Date Published: August 22, 2017
Publisher: Public Library of Science
Author(s): Diana L. Santos Ferreira, Dylan M. Williams, Antti J. Kangas, Pasi Soininen, Mika Ala-Korpela, George Davey Smith, Marjo-Riitta Jarvelin, Debbie A. Lawlor, Ronald C. W. Ma
Abstract: BackgroundA 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 findingsWe 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, VLDL-cholesterol (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.ConclusionOur findings suggest that maternal BMI–offspring metabolome associations are likely to be largely due to shared genetic or familial lifestyle confounding rather than to intrauterine mechanisms.
Partial Text: In Western populations, the proportion of women who start pregnancy overweight or obese (body mass index [BMI] ≥25 kg/m2) has increased over the last 20–30 years and is now estimated to be between 20%–50% [1,2].
Characteristics of the 3 study populations are shown in S1 Table, and the flowchart is shown in S1 Fig. The percentage of overweight or obese mothers was 20%, 15%, and 23% in ALSPAC, NFBC86, and NFBC66, respectively, and for fathers was 47% and 32% in ALSPAC and NFBC86, respectively. The highest percentage of overweight or obesity in offspring, at follow-up, in adolescent or adulthood was seen in NFBC66 with 40% (mean age 31 years), followed by ALSPAC with 21% (mean age 17 years), and NFBC86 with 11% (mean age 16 years).
We report, to the best of our knowledge, the first study that investigates the potential influence of maternal pre-pregnancy BMI on adult offspring serum metabolome to determine whether intrauterine mechanisms related to developmental overnutrition result in metabolic disruption in adults when they are in their reproductive years. We found similar associations of both maternal and paternal BMI with offspring systemic metabolism 16–17 years later and 31 years later (the latter assessed with maternal BMI only), suggesting that shared familial genetic, socioeconomic, and lifestyle characteristics rather than an intrauterine programming effect explain the associations of maternal pre-pregnancy BMI with offspring metabolic measures (Figs 2–4).