Metabolic Signature of Gestational Diabetes Mellitus and Risk of Adverse Birth Outcomes: A Prospective Birth Cohort...

Gestational diabetes mellitus (GDM) is a heterogeneous condition diagnosed solely through glucose. It is characterized by profound perturbations in the metabolome, with specific metabolic profiles linked to adverse birth outcomes. Metabolomics can reveal population heterogeneity in health and disease. Here, we used nontargeted metabolomics to systematically profile the circulating metabolome in 2,050 pregnant women during midpregnancy, identifying 30 metabolites that define the GDM metabolic signature (mGDM). Participants were stratified into four groups by distinct glycemic and metabolic profiles, namely normoglycemic non-mGDM, hyperglycemic non-mGDM, normoglycemic mGDM, and hyperglycemic mGDM, and associations with subsequent adverse birth outcomes were assessed. Compared with normoglycemic non-mGDM, normoglycemic mGDM demonstrated nearly a twofold increased risk of preterm birth (odds ratio [OR] 1.93, 95% CI 1.02-3.65) and large for gestational age (OR 2.11, 95% CI 1.53-2.92). Conversely, the hyperglycemic non-mGDM group did not show elevated risks in adverse birth outcomes versus the normoglycemic group. The hyperglycemic mGDM profile was associated with higher risks of preterm birth (OR 2.37, 95% CI 1.04-5.39), large for gestational age (OR 2.28, 95% CI 1.50-3.47), congenital malformations (OR 1.87, 95% CI 1.03-3.39), and neonatal intensive care unit (NICU) admissions (OR 1.69, 95% CI 1.09-2.61). We observed a stepwise increase in adverse outcome risk across the four-level metabolic-glycemic categories (P for trend < 0.001 for large for gestational age, 0.013 for preterm birth, and 0.018 for NICU admission). Taken together, our study outlines the metabolic profile of GDM and reveals clinically relevant heterogeneity in adverse pregnancy outcomes by metabolic signature. Integrating blood glucose and metabolomics may improve risk stratification and advance precision maternal care.

Women diagnosed with gestational diabetes mellitus (GDM) exhibit variability in symptom presentation and pregnancy outcomes. The heterogeneity in metabolic features beyond a GDM diagnosis and their influences on health outcomes is less studied. We aimed to identify the metabolic signatures of GDM, stratify pregnant women by glycemic and metabolic profiles, and further investigate the intergroup heterogeneity and their respective associations with adverse birth outcomes. Maternal metabolic dysregulation, rather than blood glucose alone, exerts more profound associations with adverse outcomes in pregnant women and their offspring. Targeted risk stratification using metabolomics offers a novel opportunity for precision medicine in GDM, potentially improving health management of pregnant women.