Impact of reproductive factors on major cardiovascular disease risk in women: a Mendelian randomization study

Abstract

Background: Cardiovascular disease is a major cause of morbidity and mortality in women. Multiple observational studies have explored the role of female reproductive history on the risk of cardiovascular disease and suggested that factors such as high parity and early menarche are associated with higher rates of cardiovascular disease later in life. However, effect estimates derived from observational studies are liable to influence by residual confounding and bias in study design. We utilise Mendelian randomisation to explore causal pathways underlying this association by leveraging genetic variability in reproductive factors using instrumental variable analysis. Methods: Uncorrelated single nucleotide polymorphisms (r2<0.001) were extracted from summary statistics of published sex-specific genome wide association studies (GWAS) for the exposures of age at first birth (n=131,987, unit = years), number of live births (n=193,953, coded into three categories of <2, 2 or >2 live births), age at menarche (n=329,345, unit = years) and age at menopause (n=106,048, unit = years). Genetic association estimates for the outcomes of coronary artery disease, ischaemic stroke, stroke of any type, heart failure and atrial fibrillation were extracted from GWAS analyses on respectively 122,733 cases, 34,217 cases, 40,585 cases, 47,309 cases and 60,620 cases. All GWAS studies were on populations of predominantly European ancestry. Inverse-variance weighted MR was utilised for primary analyses; sensitivity analyses using MR-Egger and weighted median MR were carried out. Results: Earlier age at first birth was associated with increased risk of coronary artery disease (OR per 1-year lower age = 1.49, 95% CI 1.28- 1.74, p<0.001). Lower age at menarche was also associated with increased risk of coronary artery disease (OR per 1-year lower age = 1.10, 95% CI 1.06-1.14, p<0.001) and increased risk of heart failure (OR 1.12, 95% CI 1.07-1.17, p<0.001). Finally, higher number of live births was associated with increased risk of atrial fibrillation (OR per increase in category of <2, 2 or >2 live births = 2.91, 95% CI 1.16-7.29, p=0.023), increased risk of heart failure (OR 1.90, 95% CI 1.28-2.82, p=0.001), increased risk of ischaemic stroke (OR 2.07, 95% CI 1.22-3.52, p=0.007) and of stroke of any type (OR 1.86, 95% CI 1.03-3.37, p=0.039). Conclusion: The results of this study support the emerging evidence of female-specific risk factors for cardiovascular disease, by demonstrating that that earlier age at first birth, higher number of live births, and earlier menarche are all associated with increased cardiovascular morbidity in women. The results notably highlight parity as a major sex-specific risk factor of likely causal relevance. These findings support the inclusion of reproductive history in the routine evaluation of cardiovascular risk in females and identify key markers of risk that may be used to target primary prevention measures. (Figure Presented).