Background: Cardiovascular disease is a major cause of morbidity and mortality in women. Observational studies suggest that reproductive factors are associated with cardiovascular disease risk, but these are liable to influence by residual confounding. This study aims to explore the causal role of reproductive factors on cardiovascular disease in women using Mendelian randomisation and explore potentially modifiable mediating pathways amenable to intervention.

Methods and results: Uncorrelated (r2<0.001), genome-wide significant (p<5x10 -8) SNPs were extracted from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche and age at menopause. Inverse-variance weighted Mendelian randomisation was utilised for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and stroke. Earlier genetically-
predicted age at first birth increased risk of coronary artery disease (OR per 1-year lower 1.49, 95%CI 1.28-1.74, p=3.72x10 -7 ), heart failure (OR 1.27, 95%CI 1.06-1.53, p=0.009) and stroke (OR 1.25, 95%CI 1.00-1.56, p=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure and cholesterol traits. Higher genetically-predicted number of live births increased risk of atrial fibrillation (OR per category increase <2 vs 2 vs
>2 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), ischaemic 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 1-year lower 1.10, 95%CI 1.06-1.14, p=1.68 x10 -6) and heart failure (OR 1.12, 95%CI 1.07-1.17, p=5.06x10 -7), and both associations were at least partly mediated by body mass index.

Conclusion: These results support a causal role of a number of reproductive factors on cardiovascular disease in women, and identify multiple modifiable mediators that should be considered key targets for clinical intervention.