Background
A high proportion of women start pregnancy overweight or 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) and offspring systemic
cardio-metabolic profile are causal, via intrauterine mechanisms, or due to shared familial
factors.
Methods and findings
We used 1- and 2-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 3 European birth cohorts (offspring age at blood collection:
16, 17, and 31 years). Circulating metabolic traits were quantified by high-throughput
nuclear magnetic resonance metabolomics. Results from 1-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 very-low-density lipoprotein (VLDL)-lipoproteins, VLDLcholesterol
(C), VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoprotein
acetyls, and triglycerides, and strong negative associations with high-density lipoprotein
(HDL), HDL-diameter, HDL-C, HDL2-C, and HDL3-C (all P < 0.003). Slightly 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 P > 0.05 after accounting for multiple
testing). Results were similar in each individual cohort, and in the 2-stage analysis. Offspring
BMI showed similar patterns of cross-sectional association with metabolic profile as for
parental pre-pregnancy BMI associations but with greater magnitudes. Adjustment of parental
BMI–offspring metabolic traits associations for offspring BMI suggested the parental
associations were largely due to the association of parental BMI with offspring BMI. Limitations
of this study are that inferences cannot be drawn about the role of circulating maternal
fetal fuels (i.e., glucose, lipids, fatty acids, and amino acids) on later offspring metabolic profile.
In addition, BMI may not reflect potential effects of maternal pregnancy fat distribution.