the impact of assisted reproductive technologies on maternal-child health geeta k. swamy, md duke...
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The Impact of Assisted Reproductive Technologies on
Maternal-Child Health
Geeta K. Swamy, MD
Duke University Department of ObGyn
Division of Maternal-Fetal Medicine
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Statistics
• 1996 – 2002, number of births after ART increased by 120% in the US
• In 2009, > 60,000 ART infants born in the US, accounting for 1% of all births
• ART conceptions account for 2 – 3% of all births in several European countries
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The Goals and Risks of ART• Goals of ART are to
• Optimize pregnancy rates• Produce healthy, genetically normal full-term
deliveries• Minimize the risk of multiple gestations
• The critical questions . . .• Are we doing harm when treating infertility
patients with ART?• Do the ART treatments per se cause adverse
outcomes?
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ICSI IVF
AssistedHatching
PGD
Ovarian Stimulation
Gamete Handling & Evaluation
Oocyte Collection Sperm Collection
Insemination
Zygote Identification
Micro-Manipulations
Embryo Growth
The Process of ART
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Oocyte
Sperm Zygote Embryos Transfer
CBAVDOligospermia GENETICS Environment
Environment
AgeGENETICS
Ovarian Stimulation
Culture ConditionsMedia
Gas PhaseSystemDuration
Manipulations
Assisted HatchingBlastomere Bx
IVF
ICSI
Number & Qualityof Embryos
Possible Etiology of Adverse Outcomes
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Parental risk factors for Adverse Outcomes
010203040506070
20-34 35-39 40-45
Aneuploidy
Implantation
Munne et al ’01,’04,‘06
Maternal Age (y)
Female
%
0
5
10
15
20
“0” 0-5 5-10 10-20 >20
Aneuploidy
Yoshida et al ’95
Sperm Concentration (x106/ml)
Male
%
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Endometrial ReceptivityPlacentationMaternal HealthUterine EnvironmentGestational Order
Moore and Persaud. The developing human, clinically oriented embryology. 1998
Possible Etiology of Adverse Outcomes
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Penetration into the ooplasm
Compression of the oocyte during initial penetration into the ooplasm
Stabilization prior to injection
Intracytoplasmic Sperm Injection(ICSI)
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Grading of Embryos
• Based on cell number ~ rate of growth• Amount of fragmentation• Equal size of cells ~ efficiency of division• Does not correlate with health/ability of child
Zygote Day 3 Embryo Day 5 Embryo (Fertilized Egg) (Blastocyst)
Early Embryonic Development
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Culture-Induced Effects: Day of Embryo Transfer
• Transfer after Day 5• Increased incidence of monozygotic twins (Behr et al ’00; Menezo et al ’02)
• Increased incidence of male neonates? (Menezo et al ’99; Kausche et al ‘01)
Egg
Ret
rieva
l
Days Post-Fertilization 1 2 3 4 50
Day of Embryo Transfer
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Possible AdversePregnancy Outcomes
• Multi-fetal gestations• Spontaneous Abortion• Ectopic Pregnancy• Prematurity• Small-for-gestational-age• Preeclampsia• Placental abnormalities• Congenital anomalies• Genetic abnormalities
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Multi-fetal Gestation – Fetal/Infant
SARTCORS Data Reporting System, 2007
• Spontaneous abortion• Perinatal mortality• Preterm birth/low birthweight• Fetal growth restriction• Placental abnormalities• Cord accidents – prolapse, vasa previa, entanglement• Hydramnios• Congenital malformations• Cerebral Palsy
Singletons 67.2%
Twins 28.4%
Triplets++ 4.4%
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Multi-fetal gestation- Maternal• Hyperemesis gravidarum• Anemia• Gestational diabetes• Placenta previa• Placental abruption• Pregnancy related hypertension/preeclampsia• Cesarean delivery• Postpartum hemorrhage• Excess weight gain
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Effectiveness of ART
• Agency for Healthcare Research and Quality
• Review of safety and effectiveness of interventions for ovulation induction, superovulation, & ART
• 5294 abstracts with review of 1210 full-text articles
• 478 articles included in final report
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Effectiveness of ART• Limitations
• Final number of randomized trials was small • Majority of randomized trials provided data only
on pregnancy rates, not live births or pregnancy outcomes
• Few studies were adequately powered to detect differences in pregnancy rates, live births, multiple gestations, or severe complications
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Effectiveness of ART
• Spontaneous abortion – equal incidence compared to spontaneous conception
• Ectopic pregnancy• more common after ART but related to maternal factors• removal of hydrosalpinges reduces ectopic risk
• Maternal serum screening• false positive results more likely in 2nd trimester • skewed maternal age distribution• adjustment for thresholds for invasive testing?• predictive of adverse pregnancy outcomes?
