couples to have children but, at the same time, it has further increased the imbalance with theshare of the burden of treatment relying more heavily on women. Several forms of ART have been criticizedfor causing that imbalance and for reinforcing the conventional gender roles. The increased expectationsregarding ART resulting from media publicity, the greater economic and emotional costs and the greaterphysical demands made on women, as well as failed ART, result in significant psychological distress andhave significant social consequences for the couple.
Infertile men and women suffer the effects of their infertility throughout their lifespans and develop copingmechanisms in the context of their family and sociocultural environment. In many circumstances differentforms of family and other social supports exist to help both partners. Research has focused on howwomen cope with infertility, but less information is available on the coping mechanisms of men withchildlessness.
Recommendations
• Consumers of ART services should work closely with professionals and with governments to document
Recommendations 393
the health implications of infertility.• Local and national patient support groups play an important role in advocating improved treatment of
infertility and their establishment should be encouraged.• Consumer groups should continue to play a critical role in advocating further research on ART, improving
public health education, and striving to increase equity of access to ART.• The terminology used to describe gamete and embryo donors and recipients, surrogate mothers, and
their relationship to the offspring, needs to be defined and agreed upon.• Prior to treatment, patients undergoing ART procedures involving gamete or embryo donation should
be counselled about the implications of disclosure and nondisclosure to the child of its genetic origins.Subsequently, parents should have access to support when they are considering being open with thechild about his/her genetic origins.
• Further studies should be conducted on the effects on the child of secrecy and disclosure about his/her genetic origins resulting from gamete or embryo donation.
• Further studies are needed of the consequences for parenting and child development of surrogacy,gamete and embryo donation and the use of donor insemination by lesbian and single heterosexualwomen.
• Studies are needed on the quality of parenting and the psychological well-being of children in familieswhich have had multiple births by ART.
• Long-term epidemiological studies are needed on the psychomotor and cognitive development of ARTchildren.
• In addition to the counselling provided in infertility clinics as routine support to infertile patients andtheir families, support groups, media discussions and internet exchange can also provide valuable inputsand these should be encouraged.
• The nature of gender-specific, psychosocial reactions to ART procedures and outcomes should beinvestigated.
• More research is needed on how men and women perceive and respond to infertility at different stagesin their lives.
• Research is needed on how to reduce the consequences of infertility and especially its impact on women.
394 Recommendations
Section 5: Ethical aspects of infertility and ART
Papers
Patient-centred ethical issues raised by the procurement and use of gametes and embryos in assistedreproduction (Helga Kuhse)
When reproductive freedom encounters medical responsibility: changing conceptions of reproductive choice(Simone Bateman)
Ethical issues arising from the use of assisted reproductive technologies (Bernard M. Dickens)
ART has continuously challenged social norms, moral and ethical standards and legal systems. Althoughfew areas in medicine have generated as much controversy as ART, in the past two decades ART hasnevertheless been offered to many thousands of infertile couples and more than one million children havebeen born worldwide as a result of ART interventions. The impact of the controversies and the challengecan be seen at the individual, societal and political/legal levels.
The many possibilities that ART offers to infertile couples are often outnumbered by moral and ethicaldilemmas regarding, among others, gamete donation, surrogacy, PGD, fetal reduction, embryo researchor destruction of stored embryos. Many of the ethical concerns are present at the decision-making processof the infertile couple regarding treatment. At this stage of the process, the involvement of the health careprovider is critical and has been the subject of debate. Health care professionals must respect patients’autonomy and have an obligation to ensure that patients have accurate and adequate information on therisks and benefits of particular treatments and of possible alternative treatments.
The controversies and, at the same time, the wide application of ART have impacted on the relationshipsand practices that condition and give meaning to reproduction in society. Issues of choice, reproductivefreedom and medical responsibility should be seen within the broad scope of changing values in modernsociety.
The state often attempts to capture the controversies surrounding ART through regulation. In some cases,rapid recourse to legal regulation of ART may be counterproductive because it may restrict the opportunityfor informed debate about existing options. Where laws and regulations restrict certain ART procedures,the ethics and legality of physicians’ referral to other ART services require clarification.
