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Advance Access publication November 26, 2008 Cancer Risk After Exposure to Treatments for Ovulation Induction R. Calderon-Margalit, Y. Friedlander, R. Yanetz, K. Kleinhaus, M. C. Perrin, O. Manor, S. Harlap, andO. Paltiel Initially submitted January 23, 2008; accepted for publication September 11, 2008.
Uncertainty continues as to whether treatments for ovulation induction are associated with increased risk of cancer. The authors conducted a long-term population-based historical cohort study of parous women. A total of15,030 women in the Jerusalem Perinatal Study who gave birth in 1974–1976 participated in a postpartum survey.
Cancer incidence through 2004 was analyzed using Cox’s proportional hazards models, controlling for age andother covariates. Women who used drugs to induce ovulation (n ¼ 567) had increased risks of cancer at any site(multivariate hazard ratio (HR) ¼ 1.36, 95% confidence interval (CI): 1.06, 1.74). An increased risk of uterine cancer was found among women treated with ovulation-inducing agents (HR ¼ 3.39, 95% CI: 1.28, 8.97), specif-ically clomiphene (HR ¼ 4.56, 95% CI: 1.56, 13.34). No association was noted between use of ovulation-inducingagents and ovarian cancer (age-adjusted HR ¼ 0.61, 95% CI: 0.08, 4.42). Ovulation induction was associated witha borderline-significant increased risk of breast cancer (multivariate HR ¼ 1.42, 95% CI: 0.99, 2.05). Increasedrisks were also observed for malignant melanoma and non-Hodgkin lymphoma. These associations appearedstronger among women who waited more than 1 year to conceive. Additional follow-up studies assessing theseassociations by drug type, dosage, and duration are needed.
breast neoplasms; cohort studies; incidence; lymphoma, non-Hodgkin; melanoma; ovarian neoplasms; ovulationinduction; uterine neoplasms Abbreviations: CI, confidence interval; HR, hazard ratio; ICDO-3, International Classification of Diseases for Oncology, ThirdEdition.
Approximately 10% of couples in developed countries follicle-stimulating hormone) have been used to promote seek health care for infertility (1, 2). The use of fertility treat- ovulation since the early 1960s (5), and human chorionic ment has grown substantially in recent decades, as can be gonadotropins have been used since 1932 (6).
inferred from the increasing utilization of assisted reproduc- Despite this long-term use, the scientific literature pro- tive technologies (3). It has been estimated that approximately vides inconsistent information on the association between 1% of US infants born in 2004 were conceived through ovulation induction treatment and cancer incidence. An in- assisted reproductive technologies (4).
creased risk of ovarian cancer following treatment has been Ovulation-inducing drugs are widely used for ovarian suggested in previous studies (7, 8), while more recent stud- follicle stimulation, either as independent therapies or dur- ies suggest no association (9, 10) (Table 1). Some studies ing in vitro fertilization cycles. Clomiphene citrate, in use have suggested an increased risk of breast cancer following since the 1960s, is still considered the best initial treatment treatment with clomiphene (11, 12); however, in others, in- for the majority of women with anovulatory infertility (4).
vestigators have reported a reduced risk among treated Clomiphene has also been widely used among couples with women (13, 14) or no effect on risk (15, 16). A few studies unexplained infertility (4). Similarly, human menopausal have assessed the association between ovulation induction gonadotropins (nowadays partly replaced by recombinant and cancer at other sites, such as the uterus, thyroid, and Correspondence to Dr. Ronit Calderon-Margalit, Braun School of Public Health and Community Medicine, Hadassah-Hebrew University, P.O.
Box 12272, 91120 Jerusalem, Israel (e-mail: ronitc@ekmd.huji.ac.il).
Findings From Published Studies on the Association Between Fertility Treatment and Incidence of Ovarian and Breast Cancer Clomiphene >1 year: SIR ¼ 11.1 (95% CI: 1.5, 82.3); clomiphene <1 year: no association Nulligravid women: OR ¼ 27.0 (95% CI: 2.3, 316); gravid women: OR ¼ 1.4 (95% CI: 0.52, 3.6) Clomiphene: SIR ¼ 2.7 (95% CI: 0.97, 5.8); not significantly higher than SIR for untreated infertile women (SIR ¼ 1.6, 95% CI: 0.6, 3.5) induction vs. generalpopulation and vs.
