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Follow-up Studies of Women Evaluated and Treated for Infertility

Infertility has long been recognized as a risk factor for various cancers, including breast and gynecologic cancers. More recently, concern has been raised regarding effects of drugs used to treat infertility, particularly since these drugs stimulate ovulation and raise endogenous estrogen levels. Investigators in DCEG have been involved with a number of investigations to clarify effects of fertility drug exposures on risk of various cancers.

One of these investigations involved a retrospective cohort study that identified 12,193 women who had been evaluated and/or treated for infertility at five large reproductive endocrinology practices between the early 1960’s and 1989. Detailed information was abstracted from medical records, and located patients were administered questionnaires to obtain updated information regarding disease risk factors and health status. Linkages were also performed with thirteen cancer registries and the National Death Index. The latest follow-up, which assessed cancer incidence through 2010, revealed 749 breast, 118 endometrial and 85 ovarian cancer cases, and allowed a detailed assessment of risk in relation to both clomiphene and gonadotropins.

Results regarding effects of ovulation-stimulating drugs on endometrial and ovarian cancers were largely reassuring. The only significant excess risk was that of ovarian cancer associated with clomiphene exposures among women who remained nulligravid during follow-up. This most likely reflected that these women had more resistant infertility rather than an effect of the drug exposures. For medically validated invasive breast cancers, however, there was a significantly elevated risk observed for women who received 12 or more clomiphene cycles—a dosage much higher than would be prescribed in current practice. The excess risk was highest among women who remained nulligravid during follow-up. This also leads to questions regarding the biologic plausibility of the association. Nonetheless, the results do support the need for continued monitoring of risks, particularly given the relatively young age of women in this cohort (average age at follow-up was only 50 years of age).  

In addition to evaluating effects of older fertility drugs, more recently prescribed fertility treatments have been of interest, including those associated with in vitro fertilization (IVF).  For such analyses, collaborations have been established in both Israel and Norway, given that these countries both have very high rates of such procedures. Two record linkage efforts have been undertaken, one at Maccabi Healthcare Services, the second largest health maintenance organization in Israel, and the other among a cohort of parous women in Norway. The Israeli study showed generally reassuring results regarding IVF exposures for most cancers, with the only evidence of any risk elevation being a non-significant risk for ovarian cancer among women receiving 4 or more IVF cycles. In contrast, the risk among women receiving IVF of in situ cervical cancer was significantly reduced and that of invasive cervical cancer non-significantly reduced—most likely reflecting more intensive Pap smear screening among women seeking IVF.  In contrast to the Israeli study, results from Norway suggested increasing risks of breast cancer among the women followed for the longest periods of time. These results support the need for continued follow-up to fully clarify long-term cancer risks associated with IVF exposures.

View publications related to the Follow-up Study of Women Evaluated and Treated for Infertility.

For more information, contact Louise Brinton.

Hormonal and Reproductive Epidemiology Branch - Research Areas