A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence.

Aims/hypothesis: This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence.

Methods: This study included 592 mother-child pairs with information on GDM exposure (n = 92 exposed), untargeted metabolomics data at age 6-14 years (T1) and at 12-19 years (T2), and information on adiposity and metabolic risk biomarkers at T1 and T2. We first consolidated 767 metabolites at T1 into factors (metabolite patterns) via principal component analysis (PCA) and used multivariable regression to identify factors that differed by GDM exposure, at α = 0.05. We then examined associations of GDM with individual metabolites within factors of interest at T1 and T2, and investigated associations of GDM-related factors at T1 with adiposity and metabolic risk throughout T1 and T2 using mixed-effects linear regression models.

Results: Of the six factors retained from PCA, GDM exposure was associated with greater odds of being in quartile (Q)4 (vs Q1-3) of 'Factor 4' at T1 after accounting for age, sex, race/ethnicity, maternal smoking habits during pregnancy, Tanner stage, physical activity and total energy intake, at α = 0.05 (OR 1.78 [95% CI 1.04, 3.04]; p = 0.04). This metabolite pattern comprised phosphatidylcholines, diacylglycerols and phosphatidylethanolamines. GDM was consistently associated with elevations in a subset of individual compounds within this pattern at T1 and T2. While this metabolite pattern was not related to the health outcomes in boys, it corresponded with greater adiposity and a worse metabolic profile among girls throughout the follow-up period. Each 1-unit increment in Factor 4 corresponded with 0.17 (0.08, 0.25) units higher BMI z score, 8.83 (5.07, 12.59) pmol/l higher fasting insulin, 0.28 (0.13, 0.43) units higher HOMA-IR, and 4.73 (2.15, 7.31) nmol/l higher leptin.

Conclusions/interpretation: Exposure to maternal GDM was nominally associated with a metabolite pattern characterised by elevated serum phospholipids in late childhood and adolescence at α = 0.05. This metabolite pattern was associated with greater adiposity and metabolic risk among female offspring throughout the late childhood-to-adolescence transition. Future studies are warranted to confirm our findings.