Association of infertility with type and timing of menopause: a prospective cohort study.

study questionWhat is the association between past infertility and the type and timing of menopause in midlife women? SUMMARY ANSWER: Women with a history of infertility were more likely to experience surgical menopause overall and had elevated risk of earlier surgical menopause until age 43 years but experienced no differences in the timing of natural menopause. WHAT IS KNOWN ALREADY: Infertility is experienced by 12-25% of women and is thought to reveal a propensity for poor health outcomes, such as chronic illness, later in life. However, little is known about whether infertility is linked with characteristics of the menopausal transition as women age, despite possible shared underlying pathways involving ovarian function and gynecologic disease. STUDY DESIGN, SIZE, DURATION: Secondary analysis of a prospective cohort study of 13 243 midlife females recruited in Phase 1 of the Alberta's Tomorrow Project (Alberta, Canada) and followed approximately every 4 years (2000-2022). PARTICIPANTS/MATERIALS, SETTING,

methodsData were collected through standardized self-report questionnaires. History of infertility, defined as ever trying to become pregnant for more than 1 year without conceiving, was measured at baseline. Menopause characteristics were measured at each study follow-up. Menopause type was defined as premenopause, natural menopause, surgical menopause (bilateral oophorectomy), or indeterminate menopause (premenopausal hysterectomy with ovarian conservation). Timing of natural menopause was defined as the age at 1 full year after the final menstrual period, and timing of surgical and indeterminate menopause was defined as the age at the time of surgery. We used flexible parametric survival analysis for the outcome of menopause timing with age as the underlying time scale and multinomial logistic regression for the outcome of menopause type. Multivariable models controlled for race/ethnicity, education, parity, previous pregnancy loss, and smoking. Sensitivity analyses additionally accounted for birth history, menopausal hormone therapy, body mass index, chronic medical conditions, and age at baseline. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 18.2% of women reported a history of infertility. Past infertility was associated with earlier timing of surgical menopause exclusively before age 43 years (age 35: adjusted hazard ratio 3.13, 95% CI 1.95-5.02; age 40: adjusted hazard ratio 1.83, 95% CI 1.40-2.40; age 45: adjusted hazard ratio 1.13, 95% CI 0.87-1.46) as well as greater odds of experiencing surgical menopause compared to natural menopause (adjusted odds ratio 1.40, 95% CI 1.18-1.66). Infertility was not associated with the timing of natural or indeterminate menopause. LIMITATIONS, REASONS FOR CAUTION: Information on the underlying cause of infertility and related interventions was not collected, which precluded us from disentangling whether associations differed by infertility cause and treatment. Residual confounding is possible given that some covariates were measured at baseline and may not have temporally preceded infertility. WIDER IMPLICATIONS OF THE

findingsWomen with a history of infertility were more likely to experience early surgical menopause and may therefore benefit from preemptive screening and treatment for gynecologic diseases to reduce bilateral oophorectomy, where clinically appropriate, and its associated health risks in midlife. Moreover, the lack of association between infertility and timing of natural menopause adds to the emerging knowledge that diminishing ovarian reserve does not appear to be a primary biological mechanism of infertility nor its downstream implications for women's health. STUDY FUNDING/COMPETING INTEREST(S): Alberta's Tomorrow Project is only possible due to the commitment of its research participants, its staff and its funders: Alberta Health, Alberta Cancer Foundation, Canadian Partnership Against Cancer and Health Canada, and substantial in-kind funding from Alberta Health Services. The views expressed herein represent the views of the author(s) and not of Alberta's Tomorrow Project or any of its funders. This secondary analysis is funded by Project Grant Priority Funding in Women's Health Research from the Canadian Institutes of Health Research (Grant no. 491439). N.V.S. is supported by a Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research. H.K.B. is supported by the Canada Research Chairs Program. E.A.B. is supported by an Early Career Investigator Award in Maternal, Reproductive, Child and Youth Health from the Canadian Institutes of Health Research. A.K.S. has received honoraria from Pfizer, Lupin, Bio-Syent, and Eisai and has received grant funding from Pfizer. N.V.S., H.K.B., and E.A.B. have no conflicts of interest to report. TRIAL REGISTRATION NUMBER: N/A.