FERTILITY AND STERILITY®

Copyright 1997 American Society for Reproductive Medicine

Published by Elsevier Science Inc.

Vol. 68, No.1, July 1997

Printed on acid-free paper in U. S. A.

The feasibility of assessing women's perceptions of the risks andbenefits of fertility drug therapy in relation to ovarian cancer risk*t

Barry Rosen, M.D.:j:§Jane Irvine, Ph.D.11Paul Ritvo, Ph.D.11Heather Shapiro, M.D.~Donna Stewart, M.D.~**

Karina Reynolds, M.D.:j:ttGail Robinson, M.D.**Jackie Thomas, M.D.~Jan Neuman, M.Sc.+~Joan Murphy, M.D.+

The Toronto Hospital, University of Toronto, Toronto, Ontario, Canada

Objective: To determine the feasibility of asking women undergoing fertility treatment themaximum increased risk of ovarian cancer they would be willing to tolerate in order to takeovulation-induction drugs.

Design: A prospective pilot study of women attending fertility clinics over a 2-month period.Setting: Two tertiary care fertility clinics in Toronto.Patient(s): Sixty-one English-speaking women were approached and 85% (n = 52) were

enrolled.Interventionts): A self-administered questionnaire with fertility-specific questions. Thirty­

eight women also were asked to complete standardized scales of anxiety and optimism.Main Outcome Measure(s): Women's report of the maximum level oflifetime risk of ovarian

cancer they were willing to tolerate in order to undergo fertility treatment.Result(s): Seventy-nine percent were willing to accept an increased risk of ovarian cancer.

Only 24% understood that treatment for ovarian cancer usually was not curative.Conclusion(s): A majority of patients were willing to tolerate a modest increase in their

lifetime risk of ovarian cancer because of fertility treatment, most basing their estimate ofacceptable risk on limited awareness of the issue. (Fertil Steril" 1997;68:90-4. © 1997 byAmerican Society for Reproductive Medicine.)

Key Words: Ovarian cancer, infertility, fertility drugs, ovulation induction, cancer risk per­ception, anxiety, optimism

Recent publications of one meta-analysis (1) andtwo case-control studies (2, 3) have suggested an as­sociation between the use offertility medication and

Received December 24, 1996; revised and accepted March 3, 1997.*Supported by Organon Canada Ltd., Scarborough, Ontario,

Canada.t Presented at the Canadian Fertility and Andrology Society

Annual Meeting, Lake Louise, British Columbia, Canada, Novem­ber 20 to 23, 1996.

:j: Division of Gynaecologic Oncology.§ Reprint requests: Barry Rosen, M.D., Toronto Hospital Gen­

eral Division, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4,Canada (FAX: 416-593-0288: e-mail: BROSEN@TORHOSP.TORONTO.ON.CA).

II Department of Psychology.~ Department of Obstetrics and Gynaecology.** Department of Psychiatry.tt Present address: Department of Obstetrics, St. Mary's Hos­

pital, Whitworth, Manchester, United Kingdom.

90

subsequent development of ovarian cancer. The arti­cles by Rossing et al. (2) and Whittemore et al. (1)received considerable exposure in the lay press,which has, in turn, helped to increase women'sawareness and concern about this association amongwomen seeking fertility treatment. For the individ­ual patient, the decision to use fertility drugs isbased on a balance of perceived risks and benefits.A better understanding of how women perceive therisks (ovarian cancer) and benefits (pregnancy) offertility medications would help both physicians andpatients with decisions regarding infertility drugtreatment. Presently, we are undertaking a study toassess the level of ovarian cancer risk that infertilitypatients find acceptable in their pursuit of a success­ful pregnancy, and we report here on the initial pilotstudy in which the questionnaire design and accept­ability were tested.

0015-0282/97/$17.00PII S0015-0282(97)00076-9

MATERIALS AND METHODS

Study Design

This is a survey study of women undergoing treat­ment for infertility problems at two specialty clinics.The design is cross-sectional, sampling from womenat various stages of infertility treatment, includingwomen who had never taken fertility-enhancingmedications and women who had taken one or morecycles of fertility-enhancing medications. The mainstudy aims to evaluate the association between thelevel of ovarian cancer risk that infertility patientsfind acceptable in the pursuit of pregnancy and theirpsychologic status and knowledge of ovarian cancer.This paper reports on the pilot study, which testedthe feasibility of implementing a study ofthis naturein a relatively unselected sample of women at­tending fertility clinics.

