Background: Fetal exposure to maternal excess adiposity and hyperglycemia is risk factors for childhood adverse metabolic outcomes. Using data from a prospective pre-birth cohort, we aimed to further understand the prenatal determinants of fetal metabolic programming based on analyses of maternal adiposity and glycemic traits across pregnancy with childhood metabolomic profiles.
Methods: This study included 330 mother-child pairs from the Gen3G cohort with information on maternal adiposity and glycemic markers at 5-16 (visit 1) and 24-30 (visit 2) weeks of pregnancy. At mid-childhood (4.8-7.2 years old), we collected fasting plasma and measured 1116 metabolites using an untargeted approach. We constructed networks of interconnected metabolites using a weighted-correlation network analysis algorithm. We estimated Spearman's partial correlation coefficients of maternal adiposity and glycemic traits across pregnancy with metabolite networks and individual metabolites, adjusting for maternal age, gravidity, race/ethnicity, history of smoking, and child's sex and age at blood collection for metabolite measurement.
Results: We identified a network of 16 metabolites, primarily glycero-3-phosphoethanolamines (GPE) at mid-childhood that showed consistent negative correlations with maternal body mass index, waist circumference, and body-fat percentage at visits 1 and 2 (ρadjusted = -0.14 to -0.21) and post-challenge glucose levels at visit 2 (ρadjusted = -0.10 to -0.13), while positive correlations with Matsuda index (ρadjusted = 0.13). Within this identified network, 1-palmitoyl-2-decosahexaenoyl-GPE and 1-stearoyl-2-decosahexaenoyl-GPE appeared to be driving the associations. In addition, a network of 89 metabolites, primarily phosphatidylcholines, plasmalogens, sphingomyelins, and ceramides showed consistent negative correlations with insulin at visit 1 and post-challenge glucose at visit 2, while positive correlation with adiponectin at visit 2.
Conclusions: Prenatal exposure to maternal higher adiposity and hyperglycemic traits and lower insulin sensitivity markers were associated with a unique metabolomic pattern characterized by low serum phospho- and sphingolipids in mid-childhood.