9,044 unexposed Clomiphene only: SIR ¼ 1.40 (95% CI: 1.05, 1.83); hMG only: SIR ¼ 0.66 (95% CI: 0.21, 1.54); clomiphene, then hMG: 1.06 (95% CI: 0.59, 1.75) Infertility: SIR ¼ 1.29 (95% CI: 1.1, 1.4); clomiphene: SIR ¼ 1.29 (95% CI: 1.1, 1.5); gonadotropins: SIR ¼ 1.40 (95% CI: 0.9, 2.0).
and 20 years of follow-up:RR ¼ 1.6 (95% CI: 1.0, 2.5); high dose of gonadotropins:RR ¼ 1.79 (95% CI: 1.0, 3.3) Ovulation induction (yes/no): SIR ¼ 0.93 (95% CI: 0.79, 1.09); <12 months of exposure: Clomiphene: OR ¼ 2.1 (95% CI: 0.99, 4.3); hMG: OR ¼ 0.6 (95% CI: 0.1, 2.2); clomiphene, thenhMG: OR ¼ 0.8 (95% CI: 0.3, 2.2) or gonadotropin-releasing hormone. Progestins: RR ¼ 3.36 (95% CI: 1.3, 8.6); hMG, 5–9 years from exposure: hazard ratio ¼ 1.96(95% CI: 1.06, 3.64) Clomiphene: RR ¼ 0.5 (95% CI: 0.2, 1.2); hCG: Abbreviations: CI, confidence interval; hCG, human chorionic gonadoptropins; hMG, human menopausal gonadotropins; NA, not available; OR, odds ratio; RR, rate ratio; SIR, standardized incidence ratio.
Downloaded from http://aje.oxfordjournals.org colon, and malignant melanoma; results have been incon- well as site-specific cancer at sites for which the total num- sistent (17). Overall, most investigators studying the asso- ber of events exceeded 30. These included non-Hodgkin ciation between fertility treatment and cancer have reported lymphoma (morphologic codes 95903–96502, 96674– on outcomes occurring before the age at which women are 97143, and 97273; n ¼ 50), malignant melanoma (morpho- at substantial risk of cancer and/or have used the general logic codes 87202–87743; n ¼ 78), and solid tumors of the population as the comparison group, precluding control for breast (ICDO-3 codes 50.0–50.9; n ¼ 530), colon and rec- major confounders and risk factors (17). Some of these tum (ICDO-3 codes 18.0–20.9; n ¼ 102), ovary (ICDO-3 studies compared exposures within cohorts of infertile codes 56.0–56.9; n ¼ 43), uterus (ICDO-3 codes 54.0–55.9; women (Table 1); however, it is likely that infertile women n ¼ 44), thyroid (ICDO-3 codes 73.0–73.9; n ¼ 68), uter- who were not assigned to fertility treatment had different ine cervix (ICDO-3 codes 53.0–53.9; n ¼ 43), and brain causes of infertility than those who underwent ovulation (ICDO-3 codes 70.0, 71.0–72.9, 75.1, and 75.2; ICDO-3 induction. Those causes may be associated with a different code 30.0 with morphologic code 95223; and ICDO-3 code risk of cancer (16, 18), calling into question the compara- 75.3 with morphologic code 93611; n ¼ 58).
Ovulation induction treatments were coded in the ques- We aimed to study the association between ovulation- tionnaires as clomiphene citrate (n ¼ 312), human meno- inducing treatments and the incidence of cancer in a unique pausal gonadotropins (n ¼ 61), other (n ¼ 54), unknown population-based cohort of parous women.
(n ¼ 87), and combinations of some or all of the above.
Treatments were further categorized into any treatment ver-sus none and treatments that included clomiphene versus no Maternal demographic and social variables included age at earliest birth in the subcohort as a continuous variable; The Jerusalem Perinatal Study is a population-based mother’s geographic origin, defined according to her father’s cohort study of all births to residents of West Jerusalem, country of birth (categorized as Israeli, North African, West Israel, and its surroundings in 1964–1976 (19). The database Asian, European (including North America, Europe, Australia/ includes demographic, obstetric, and neonatal information New Zealand, and South Africa), and non-Jewish); mater- on 92,408 births to 41,206 mothers collected from birth nal education (12 and >12 years); and social class (socioeco- notifications and maternity ward log books. Between nomic status), defined according to occupation of the child’s November 1974 and December 1976, 15,426 mothers were interviewed in the hospital on the first or second day after Body mass index was calculated as the ratio between self- giving birth. This postpartum subcohort included 98% of reported prepregnancy weight (kg) and squared height (m2) births occurring in the 3 major obstetric units in West and was subdivided into the categories <25 and 25.
