STUDY QUESTION Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION A retrospective, population-based cohort study including all 146 024 infertile women aged 20–45 years and living in Denmark in the period 1995–2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07–2.48) and papillary (HR 1.66, 95% CI 1.04–2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. LIMITATIONS, REASONS FOR CAUTION Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER N/A.

Study question Is the use of fertility drugs among infertile women associated with tumors of the central nervous system (CNS)? Summary answer The use of most specific types of fertility drugs is not associated with an increased risk of CNS tumors overall. What is known already Few previous studies have investigated the association between fertility drugs and CNS tumors. Studies have reported inconsistent results regarding the risk of CNS tumors associated with assisted reproductive technologies such as in vitro fertilization (IVF). No studies have reported the risk associated with various specific fertility drugs. Study design, size, duration Retrospective population-based cohort study of all women included in the Danish Infertility Cohort. The study cohort consisted of 148 016 infertile women after exclusion of women who emigrated, died, were diagnosed with cancer before infertility diagnosis, and women for whom information on level of education was missing. The cohort was linked to various national health- and civil registers to study all 20- to 45-year old infertile women in Denmark during 1995-2017. Participants/materials, setting, methods The study cohort was linked to various national health and population registers to obtain information on fertility drugs (clomiphene citrate, gonadotropins, human chorionic gonadotropin, gonadotropin-releasing hormone receptor modulators and progesterone), CNS tumors, relevant covariates and vital and emigration status. Cox proportional hazard regression models were used to calculate hazard ratios and 95% confidence intervals for CNS tumors overall and for gliomas, meningiomas and diverse benign tumors of the brain and other parts of the CNS. Main results and the role of chance During a median 11.3 years of follow-up, 328 women were diagnosed with a CNS tumor. No marked associations were observed between use of most types of fertility drugs (clomiphene citrate, gonadotropins, gonadotropin releasing hormone receptor modulators and progesterone) and CNS tumors. However, ever use of human chorionic gonadotropin was associated with an increased rate of gliomas (HR 2.13 95% CI 0.90-5.01) but a decreased rate of meningiomas (HR 0.49 95% CI 0.28-0.87). No clear associations with CNS tumors were observed according to time since first use or cumulative dose for any specific fertility drugs. Additional studies with longer follow-up are necessary to support these findings. Limitations, reasons for caution The median age at end of follow-up (43.5 years) was lower than the median age for CNS tumors diagnosis (60 years). Information on estrogen use, treatment regimens and number of cycles is only partly available in the registers and these were not included in this study. Wider implications of the findings This study presents reassuring results regarding the risk of tumors of the CNS among women treated with fertility drugs. Our study is only generalizable to premenopausal women, and the risk for postmenopausal women remains to be assessed. Trial registration number not applicable

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