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

Abstract

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 ( $\text{H}{\text{R}}_{\text{adjusted}}=1.08$ , 95% CI: 1.03 to 1.14, $P=0.002$ ; $\text{R}{\text{R}}_{\text{adjusted}}=1.05$ , 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 ( $\text{H}{\text{R}}_{\text{adjusted}}=1.10$ ; 95% CI: 1.01 to 1.21; $P=0.034$ ) and without ( $\text{R}{\text{R}}_{\text{adjusted}}=1.34$ ; 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 ( $\text{HR}=1.09$ ; 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.