Poster Presentation GENEMAPPERS 2026

Investigating the potential causal relationship between parity and long-term maternal cardiometabolic health outcomes (#56)

Caroline Brito Nunes 1 , Abigail Fraser 2 , Gunn-Helen Moen 1 3 4 , David M Evans 1 2 4
  1. The University of Queensland Institute for Molecular Bioscience, St Lucia, Queensland, Australia
  2. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
  3. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
  4. Frazer Institute, The University of Queensland, Brisbane, Australia

Introduction: Pregnancy induces substantial physiological changes, and the cumulative stress of multiple pregnancies and childrearing has been proposed to influence long-term maternal cardiometabolic health outcomes.

Method: We separately regressed number of children ever born (NEB) on later-life cardiometabolic outcomes in up to 172,122 females and 138,390 males from the UK Biobank (UKBB) and assessed heterogeneity in regression coefficients between sexes to explore potential childbearing and sex-specific childrearing effects. To strengthen causal inference, we performed i) sex-stratified two-sample Mendelian randomization (MR) where males served as negative controls, and ii) a novel spousal MR approach in 53,237 UKBB spousal pairs, which leveraged one partner’s genotype to estimate causal effects on the other’s health, potentially reducing bias from horizontal pleiotropy.

Results: Observational analyses revealed sex-specific associations between NEB and cardiometabolic traits, persisting after adjustment for socioeconomic status and multiple test correction (P<6.25x10-3). In females, NEB was inversely associated with blood pressure and cholesterol; in males, it was positively associated with ApoB and LDL. While NEB showed some consistent associations across sexes, effect sizes differed: females showed stronger inverse associations with HDL and ApoA1, while males showed stronger positive associations with BMI, body fat percentage, and basal metabolic rate (BMR). MR analyses supported a causal effect of higher NEB on increased type 2 diabetes risk in females (P<6.25x10-3), with weak evidence (P<0.05) for lower blood pressure, and elevated BMI and BMR. Spousal MR provided robust evidence for a causal effect of NEB on increased BMI in females (P<6.25x10-3), with suggestive effects with higher BMR and lower HDL (P<0.05). In males, MR results showed weak evidence of causal effects (P<0.05).

Conclusion: By triangulating evidence across methods, our findings suggest a possible causal link between NEB and long-term cardiometabolic health in females, with BMI and BMR representing key pathways linking parity to chronic disease risk.