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Preterm Birth - Singletons
• 11 studies• IVF/ICSI 70 to 150% increase in delivery < 37 wks• 4 systematic reviews consistently found an increased
risk of preterm birth among singletons following IVF
ReferenceOdds Ratio
95% CI
McGovern et al, Fertil Steril. 2004 1.98 1.89 – 2.08
Jackson et al, Obstet Gynecol 2004 1.95 1.73 – 2.20
Helmerhorst et al, BMJ. 2004 2.04 1.80 – 2.37
MacDonald et al, J Obstet Gynaecol Can 2005 1.93 1.36 – 2.20
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Preterm Birth - Singletons
• ~ 2-fold increased risk after ART• inadequate data to differentiate between
indicated vs. spontaneous preterm birth• Etiology unclear
• Implantation• Progesterone• Subclinical infection
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Preterm Birth - Twins
• Increased risk preterm birth but relative increase is substantially lower than that for singletons
• Helmerhorst et al, BMJ 2004• OR 1.07 [95% CI 1.02–1.13] for delivery < 37 weeks• OR 0.95 [95% CI 0.78–1.15] for delivery < 32 weeks
• Etiology• Higher proportion of spontaneous twins born prematurely• ART twinning may confer “healthier” embryos healthier
pregnancy
• Small increase in relative risk substantially impacts absolute number or attributable risk
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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SGA - Singletons
• 3 systematic reviews all found significantly increased risks of small-for-gestational-age (SGA)
• Etiology• Implantation/placentation• ART treatments• Maternal/embryonic factors
ReferenceOdds Ratio
95% CI
MacDonald et al, J Obstet Gynaecol Can 2005 1.59 1.20, 2.11
Jackson et al, Obstet Gynecol 2004 1.60 1.25, 2.04
Helmerhorst et al, BMJ 2004 1.40 1.15, 1.71
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Preeclampsia
• 9 studies• Consistently increased risk after ART as shown in
several studies• Meta-analysis by Jackson et al, Obstet Gynecol 2004
• OR 1.55, 95% CI 1.23–1.95• Adjustment for confounders, e.g. maternal age, parity
• Etiology• Maternal risk factors, e.g. obesity, PCOS/insulin
resistance/metabolic syndrome• Implantation
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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Perinatal outcomes - singletons after IVF
• Meta-analysis of 15 studies of 12,283 IVF and 1.9 million spontaneously conceived singletons
Outcome # Studies OR (95% CI)
Spontaneous preterm birth 5 2.1 (1.7, 2.7)
Gestational diabetes 4 2.0 (1.4, 3.0)
Preeclampsia 8 1.6 (1.2, 2.0)
Placenta previa 6 2.9 (1.5, 5.4)
Vaginal bleeding 7 2.5 (1.9, 3.3)
Perinatal mortality 8 2.2 (1.6, 3.0)
Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.
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Perinatal outcomes - singletons after IVF
• Labor & Delivery Outcomes
Outcome # Studies OR (95% CI)
Labor induction 7 1.2 (1.0, 1.3)
Cesarean – elective 7 1.9 (1.5, 2.5)
Cesarean – emergent 7 1.5 (1.1, 2.0)
NICU admission 5 1.6 (1.3, 2.0)
Neonatal death 7 2.0 (1.2, 3.4)
Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.
