Lifetime Cumulative Effect of Reproductive Factors on Stroke and Its Subtypes in Postmenopausal Chinese Women: A Prospective Cohort Study

Abstract

Background and objectives: Multiple reproductive factors are associated with stroke. Little is known about the cumulative effects of reproductive factors during a reproductive life course on stroke and its subtypes, especially among female Chinese individuals. The objective of this study was to assess the associations of lifetime cumulative estrogen exposure due to reproductive factors with stroke and its etiologic subtypes among postmenopausal Chinese women.

Methods: Postmenopausal women without prior stroke at baseline (2004-2008) were selected from the China Kadoorie Biobank (CKB). Lifetime cumulative estrogen exposure due to reproductive factors was assessed using 3 composite indicators: reproductive lifespan (RLS), endogenous estrogen exposure (EEE), and total estrogen exposure (TEE). Stroke and its subtypes, ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), were identified through linkage to a disease registry system and health insurance data during follow-up (2004-2015). Multivariable-adjusted Cox proportional hazards regression models were applied to estimate the adjusted hazard ratio (aHR) and 95% CIs for the risk of stroke by quartiles of RLS, EEE, and TEE, respectively.

Results: A total of 122,939 postmenopausal participants aged 40-79 years without prior stroke at baseline were included. During a median follow-up period of 8.9 years, 15,139 cases with new-onset stroke were identified, including 12,853 cases with IS, 2,580 cases with ICH, and 269 cases with SAH. Compared with the lowest quartile (Q1) of RLS, the highest quartile (Q4) had a lower risk of total stroke (aHR: 0.95, 95% CI 0.92-0.98), IS (aHR: 0.95, 95% CI 0.92-0.98), and ICH (aHR: 0.87, 95% CI 0.81-0.94). Both EEE and TEE displayed a graded association with the subsequent descending risk of total stroke (aHR for Q4 vs Q1: EEE: 0.85, 95% CI 0.82-0.89; TEE: 0.87, 95% CI 0.84-0.90), IS (aHR for Q4 vs Q1: EEE: 0.86, 95% CI 0.83-0.90; TEE: 0.86, 95% CI 0.83-0.89), and ICH (EEE: 0.73, 95% CI 0.65-0.81; TEE: 0.83,95% CI 0.76-0.91), with a p for trend < 0.001 for all these associations.

Discussion: Individuals' cumulative estrogen exposure due to reproductive factors could potentially be a valuable indicator for risk stratification of stroke events after menopause.