Ovarian cancer risk after the use of ovulation-stimulating drugs

Abstract

Objective: To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer.

Methods: A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors.

Results: The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7).

Conclusion: The results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks.

Level of evidence: II-2