Reproductive Factors in Women Contribute to Risk of Cardiovascular Disease, According to New Study

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A new Mendelian randomization study provides evidence for a causal relationship between sex-specific factors and cardiovascular disease (CVD) in women and identifies key potential modifiable pathways to mitigate the increased risk.

Findings published in the Journal of the American Heart Association showed that earlier first birth, higher number of live births, and earlier menarche are all associated with increased CVD in women, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke.

“The results support the emerging research focus on female-specific risk factors, stressing the importance of their routine evaluation in clinical risk stratification,” wrote a team of researchers from Imperial College London, University of Cambridge, and Yale School of Public Health.

Observational studies have suggested that some reproductive factors are associated with CVD in women, “but these are liable to influence by residual confounding,” according to investigators. To provide more reliable estimates of causal effects of risk factors in this setting, the researchers used a Mendelian randomization framework.

Investigators first extracted uncorrelated, genome-wide significant single nucleotide polymorphisms from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. They then used inverse-variance weighted Mendelian randomization to evaluate outcomes of AF, CAD, HF, ischemic stroke, and stroke.

“For any associations discovered, potential mediating pathways through traditional, modifiable cardiovascular risk factors of body mass index (BMI), type 2 diabetes (T2D), systolic blood pressure (SBP), high- density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol were also explored,” wrote first author Maddalena Ardissino, BSc, MSc, MBBS, MRCP, National Heart and Lung Institute, Imperial College London, and colleagues.

FINDINGS

Results showed that earlier genetically predicted age at first birth increased the risk of CAD (odds ratio [OR] per year 1.49, 95% CI 1.28-1.74; P=3.72x10^-7), HF (OR 1.27, 95% CI 1.06-1.53; P=.009), and stroke (OR 1.25, 95% CI 1.00-1.56; P=.048). Odds were partially mediated through BMI, T2D, blood pressure, and cholesterol traits, according to researchers.

Higher genetically predicted number of live births was associated with increased risk of AF (OR per increase in category of <2, 2, or >2 live births 2.91, 95% CI 1.16-7.29; P=.023), HF (OR 1.90, 95% CI 1.28-2.82; P=.001), ischemic stroke (OR 1.86, 95% CI 1.03–3.37; P=.039), and stroke (OR 2.07, 95% CI 1.22–3.52; P=.007). Earlier genetically predicted age at menarche was associated with an increased risk of CAD (OR per year 1.10, 95% CI 1.06-1.14; P=1.68x10^-6) and HF (OR 1.12, 95% CI 1.07-1.17; P=5.06x10^-7). Both associations were partially mediated by BMI, noted investigators.

“The results highlight that close monitoring and early modification of cardiometabolic factors is a key strategy that will at least partly mitigate the increased cardiovascular risk conferred by these reproductive factors,” wrote Ardissino et al.

Further research is needed to understand the extent of the association between reproductive factors and CVD risk, including whether there is a linear or nonlinear relationship between a factor and increased risk.

Reference: Ardissino M, Slob EAW, Carter P, et al. Sex-specific reproductive factors augment cardiovascular disease risk in women: A Mendelian randomization study. J Am Heart Assoc. 2023;12:e027933.