Early menopause and its association with cardiovascular outcomes (PURE): a multinational prospective cohort study

Background Premature menopause is a risk factor for cardiovascular disease that is specific to women, but this association between premature menopause and cardiovascular disease has not been systematically assessed across ethnicities or across low-income, middle-income, and high-income countries. We aimed to estimate the prevalence of premature menopause and its association with cardiovascular events across various income-group countries and ethnicities. Methods The Prospective Urban Rural Epidemiologic (PURE) study was a multinational prospective cohort study in which 125 073 women from 28 countries aged 35–70 years were assessed for an association between age of menopause onset (not yet reached menopause, premature menopause [aged <40 years], early menopause [aged 40–45 years), and common age menopause (aged ≥45 years]) and cardiovascular events (myocardial infarction, stroke, or heart failure), using a mixed Cox proportional hazards model adjusted for age and INTERHEART risk score. The risk of early menopause was estimated using current status proportional hazards models. Recruitment varied from community announcements to mail and telephone calls inviting participants to central clinics as practical with an aim to be representative. Data were collected using standardised questionnaires through trained researchers. Findings Between Jan 5, 2005, and Dec 4, 2016, 111 619 women (mean age 50·6 years) from 28 countries (two of which did not have menopause data) were recruited with menopause data. 48 249 (43·2%) of 111 619 women were from rural areas and the median follow-up time was 14·6 years (IQR 12·0–16·1). Women in low-income and middle-income countries (LMICs) had a 53% (95% CI 46–61%) increased risk of premature menopause, with half of them reaching menopause by age 47·5 years compared with 50·6 years in high-income countries. South Asian women had a 34% (95% CI 27–42%) increased risk compared with European women, with half of south Asian women reaching menopause by age 47·4 years compared with 50·7 years for European women. Decreased menopause age was significantly associated with increased risk of major cardiovascular disease events (not yet reached menopause group adjusted hazard ratio 0·90 [95% CI 0·83–0·98]; early menopause group 1·14 [1·05–1·23]; and the premature menopause group 1·27 [1·15–1·40]) compared with common age menopause, adjusting for age and INTERHEART risk score, with similar associations for myocardial infarction and stroke. The findings were consistent across ethnicities and country-income groups. Interpretation Premature menopause was more common in LMICs and south Asian women and consistently associated with cardiovascular events across country-income group and ethnic groups. This finding suggests that women with premature and early menopause could be a target population for cardiovascular preventative interventions. Funding Full funding sources are listed at the end of the paper (see Acknowledgments).