Whether at the individual, societal or legal level, there are many unresolved issues in ART, including whethergamete and/or embryo donors and/or surrogate mothers should receive financial payment and, if so,whether or not it should be regulated; whether or not the right to equitable access to infertility treatmentincluding ART should be provided to individuals and partners other than heterosexual married couples;the ethical acceptability of sperm and embryo management for purposes of sex selection; the fate ofstored embryos if no contact can be made with the donors after a specified time interval.
Recommendations
• Procedures need to be established to ensure continuing multidisciplinary debate to shape the ethicalframework of ART. This debate must include public participation.
• Procedures should be developed to allow stored embryos, for which there will be no clinical use, to beused for research or discarded. This research could be used to improve ART or the understanding of
Recommendations 395
embryo development, but must be legally permissible and carried out only with the prior informedconsent of the donors.
• Informed consent should be provided by the donors of gametes, prior to their donation. This consentshould address all possible immediate and future uses of the gametes:—for gamete or embryo research—to create embryos that will be used for treatment of the donors—to create embryos that will be used to treat others—the final disposition of the gametes if not used for treatment or research.The gamete providers should state what can, and cannot, be done with the gametes they provide orthe embryos derived therefrom.
• Newly introduced procedures, as well as those currently used in ART, should be followed by surveillanceof all treated individuals and offspring and include child development.
• It is proposed that the following terminology relating to ART should be used in the context of theabove recommendations:—Animal studies in vitro and in vivo, and studies on human cells, gametes or embryos for which
appropriate informed consent has been obtained, should be described as “preclinical research”;—Initial clinical studies designed to test a scientific hypothesis derived from “preclinical research”
should be described as “clinical research”.—This is followed by well-designed, “randomized controlled trials” to provide statistical validation of
the hypothesis developed from the “clinical research”.
396 Recommendations
Section 6: National and international surveillance of ART and their outcomes
Papers
The Swedish experience in assisted reproductive technologies surveillance (Karl Nygren)The Latin American Registry of Assisted Reproduction (Fernando Zegers-Hochschild)Assessment of outcomes for assisted reproductive technology: overview of issues and the US experience
in establishing a surveillance system (Laura A. Schieve et al.)International registries of assisted reproductive technologies (Karl Nygren)
ART has been developed over the past two decades, during which time it has received considerable mediaand public attention. Concerns about safety and efficacy of the various ART procedures have led togovernmental inquiries, legislation in some countries and, in others, action by professional bodies to developmonitoring schemes. A number of countries have set up ART surveillance providing information for policy-makers, health care professionals and consumers. There is significant variation among countries in thequality and quantity of data available, as well as in the definitions used to describe the procedures andtheir outcomes.
Both national and international data collection of reported ART results are still in the early stages ofdevelopment, mainly as a result of difficulties in reaching consensus on definitions and the lack ofstandardized methodologies for data collection and analysis.
Recommendations
• The definitions of terms commonly used in ART should be agreed upon between ART providers andnational and international registries.
• Guidelines need to be developed for the establishment of national and international ART registries.• National ART surveillance programmes should be developed. These programmes should include non-
ART methods of treatment and IUI with ovarian hyperstimulation.• ART registries should be linked, where possible, with national health registries.• Regional and global systems for managing data on ART outcomes should be further developed to allow
analysis of time trends, of geographical differences and to provide information on new ART procedures.• The principal outcome statistic of ART results should be singleton and multiple live-birth rates per
treatment cycle initiated.• National and international data on twin and higher-order multiple pregnancy rates resulting from ART
and other forms of infertility treatment should be published.• ART statistics need to emphasize the birth rates of healthy infants as well as rates of malformations,
neonatal morbidity and mortality, and abnormalities of pregnancy.• Malformation rates should include those associated with abortion, stillbirth and live birth.• Data on fetal reductions should be included in ART registries.