Abstract
IMPORTANCE: Menstrual cycle characteristics may be associated with an increased risk of cardiovascular disease (CVD). However, existing studies are limited, and few have explored the mediating role of established CVD risk factors. OBJECTIVE: To explore the associations of menstrual cycle characteristics across the reproductive lifespan with the risk of CVD and to what extent these associations were mediated by hypercholesterolemia, chronic hypertension, and type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study prospectively followed Nurses' Health Study II participants between 1993 and 2017 who reported menstrual cycle regularity and length for ages 14 to 17 years and 18 to 22 years at enrollment in 1989 and updated current cycle characteristics in 1993 (at ages 29 to 46 years). Data analysis was performed from October 1, 2019, to January 1, 2022. EXPOSURES: Menstrual cycle regularity and length across the reproductive lifespan. MAIN OUTCOMES AND MEASURES: Incident CVD events of interest, including fatal and nonfatal coronary heart disease (CHD; myocardial infarction [MI] or coronary revascularization) and stroke. RESULTS: A total of 80 630 Nurses' Health Study II participants were included in the analysis, with a mean (SD) age of 37.7 (4.6) years and body mass index of 25.1 (5.6) at baseline. Over 24 years of prospective follow-up, 1816 women developed their first CVD event. Multivariable Cox proportional hazards models showed that, compared with women reporting very regular cycles at the same ages, women who had irregular cycles or no periods at ages 14 to 17, 18 to 22, or 29 to 46 years had hazard ratios for CVD of 1.15 (95% CI, 0.99-1.34), 1.36 (95% CI, 1.06-1.75), and 1.40 (95% CI, 1.14-1.71), respectively. Similarly, compared with women reporting a cycle length of 26 to 31 days, women reporting a cycle length 40 days or more or a cycle too irregular to estimate from ages 18 to 22 or 29 to 46 years had hazard ratios for CVD of 1.44 (95% CI, 1.13-1.84) and 1.30 (95% CI, 1.09-1.57), respectively. Mediation analyses showed that subsequent development of hypercholesteremia, chronic hypertension, and type 2 diabetes only explained 5.4% to 13.5% of the observed associations. CONCLUSIONS AND RELEVANCE: In this cohort study, both irregular and long menstrual cycles were associated with increased rates of CVD, which persisted even after accounting for subsequently established CVD risk factors.