Questionnaire Administration

Physicians and clinic nurses identified eligibleparticipants to the study coordinator, who explainedthe study to all participants. Briefly, the study coor­dinator introduced herself to a potential subject,gave the woman an information sheet on the study,and summarized what it contained. The informationsheet explained that this was a study of infertilitypatients' views on fertility drugs. It would involvecompleting a 15-minute self-administered question­naire at this time, while the woman was waiting tosee her infertility specialist, and deciding to partici­pate or not participate in the study would not affecther treatment. Further, it was explained that duringthe last 2 to 3 years fertility treatments have beenidentified as possibly having an association with ad­ditional health issues and that this study was beingdone to evaluate the impact of this new informationon women's decisions regarding fertility treatments.Women also were assured that their questionnaireresponses would be confidential and would not beshared with their treating physician. Women whoagreed to participate were asked to provide writtenconsent. An information pamphlet on the possibleconnection between fertility drugs and ovarian can­cer also was given to everyone after completion ofthe questionnaire. It was offered similarly to every­one who declined study participation. The study pro­tocol was approved by the Toronto Hospital Commit­tee for Research on Human Subjects.

Questionnaire

The questionnaire obtained information in a vari­ety of domains.1. demographics

Vol. 68, No.1, July 1997

2. reproductive history3. infertility history4. perceived probability of personally having a suc­

cessful pregnancy5. perceived probability of fertility patients, in gen­

eral, achieving a successful pregnancy6. awareness of the possible link between fertility

drugs and ovarian cancer7. the increased risk of ovarian cancer related to

fertility treatment that was acceptable8. views regarding the efficacy of current treat­

ments for ovarian cancer9. views regarding the efficacy of actions the patient

and her doctor could take to maintain her healthExamples of key questions are provided here. A copyof the full questionnaire can be obtained by writingto the corresponding author. To obtain the respon­dents' opinions oftheir chances of a successful preg­nancy, we asked the following:1. What do you feel your chances are ofgetting preg­

nant as a result of fertility treatment?a. < 10% chance of pregnancyb. 10% to 24% chance of pregnancyc. 25% to 49% chance of pregnancyd. 50% to 74% chance of pregnancye. >74% chance of pregnancyf. don't know

The following question asked respondents abouttheir perceptions of the risk of developing ovariancancer from taking fertility drugs:2. The lifetime risk of developing ovarian cancer in

women is 1.5% (1.5 women out of 100). If takingfertility drugs increased your lifetime risk of de­veloping ovarian cancer, what is the maximumrisk you would accept?a. no increased riskb. 1.5% to 2% lifetime risk, or 1 to 2 women out

of 100c. 2.1% to 4% lifetime risk, or 2.1 to 4 women out

of 100d. 4.1% to 6% lifetime risk, or 4.1 to 6 women out

of 100e. 6.1% to 10% lifetime risk, or 6.1 to 10 women

out of 100f. 10.1% to 15% lifetime risk, or 10.1 to 15 women

out of 100g. > 15% lifetime risk, or > 15 women out of 100

In addition to the above questionnaire, two well-vali­dated questionnaires were used to assess levels ofanxiety and optimism: The State-Trait Anxiety In­ventory (4) and the Life Orientation Test (5).

RESULTS

Demographics

Women attending The Toronto Hospital Reproduc­tive Biology Unit (n = 52) and a private clinic (n

Rosen et al. Risks and benefits of fertility treatment 91

* Total number of subjects = 52.t Values are means ± SD.:j: Values are number of subjects with percentage in paren­

theses.