Jerusalem and covered 91% of all births in the area at the First birth in the Jerusalem Perinatal Study cohort was time. The questionnaire collected information on obstetric considered a proxy for the first birth in a woman’s life, and and gynecologic history, time to conception, and whether family size in the cohort was considered a surrogate for the couple had sought advice for infertility, including me- parity, divided into 1, 2–3, and 4 offspring. Ovulatory chanical treatments such as tubal insufflation. Women were disorders were defined as either irregular menstrual periods asked whether they had received medical treatment for in- or regular menstrual periods with cycle lengths of less than duction of ovulation prior to the index pregnancy.
21 days or more than 35 days. Other reproductive variables Linkage of the cohort with the Israel Population Registry included use of oral contraceptives (ever vs. never), mechan- using mothers’ identity numbers permitted tracing and as- ical assessments and treatments for infertility (combination of certainment of vital status for 97.5% (n ¼ 15,047) of moth- the codes for tubal insufflation, dilation and curettage, and ers. Information on cancer incidence as of December 31, other vs. none), and time to conception.
2004, was obtained by linking the ascertained cohort withthe Israel Cancer Registry, which receives notification of all malignancies diagnosed throughout the country. Since 1981,reporting of cases to the Registry has been mandatory by For every woman, follow-up time was counted from the law, but reporting was considered relatively complete even earliest birth in the subcohort (i.e., births that took place before this. We excluded from this study 17 mothers who after November 1974) until the diagnosis of cancer, death, were diagnosed with cancer prior to their first birth in the or December 31, 2004. Bivariate and multivariate Cox pro- portional hazards models were used to calculate hazard ra- The study was approved by the institutional review tios for the development of cancer among women who boards of Hadassah-Hebrew University (Jerusalem, Israel) received any ovulation induction or clomiphene in particular and Columbia University (New York, New York).
in comparison with women who received no ovulationinduction.
Data were virtually complete for all variables except body mass index, where missing values were present for 8% of Cancer diagnoses were coded according to the Interna- the study population. Missing values were replaced by the tional Classification of Diseases for Oncology, Third Edi- reference category (body mass index < 25) after examina- tion (ICDO-3). We analyzed the incidence of all cancer as tion of the data and sensitivity analysis.
Age 50 years was used as the cutoff point for estimation of pre- or postmenopausal status. A time-dependent survivalanalysis was performed for the association between fertility No association was found between fertility treatment treatment and cancer incidence, testing for interaction be- and cancers of the colon (age-adjusted HR ¼ 1.05, 95% tween menopausal status and fertility treatment.
CI: 0.39, 2.86), thyroid (HR ¼ 1.60, 95% CI: 0.58, 4.40), In order to estimate possible misclassification of expo- or cervix (HR ¼ 1.68, 95% CI: 0.40, 7.04) (Table 3).
sure, we conducted sensitivity analyses in which we re- No brain cancer events were diagnosed among treated stricted the exposure either to women who were treated women, but the small numbers precluded any further with clomiphene and human menopausal gonadotropins or women who were treated with clomiphene and/or an un- tumors, 1 had been treated with clomiphene and was diag- In the tables we present hazard ratios, 95% confidence nosed with a germ-cell tumor (morphologic code 90603).
No association was found between clomiphene exposureand cancer of the ovaries (age-adjusted HR ¼ 0.98, 95%CI: 0.14, 7.11) (Table 3).
Breast cancer. Women who underwent ovulation induc- tion treatment had a significantly increased risk of develop- Table 2 shows the characteristics of the study population ing breast cancer (age-adjusted HR ¼ 1.65, 95% CI: 1.15, by type of treatment. Compared with untreated women, 2.36). Controlling for geographic origin, socioeconomic sta- those who received treatment to induce ovulation were more tus, body mass index, and parity weakened this association affluent, more educated, and more likely to have fathers (HR ¼ 1.42, 95% CI: 0.99, 2.05) (Table 4). The results were born in Israel or Europe. Treated women were older at the minimally altered with further adjustment for history of oral time of their first birth, had lower parity than untreated contraceptive use (HR ¼ 1.47, 95% CI: 1.02, 2.11) or age at women, and were more likely to have waited more than first birth (HR ¼ 1.42, 95% CI: 0.99, 2.05), and there was no interaction of the association with either age at first birth(30 years vs. >30 years) or menopausal status. No asso-ciation was found between ovulation induction and breast cancer among primiparous women (Table 3).
