Sex‐Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study

Abstract

Background Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. Methods and Results Uncorrelated (r22 live births, 2.91 [95% CI, 1.16–7.29], P=0.023), heart failure (OR, 1.90 [95% CI, 1.28–2.82], P=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03–3.37], P=0.039), and stroke (OR, 2.07 [95% CI, 1.22–3.52], P=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06–1.14], P=1.68×10−6) and heart failure (OR, 1.12 [95% CI, 1.07–1.17], P=5.06×10−7); both associations were at least partly mediated by body mass index. Conclusions These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.

Keywords

• age at first birth
• cardiovascular disease
• menarche
• menopause
• parity
• reproductive