Effect of common pregnancy and perinatal complications on offspring metabolic traits across the life course: a multi-cohort study

ABSTRACT Backgroun Common pregnancy and perinatal complications are associated with offspring cardiometabolic risk factors. These complications may influence multiple metabolic traits in offspring and these associations might differ with offspring age. Methods We used data from eight population-based cohort studies to examine and compare associations of pre-eclampsia (PE), gestational hypertension (GH), gestational diabetes (GD), preterm birth (PTB), small (SGA) and large (LGA) for gestational age (vs. appropriate size for gestational age (AGA)) with up to 167 plasma/serum-based nuclear magnetic resonance-derived metabolic traits encompassing lipids, lipoproteins, fatty acids, amino acids, ketones, glycerides/phospholipids, glycolysis, fluid balance, and inflammation. Confounder-adjusted regression models were used to examine associations (adjusted for maternal education, parity age at pregnancy, ethnicity, pre/early pregnancy body mass index and smoking, and offspring sex and age at metabolic trait assessment), and results were combined using meta-analysis by five age categories representing different periods of the offspring life course: neonates (cord blood), infancy (mean ages: 1.1-1.6y), childhood (4.2-7.5y); adolescence (12.0-16.0y), and adulthood (22.0-67.8y). Results Offspring numbers for each age category/analysis varied from 8,925 adults (441 PTB) to 1,181 infants (135 GD); 48.4% to 60.0% were females. Pregnancy complications (PE, GH, GD) were each associated with up to three metabolic traits in neonates ( P ≤0.001) with some limited evidence of persistence to older ages. PTB and SGA were associated with 32 and 12 metabolic traits in neonates respectively, which included an adjusted standardised mean difference of -0.89 standard deviation (SD) units for albumin with PTB (95%CI: -1.10 to -0.69, P =1.3×10 −17 ) and -0.41SD for total lipids in medium HDL with SGA (95%CI: -0.56 to -0.25, P =2.6×10 −7 ), with limited evidence of persistence to older ages. LGA was inversely associated with 19 metabolic traits including lower levels of cholesterol, lipoproteins, fatty acids, and amino acids, with associations emerging in adolescence, (e.g., -0.11SD total fatty acids , 95%CI: -0.18 to -0.05, P =0.0009), and attenuating with older age across adulthood. Conclusions These reassuring findings suggest little evidence of wide-spread and long-term impact of common pregnancy and perinatal complications on offspring metabolic traits, with most associations only observed for new-borns rather than older ages, and for perinatal rather than pregnancy complications.