During 424,193 person-years of follow-up (median, 29), Women who were exposed to ovulation induction in gen- 1,215 women developed cancer (median age at diagnosis, eral or clomiphene in particular had twice the risk of breast 49.4 years). Women who received ovulation induction treat- cancer as untreated women, but only among women who ment had an age-adjusted 50% increased risk of developing waited more than 12 months to conceive (Table 5). Analysis cancer at any site (Table 3). Adjustment for socioeconomic by time from birth showed significantly increased risks of status, mother’s geographic origin, and body mass index did breast cancer in the first 20 years (Table 6).
not materially change the association. Additional adjust- Women who were treated only with clomiphene (n ¼ ment for parity yielded a hazard ratio of 1.36 (95% 312) had an age-adjusted hazard ratio of 1.74 (95% CI: confidence interval (CI): 1.06, 1.74) (Table 4). Further ad- 1.09, 2.79; P ¼ 0.02), irrespective of time to conception, justments either for ovulation disorders or for mechanical and a multivariate hazard ratio of 1.51 (95% CI: 0.94, treatments or assessments for infertility did not alter the 2.42; P ¼ 0.092). Women who were treated only with clo- results (not shown). There was no interaction of menopausal miphene and waited more than 12 months to conceive had status with the association between fertility treatment and an age-adjusted hazard ratio of 2.82 (95% CI: 1.40, 5.65; Analyses restricted to primiparous women or to women Uterine cancer. Women who received ovulation induc- who received clomiphene yielded virtually unchanged re- tion treatment had a 3-fold increased risk of uterine cancer (age-adjusted HR ¼ 3.32, 95% CI: 1.31, 8.42) compared When results were stratified by time to conception (Table 5), with unexposed women. Controlling for age, socioeconomic treated women who waited more than 12 months to conceive status, geographic origin, body mass index, family size, and had double the risk of cancer compared with untreated women ovulatory disorders did not materially change this associa- (age-adjusted hazard ratio (HR) ¼ 2.03, 95% CI: 1.36, 3.01), tion (HR ¼ 3.39, 95% CI: 1.28, 8.97) (Table 4).
whereas exposed women who had a shorter time to conception Clomiphene treatment was associated with an age- did not experience an increased risk of cancer (HR ¼ 1.23, adjusted hazard ratio of 4.33 (95% CI: 1.55, 12.13) for the 95% CI: 0.80, 1.89; P for interaction ¼ 0.153).
development of uterine cancer. In the multivariate model, When results were stratified by time since birth, signifi- the adjusted hazard ratio for cancer of the uterus among cantly increased risks were observed during the first 20 women who were treated with clomiphene was 4.56 (95% CI: 1.56, 13.34; P ¼ 0.006). Mothers treated with clomi- The sensitivity analysis of exposure yielded similar re- phene who waited more than 12 months to conceive had sults (Table 7). Similarly, exclusion of women with un- an 8-fold increased risk of uterine cancer (age-adjusted known treatment had a minimal effect on the association HR ¼ 8.26, 95% CI: 1.24, 55.0; P ¼ 0.029) (Table 5).
(for all cancer, adjusted HR ¼ 1.38, 95% CI: 1.05, 1.82; Of 5,814 primiparous mothers, uterine cancer was diag- nosed among 9 untreated women and 4 treated women, Distribution of Participants According to Type of Ovulation Induction Treatment and Selected Characteristics, Jerusalem Perinatal Study, 1974–2004 (tubal insufflation, dilationand curettage, other) a Numbers in parentheses, standard deviation.
b Number of children at the end of data collection.
d Defined as irregular menstrual periods or menstrual cycles with lengths of <21 days or >35 days.
yielding a 6-fold increased risk (after adjustment for age, primiparous women was associated with a similarly adjusted body mass index, and ovulatory disorders, HR ¼ 6.69, 95% hazard ratio of 8.33 (95% CI: 2.25, 30.85; P ¼ 0.002) (not CI: 2.05, 21.8; P ¼ 0.002). Clomiphene treatment in Age-Adjusted Hazard Ratio for Incident Cancer According to Type of Ovulation Induction Treatment, Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004 Abbreviations: CI, confidence interval; HR, hazard ratio.
a Age-adjusted HR for comparison of treated mothers with untreated mothers.