= 9) in downtown Toronto were approached aboutparticipation in this study. The patients were re­cruited in the spring of 1996 in accordance with twoeligibility criteria: [1] fluency in English and [2] in­fertility diagnosis. The average age was 33.7 years.All but two subjects had completed high school and80% had finished either community college or uni­versity. On average, the women had been seeing aphysician for 1.8 years for their infertility investiga­tions and treatment and had been attempting preg­nancy for 3.2 years (Table 1). Twenty-eight womenwere nulligravid, 15 had become pregnant but hadnot carried to term, and 9 women had had a childsuccessfully. Twelve women had not taken any medi­cation at the time of this questionnaire, 23 had takenonly clomiphene citrate, and 17 had taken gonado­tropins.

Table 1 Demographics and Reproductive andFertility History"

Age]No. of years seeing doctor for treatment]No. of years trying to get pregnant]Education:j:

High schoolCommunity collegeUniversity

Never pregnantPreviously pregnant, no live birthzOn no fertility medication:j:Taking clomiphene citrate only:j:Taking hMG:j:

33.7 ± 4.81.8 ± 1.63.2 ± 2.2

10 (19)15 (29)27 (52)28 (54)15 (29)12 (23)23 (44)17 (33)

average, the questionnaire took 15 minutes to com­plete.

Perceptions of Risks and Benefits

With regard to assessing their view of fertilitytreatment benefits, a majority of respondents (69%)estimated that <50% of women receiving fertilitytreatment would have a successful pregnancy. (Fig.1) Seventeen percent responded that they did notknow what the successful pregnancy rate would be,and only 14% thought it would be >50%.

With regard to risks related to ovarian cancer, 32(67%)of 47 women indicated an awareness ofa possi­ble relationship between fertility drugs and ovariancancer. Five women did not answer this question.Newspapers, magazines, and fertility specialistswere cited most often as providing this informationto individuals in the study. When asked about thestrength of the link between fertility drugs and ovar­ian cancer, 20% of the 35 respondents indicated aquestionable or weak link, 20% indicated a stronglink, and 60% indicated some link.

One of the main purposes of this study was todetermine the maximum level of risk for ovariancancer the women would be willing to accept whendeciding to take fertility-enhancing medication. Thequestion first explained that the average lifetimerisk of ovarian cancer was 1.5% and then asked par­ticipants to check the maximum level of risk theywould accept. Of the 48 women who responded tothis question, 10 (21%) would accept no increasedrisk, 24 (50%) would accept a maximum risk of 2%to 4%, 11 (23%) would accept an increased risk be­tween 4% and 10%, and 3 (6%) would accept a maxi­mum risk> 10% (Fig. 2).

Feasibility Results

Patients were recruited from both a universityclinic and a private clinic. Fifty-two (85%) of 61 pa­tients approached agreed to participate. Sixty-sevenpercent of the 32 questionnaire items that were ap­plicable to all respondents were endorsed by all 52subjects (i.e., after eliminating items that were an­swered only if a woman was taking fertility-enhanc­ing medications or only by women who knew aboutthe link between fertility-enhancing medicationsand ovarian cancer risk). A closer inspection of theresponses to each item revealed that primarily oneitem contributed to the low completion rate. Thisitem asked women to rate their perceptions of thestrength of the link between fertility-enhancingmedications and ovarian cancer risk. Eliminatingthis item revealed that 90% of the women endorsedall remaining 31 items. In other words, 97% of theitems were endorsed by 2::90% of the sample. On

92 Rosen et at Risks and benefits of fertility treatment

Ovarian Cancer Knowledge

Most women did not appear to have accurate infor­mation about ovarian cancer survival. Overall sur-

60

so :1go1<0

! 30

C~ 20IIQ.

10

0

Figure 1 Women's estimate of their own and others' chances ofachieving a pregnancy successfully.

Fertility and Sterility"

larger series of studies aimed at comparing the riskinformation that fertility specialists convey to infer­tile women with the perceptions women actually re­tain and use in treatment decisions. In conductingthese studies, our research group also is concernedwith understanding the psychologic factors that af­fect risk perception, perceptions of treatment effi­cacy, and health orientation. A parallel study is cur­rently under way to assess physicians' willingnessto accept an increased risk when prescribing thesemedications.

Overall, the pilot results indicated that it was fea­sible to conduct this kind of survey among womenundergoing infertility treatment. Both the high par­ticipation rate of 85% and the high questionnairecompletion rate (90% of the sample responded to 31of the 32 items) attest to the feasibility of conductingthis study. The demographics of women sampled inthe pilot study indicate that they are characteristicof women in published reports who are undergoinginfertility treatment (7).

