Predictive Metabolomic Markers in Early to Mid-Pregnancy for Gestational Diabetes: A Prospective Test and Validation Study

 Gestational diabetes (GDM) predisposes pregnant individuals to perinatal complications and long-term diabetes and cardiovascular diseases. We developed and validated metabolomic markers for GDM in a prospective test-validation study. In a case-control sample within the PETALS cohort (91 GDM, 180 non-GDM; discovery set), a random PETALS subsample (42 GDM, 372 non-GDM; validation set 1), and a case-control sample within the GLOW trial (35 GDM, 70 non-GDM; validation set 2), fasting serum untargeted metabolomics were measured by gas chromatography/time-of-flight mass spectrometry. Multivariate enrichment analysis examined metabolites-GDM associations. Ten-fold cross-validated LASSO regression identified predictive metabolomic markers at gestational weeks (GW) 10-13 and 16-19 for GDM. The purinone metabolites at GW 10-13 and 16-19, and the amino acids, amino alcohols, hexoses, indoles, and pyrimidines metabolites at GW 16-19 were positively associated with GDM risk (FDR <0.05). A 17-metabolite panel at GW 10-13 outperformed the model using conventional risk factors including fasting glycemia (discovery AUC: 0.871 vs. 0.742; validation 1: 0.869 vs. 0.731; validation 2: 0.972 vs. 0.742; P <0.01). Similar results were observed for a 13-metabolite panel at GW 17-19. Dysmetabolism is present early in pregnancy among individuals progressing to GDM. Multi-metabolite panels in early pregnancy can predict GDM risk beyond conventional risk factors.