Investigating the potential causal relationship between parity and long-term maternal cardiometabolic health outcomes using Mendelian randomization

Background: Multiple observational studies have reported associations between greater parity and increased CVD risk. Whether these associations reflect causal effects or are confounded by socioeconomic factors remains unclear. Methods: We investigated associations between number of children ever born (NEB) and 16 cardiometabolic traits in up to 172,122 females and 138,390 males in the UK Biobank, and an independent sample of 53,237 UK Biobank spousal pairs. We additionally conducted sex-stratified two-sample Mendelian randomization (MR) and applied a novel spousal MR framework, in which an individual's spouse's genotype was used as the instrumental variable to estimate the causal effect of NEB on cardiometabolic health outcomes, as an approach to minimize bias from horizontal pleiotropy. Results: NEB was associated with multiple cardiometabolic traits in the multivariable regression, even after adjustment for socioeconomic status, with differences in the strength of association observed between males and females. Traditional MR provided evidence that higher NEB causally increases type 2 diabetes risk in females, body mass index (BMI) in both sexes, female basal metabolic rate (BMR) and male body fat percentage but decreases female blood pressure. Spousal MR corroborated positive effects on female BMI and BMR and additionally suggested inverse causal effects on female HDL cholesterol and ApoA1 and male blood glucose. Conclusion: These findings indicate a possible causal relationship between NEB and long-term cardiometabolic health, although causal effects are likely to be small.