Association of Total Reproductive Years with Incident Atrial Fibrillation, and Subsequent Ischemic Stroke in Women with Natural Menopause

Background: The association of lifetime exposure to endogenous sex hormone with incident atrial fibrillation (AF) and subsequent ischemic stroke has never been studied. Methods: This study involved 4 638 299 natural postmenopausal waomen aged ≥40 years without prior history of AF and with national breast cancer check-up between January 1, 2009 and December 31, 2014. The primary end point was incident AF, and the secondary end point was subsequent ischemic stroke once AF has developed. Cox proportional hazard regression analysis was used to estimate the risk of end points. Results: During the mean follow-up of 6.3 years, shorter total reproductive years (<30 years) were associated with 7% increased risk of AF after adjusting for confounding variables (adjusted hazard ratio [aHR], 1.07 [95% CI, 1.05-1.09]). Risk of AF declined progressively with every 5-yearly increment in total reproductive years (P-for-trend <0.001). However, the prolonged (≥2 years) use of hormone replacement therapy after menopause was paradoxically associated with a 3% increase in AF risk (aHR, 1.03 [95% CI, 1.01-1.05]). For the secondary end point analysis, the risk of ischemic stroke after AF development significantly decreased with each 5-yearly increment in total reproductive years (with <30 years as reference; aHR, 0.93 [95% CI, 0.88-0.99] for 30-34 years; aHR, 0.84 [95% CI, 0.79-0.89] for 35-39 years; and aHR, 0.88 [95% CI, 0.80-0.97] for ≥40 years, P-for-trend <0.001). Conclusions: In women with natural menopause, shorter lifetime exposure to endogenous sex hormone, that is, shorter total reproductive years, was significantly associated with a higher risk of AF and subsequent ischemic stroke. Paradoxically, prolonged exogenous hormone replacement therapy increased the risk of incident AF.