Meta-analysis: Early Age at Natural Menopause and Risk for All-Cause and Cardiovascular Mortality

AIMS: The aim of this meta-analysis was to comprehensively evaluate the association of early age at natural menopause with the risk for all-cause and cardiovascular mortality. METHODS: Literature retrieval was done on August 4, 2020. Article selection and data extraction were completed independently and in duplicate. Early age at natural menopause was grouped into premature menopause (<40 years), early menopause (40-44 years), and relatively early menopause (45-49 years). Effect-size estimates are summarized as hazard ratio (HR) or relative risk (RR) with 95% confidence interval (CI). RESULTS: Sixteen articles involving 321,233 women were meta-analyzed. Overall analyses revealed a statistically significant association of early age at natural menopause with all-cause mortality risk (HR(adjusted) = 1.08, 95% CI: 1.03 to 1.14, P = 0.002; RR(adjusted) = 1.05, 95% CI 1.01 to 1.08, P = 0.005), but not with cardiovascular mortality risk. In dose-response analyses, the association with all-cause mortality was significant for premature menopause with (HR(adjusted) = 1.10; 95% CI: 1.01 to 1.21; P = 0.034) and without (RR(adjusted) = 1.34; 95% CI: 1.08 to 1.66; P = 0.007) considering follow-up intervals. As for cardiovascular mortality, marginal significance was noted for premature menopause after considering follow-up intervals (HR = 1.09; 95% CI: 1.00-1.19; P = 0.045). Subgroup analyses indicated that gender, country, and follow-up periods were possible causes of heterogeneity. There was an overall low probability of publication bias. CONCLUSIONS: Our findings indicate that premature menopause is a promising independent risk factor for both all-cause and cardiovascular mortality.