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Perinatal outcomes - singletons
• Compared with non-assisted singleton pregnancies, ART singleton pregnancies have significantly worse outcomes for:
• Antenatal
• Perinatal
• Neonatal
• Most odds ratios are >2
• All but one of these ART-related adverse outcomes for singletons are not evident for twins
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Congenital anomalies after ART
• 30-40% increased risk of major malformations among infants born after ART
• In studies with sufficient size and data to allow controlling for potential confounders, risks decrease
• Hansen et al. meta-analysis pooled OR estimates
Group Odds Ratio 95% CI
Singletons 1.31 1.17, 1.46
IVF-only 1.94 1.50, 2.50
ICSI-only 1.28 1.14, 1.43
Hansen M, et al. Human Reproduction 2005; 20(2): 328-38)
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Genetic Risk: ICSI vs. Control
• 1586 ICSI fetuses karyotyped via invasive prenatal testing with 3% abnormal
Van Steirteghem et al ’02 Hum Reprod Update;8:111-6
* Significantly different from expected population levels
Abnormality N % 95% CI Population levels, %
Non-inherited 25 1.6* 1.02, 2.32 0.45, 0.87
Sex chromosome 10 0.6* 0.30, 1.16 0.19, 0.27
Autosomal 15 0.9 0.52, 1.56 0.26, 0.60
Inherited 22 1.4* 0.87, 2.09 0.47, 0.22
TOTAL 47 3.0 2.19, 3.92 0.92
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• Angelman’s Syndrome (ch 15)• Rare subtype estimated at 1/300,000• 3 isolated cases reported among ICSI births• 1 case had a fertile father• All had epigenetic defect with loss of
methylation of maternal allele
Imprinting Defects after ART
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• Beckwith-Weidemann’s Syndrome (ch 11)• Baseline risk of 1/15,000• 3 registry studies found incidences of 3/65,
6/143 and 6/149• RR estimate increase ~ 4 to 6-fold• All cases due to imprinting defect
Imprinting Defects after ART
• Clinical evidence is suggestive but not sufficient to conclude that ART techniques may increase frequencies
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Neuro-Developmental Outcomes
• Increased risk of cerebral palsy after ART is related to the increased risk of preterm birth
• Stromberg et al, Lancet 2002• Cerebral palsy (overall OR 3.7, 2.8 in singletons)• Developmental delay (OR 4.0)
• Hvidtjorn et al, Pediatrics 2006• Prematurity and multi-fetal gestation are individually
independent risk factors for CP• After adjustment for both, prematurity remains as a
strong independent risk factor
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• Insufficient to define ART success as establishment of pregnancy or achieving a live birth
• Emphasis should be on healthy term infants
• Counseling should be non-directive, provided well in advance of any invasive procedures, in a relaxed and unrushed environment
Reddy, et al, Obstet Gynecol, 109 (4), Apr 2007
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• Couples should be informed of treatment risks and pregnancy rates as well as risks of adverse pregnancy/birth outcomes for which well-documented outcome data exist • Multi-fetal gestation & number of embryos transferred• Preterm birth, SGA, preeclampsia• Congenital anomalies• Genetic abnormalities (parental risk factors, prenatal
diagnosis)
Reddy, et al, Obstet Gynecol, 109 (4), Apr 2007
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• Meta-analyses reveal worse perinatal outcomes for ART singletons
• Conversely, IVF twins seem to be no higher risk than spontaneous twins
• The etiology for these adverse outcomes in singletons is unknown but may be related to• Infertility per se• Ovarian stimulation: hormone milieu? placentation? • Lab technology
Summary
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• Slightly higher risk of major malformations in ART babies (3.5% vs. 2.5%), some related to maternal age, infertility and parental disease
• Psycho-motor development is normal, neuro-developmental outcome influenced by neonatal problems
• Increased incidence of very rare disorders remains possible (etiology unknown, but may be lab-related)
• Patients should be counseled about potential risks, their possible etiologies and our current knowledge base
Summary
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• Etiologies of many of the adverse outcomes
• Need to identify infertility in the general population (appropriate comparison groups)
• Teasing out infertility versus treatment-related issues (e.g. ART for tubal ligation versus disease-related)
• Linkage of lab technologies with gestational complications, birth, infant and child health outcomes: • Culture media• ICSI, AH, PGD• Prolonged embryo culture• Frozen versus fresh transfers
Future research directions. . .