Newborn Adiposity and Cord Blood C-Peptide as Mediators of the Maternal Metabolic Environment and Childhood Adiposity

Background:  Excessive childhood adiposity is a risk factor for adverse metabolic health. We investigated associations of newborn body composition and fetal hyperinsulinemia with childhood anthropometrics and explored whether these newborn measures mediate associations of maternal mid-pregnancy glucose and BMI with childhood adiposity. Methods: Data on mother/offspring pairs (N=4832) from the epidemiological Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and HAPO Follow Up Study (HAPO FUS) were analyzed. Linear regression was used to study associations between newborn and childhood anthropometrics. Structural equation modeling was used to explore newborn anthropometric measures as potential mediators of the associations of maternal BMI and glucose during pregnancy with childhood anthropometric outcomes.  Findings: In models including maternal glucose and BMI adjustments, newborn adiposity (sum of skinfolds) was associated with child outcomes (adjusted mean difference, 95% CI, p-value) BMI(0·26,0·12-0·39,<0·001), BMI z-score(0·072,0·033-0·11,<0·001), fat mass (kg)(0·51,0·26-0·76,<0·001), percent bodyfat(0·61, 0·27-0·95,<0·001), and sum of skinfolds (mm)(1·14,0·43-1·86,0·0017). Structural equation models demonstrated significant mediation by newborn sum of skinfolds and cord C-peptide of maternal BMI effects on childhood BMI (proportion of total effect 2·5% and 1·0%, respectively), fat mass(3·1%,1·2%), percent bodyfat(3·6%,1·8%), and sum of skinfolds(2·9%,1·8%), and significant mediation by newborn sum of skinfolds and cord C-peptide of maternal glucose effects on child fat mass (proportion of total association 22·0% and 21·0%, respectively), percent bodyfat(15·0%,18·0%), and sum of skinfolds(15·0%,20·0%). Interpretation: Newborn adiposity is independently associated with childhood adiposity, and along with fetal hyperinsulinemia, mediate, in part, associations of maternal glucose and BMI with childhood adiposity. Funding Statement: United States National Institutes of Health Declaration of Interests: The authors do not have any conflicts of interest to disclose. Ethics Approval Statement: Institutional review boards at each field center approved both studies. Participants provided written informed consent and, where required, assent.