The majority of our subjects (67%) reported beingaware ofthe potential increased ovarian cancer riskrelated to fertility treatment. Nonetheless, 79% ofour subjects were willing to accept the potential in­creased risk of ovarian cancer related to taking fer­tility drugs. The majority, therefore, are aware ofthepotential link between fertility drugs and ovariancancer and are willing to accept this in the pursuitof a successful pregnancy. However, 62% stated theydid not know whether treatment for ovarian cancerwas curative and only 24% of women realized it usu­ally was not curative. These answers suggest thata majority of women in this study sample lackedaccurate information about ovarian cancer outcome.The overall willingness to accept an increased risktherefore may be artificially elevated because so fewwomen in our sample clearly understood the exactnature of ovarian cancer. It is possible that theiranswers would be different if the women had beenpresented with ovarian cancer survival statistics be­fore being asked to answer this question. One mightspeculate that if answers from this pilot study proverepresentative of this population, a more detailedexplanation about the expected outcome of ovariancancer is necessary before prescribing fertility- orovulation-enhancing medications.

Results of the State-Trait Anxiety Inventory indi­cated a moderate elevation in anxiety levels. Be­cause anxiety can disrupt patients' ability to processmedical information effectively, their decision mak­ing at such times may not be reliable (8), The inverserelationship observed between anxiety and opti­mism is consistent with the numerous reports link­ing optimism to better adaptation to stressful situa­tions, particularly those involving medical treat-

15

20

25

vival for all stages of ovarian cancer is 35% to 40%,and for women who present with advanced stage(70%), survival is only 10% to 15% (6). When askedabout whether treatment was curative, 7 women re­sponded yes, 13 chose no, and 31 (62%) did not know.Regarding perceptions related to reducing cancerrisk, 29% believed that by doing healthy things onecould reduce the risk a great deal, 45% believed itcould be reduced a moderate amount, and 26% be­lieved it could be reduced a minor amount. Overall,49% believed that the risk ofcancer could be reduceda great deal by following the physician's advice(screening, prevention, and lifestyle change), 41%believed that it could be reduced a moderate amount,and 10% believed it could be reduced a minoramount in this way. As a summary question at theend of the questionnaire, participants were asked toweigh the pros and cons of fertility treatment. Allbut 1 individual thought the pros outweighed thecons.

DISCUSSION

This pilot study was undertaken to determine thefeasibility of assessing fertility patients' willingnessto accept an increased risk of ovarian cancer whentaking fertility medication. The study is part of a

Psychologic Variables

The mean state anxiety score was 42.0 with a SDof 14.0. The mean trait anxiety score was 40.7 witha SD of 8.6. These means are slightly elevated abovelevels typically seen in employed adult women (4).The mean optimism score on the Life OrientationTest was 24.4, with a SD of 8.0. Population normsfor the optimism measure were not available; how­ever, as expected, optimism scores were inverselycorrelated with state tr = -0.42, P < 0.02) and traitanxiety (r = -0.76, P < 0.001).

o· s,s,. ~

lifetime nskof ovanancancer

30

Figure 2 Maximum acceptable lifetime risk of ovarian cancerbecause of the use of ovulation-induction drugs.

Vol. 68, No.1, July 1997 Rosen et al. Risks and benefits of fertility treatment 93

ment (9- 14). In the main study it will be importantto examine the inter-relationships between opti­mism , anxiety, risk knowledge, and tolerance forovarian cancer ri sk because of ovulation drugtherapy.

In conclusion, this study app ears to support thefeasibility of obtaining estimates of acceptable riskfrom patients. For the most part, the majority ofpatients seem to find a modest amount of increasedrisk of ovarian cancer acceptable in relation to fertil­ity treatment. However, it is evident that only a mi­nority had accurate knowledge about the expectedoutcome of ovarian cancer. This is a relatively smallpilot sample, and definitive findings must await com­pletion of the full study.

Ackn owledgment. We thank Gregory O'Connell, M.D., of theDivision of GynaecologicOncology at McMaster University, Ham­ilton, for his advisory role in th e study.

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