Background- A high proportion of women start pregnancy overweight/obese. According to the developmental overnutrition hypothesis, this could lead offspring to have metabolic disruption throughout their lives, and, thus perpetuate the obesity epidemic across generations. Concerns about this hypothesis are influencing antenatal care. However, it is unknown whether maternal pregnancy adiposity is associated with long-term risk of adverse metabolic profiles in offspring, and if so, whether this association is causal, via intrauterine mechanisms, or explained by shared familial (genetic, lifestyle, socioeconomic) characteristics. We aimed to determine if associations between maternal body mass index (BMI) with offspring systemic metabolite profile are causal via intrauterine mechanisms or familial factors. Methods and Findings- We used one and two-stage individual participant data (IPD) meta-analysis, and a negative-control (paternal BMI) to examine the association between maternal pre-pregnancy BMI and offspring serum metabolome from three European birth cohorts (offspring age at metabolite assessment 16, 17 and 31 years). Circulating metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics. Results from one-stage IPD meta-analysis (N=5327 to 5377 mother-father-offspring trios) showed that increasing maternal and paternal BMI was associated with an adverse cardio-metabolic profile in offspring. We observed strong positive associations with VLDL-lipoproteins, VLDL-C, VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoprotein acetyls, and triglycerides, and strong negative associations with HDL-lipoprotein, HDL-diameter, HDL-C, HDL2-C and HDL3-C (all P < 0.003). Stronger magnitudes of associations were present for maternal compared with paternal BMI across these associations, however there was no strong statistical evidence for heterogeneity between them (all bootstrap P > 0.003, equivalent to 0.05 after accounting for multiple testing). Results were similar in each individual cohort, and in the two-stage analysis. Offspring BMI showed similar patterns of cross-sectional association with metabolic profiles as for parental pre-pregnancy BMI associations, but with greater magnitudes. Adjustment of the parent BMI-offspring metabolite associations for offspring BMI suggested the parental associations were largely due to the association of parental BMI measures with offspring BMI. Conclusion- Our findings suggest that maternal BMI- offspring metabolome associations are likely to be largely due to shared genetic or familial lifestyle confounding, rather than intrauterine programming mechanisms. They do not support the introduction of measures to reduce maternal BMI in order to prevent adverse offspring cardio-metabolic health.

Association of pre-pregnancy body mass index with future offspring metabolic profile: findings from three independent European birth cohorts