Malignant melanoma. Treatment for ovulation induction of the uterus following treatment with clomiphene citrate.
in general was not associated with the development of Furthermore, this study’s results suggest increased risks of malignant melanoma (multivariate HR ¼ 1.68, 95% CI: 0.72, breast cancer, malignant melanoma, and non-Hodgkin lym- 3.92). However, women treated with clomiphene experienced phoma following ovulation induction treatment that were a significantly increased risk of malignant melanoma, with more pronounced among women who waited more than 1 a multivariate-adjusted hazard ratio of 2.56 (95% CI: 1.10, year to conceive, perhaps representing a dose-response re- lation. The results of the current study do not support an Non-Hodgkin lymphoma. For non-Hodgkin lymphoma, increased risk of ovarian cancer following ovulation induc- treatment for ovulation induction was associated with a multivariate-adjusted hazard ratio of 2.63 (95% CI: 1.02, Possible limitations of this study include the absence of 6.82) (Table 4). The increased risks were evident especially detailed information regarding type of infertility, type of among primiparous women (Table 3) and in the first 5 years treatment, dosage, and number of cycles and lack of in- following birth (Table 7). Clomiphene treatment was not formation regarding treatment in other pregnancies. While associated with a significantly increased risk of non-Hodgkin introduction of family size into our multivariate models re- lymphoma (multivariate HR ¼ 2.46, 95% CI: 0.74, 8.13) duced the magnitude of all associations studied, suggesting that family size is a confounder, parity might also be a sur-rogate for treatment in previous pregnancies; therefore, con-trolling for family size might partially mask the effects of ovulation induction. While treatments were self-reported inthis study, the proportion of women reporting exposure to In this study, women who were treated for ovulation in- clomiphene treatment (64% of all treated women) was sim- duction experienced a significantly higher overall risk of ilar to that reported in other studies with data from the 1970s cancer. This increased risk was especially evident for cancer (7, 15). Moreover, according to the sensitivity analysis, Hazard Ratio for Incident Cancer (Multivariate Analysis) According to Type of Ovulation Induction Treatment, Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004 Abbreviations: CI, confidence interval; HR, hazard ratio.
a Results were adjusted for age, socioeconomic status, country of birth, and body mass index.
b Results were adjusted for family size in addition to the variables included in model 1.
c Results were additionally adjusted for ovulatory disorders.
misclassification of treatment, if any existed, did not mate- clomiphene and gonadotropins among women with an intact hypothalamic-hypophysic-ovarian axis are approximately The current study included only parous women; thus, 40% (4) and 80%–90% (20), respectively, this study is rel- its results cannot be generalized to women who were treated evant for a major subset of women who were treated and but failed to conceive. However, since the success rates for conceived. While investigators in most other cohort studies Age-Adjusted Hazard Ratio for Incident Cancer According to Type of Ovulation Induction Treatment and Time to Conception, Abbreviations: CI, confidence interval; HR, hazard ratio.
Age-Adjusted Hazard Ratio for Incident Cancer According to Any Type of Ovulation Induction Treatment Among All Women and Primiparous Mothers, by Cancer Site and TimeSince Birth, Jerusalem Perinatal Study, 1974–2004 Abbreviations: CI, confidence interval; HR, hazard ratio.
either did not control for parity or controlled for parity at the tios of 5.7–11.5 for uterine cancer among women treated time treatment was initiated, considering women who sub- with clomiphene; however, these standardized incidence ra- sequently gave birth as nulliparous, this study had no re- tios were not significantly different from those obtained for untreated infertile women. Althuis et al. (24) suggested We did not observe an association between ovulation in- a dose-response relation for clomiphene with standardized duction and ovarian cancer, a finding supported by the re- incidence ratios of 1.63 (95% CI: 0.8, 3.4) and 2.16 (95% sults of other studies (9, 10, 18, 21); it is possible that the CI: 0.9, 5.2) among women treated for fewer than 6 cycles association found in previous studies (7, 8) between ovula- and 6 or more cycles, respectively. Two small case-control tion induction in general and clomiphene in particular and studies showed no significant associations, representing per- ovarian cancer was restricted to nulliparous women, since haps lack of statistical power (25, 26). Among women who nulliparity is a major risk factor for ovarian cancer (22).
underwent in vitro fertilization (16), women treated with This suggestion could also be implied from a meta-analysis fertility drugs had a 5-fold increased risk of uterine cancer (23) in which a 1.5-fold increased risk of ovarian cancer was within the first year only, suggesting surveillance bias. How- evident when treated women were compared with the ever, in this latter study, very few were treated for more than general population but no excess in risk was shown when 6 cycles, and the follow-up period was relatively short. Our treated women were compared with untreated infertile findings cannot be explained by other risk factors for uterine cancer, such as nulliparity, since all women in our cohort The increased risk of uterine cancer observed in this study gave birth; nor can they be explained by ovulation disorders was prominent among women treated with clomiphene.
or obesity, for which we controlled in our multivariate anal- Modan et al. (18) demonstrated standardized incidence ra- ysis. Like tamoxifen, clomiphene is a selective estrogen Results From Sensitivity Analysis of Multivariate-Adjusted Hazard Ratios for Incident Cancer Among Women Exposed to Ovulation Induction Treatment, Overall and by Cancer Site, Jerusalem Perinatal Study, 1974–2004a Clomiphene and/or Human Menopausal Gonadotropins Abbreviations: CI, confidence interval; HR, hazard ratio.
a In all models, results were adjusted for age, geographic origin, socioeconomic status, body mass index, and b Results were also adjusted for ovulation disorders.
receptor modulator. While tamoxifen has been proven to We could not find any previous publications on fertility reduce recurrence rates of breast cancer and improve sur- treatments and their association with non-Hodgkin lym- vival, it is well established that it increases the risk of en- phoma. Reproductive factors such as age at menarche and dometrial cancer 2- to 7-fold (27, 28). The structural parity have been suggested to be associated with non-Hodgkin similarities as well as the similarities in ovulation induction lymphoma in a pattern quite similar to that for breast properties (29) raise the possibility of clomiphene as a car- cancer (30). However, unlike the case with breast cancer, oral contraceptives have been suggested to be protective Our results might suggest that clomiphene as the only against non-Hodgkin lymphoma (31). While 1 study sug- treatment is associated with an increased risk of breast can- gested that hormone replacement therapy increases the cer. Similarly to the results of Lerner-Geva et al. (11), we risk of non-Hodgkin lymphoma (32), other studies failed observed an increased risk of breast cancer of comparable to demonstrate such an association (33, 34). If indeed magnitude for women treated only with clomiphene which estrogens are related to the incidence of non-Hodgkin disappeared when all women exposed to clomiphene were lymphoma, an association between ovulation induction included in the analysis. Brinton et al. (12) suggested an and non-Hodgkin lymphoma is plausible.
increased breast cancer risk for clomiphene only after 20 years We found an increased risk of malignant melanoma only of follow up, irrespective of dosage or number of treat- among women treated with clomiphene. Althuis et al. (35) ment cycles. Potashnik et al. (13) suggested an increased suggested a doubled risk among clomiphene-treated women risk of breast cancer only among women who received short- followed for more than 15 years; however, the increased risk term treatment or a low dose of clomiphene. Contradic- associated with clomiphene treatment was demonstrated tory results include those of Terry et al. (29), who showed only among nulliparous women (35). Hannibal et al. (36) a significantly reduced risk of breast cancer among women suggested an increased risk for gonadotropins (but not clo- with ovulatory infertility who underwent ovulation induc- miphene) among parous women only. Other studies of the tion, with a dose-response pattern, and those of Rossing possible hormonal factors contributing to malignant mela- et al. (14), which suggested a nonsignificantly reduced risk noma include conflicting reports on the association between following receipt of clomiphene. Jensen et al. (15) demon- exogenous estrogen use and melanoma risk (37, 38) and strated no association between treatment with clomiphene, a suggestion that older age at first birth might be associated human chorionic gonadoptropins, or other gonadotropins and breast cancer. Similar to their results for uterine cancer, The strengths of this study included the design of the Venn et al. (16) found an increased risk of breast cancer within-cohort comparison and the completeness of follow- among in-vitro-fertilization-treated women only within 12 up data on cancer incidence. Our study contained a small number of women who were treated in the 1970s and thus exposed to different treatment protocols in the era preceding 2. Juul S, Karmaus W, Olsen J. Regional differences in waiting widespread use of in vitro fertilization. However, this is also time to pregnancy: pregnancy-based surveys from Denmark, one of the study’s main strengths, allowing follow-up to the France, Germany, Italy and Sweden. The European Infertility age of increasing cancer incidence in women. Our results and Subfecundity Study Group. Hum Reprod. 1999;14(5): suggest that the increased risk was most pronounced in the 3. Henne MB, Bundorf MK. Insurance mandates and trends in first 20 years following exposure. These results parallel infertility treatments. Fertil Steril. 2008;89(1):66–73.
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Conflict of interest: none declared.
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