Neonatal Circulating Amino Acids and Lipid Metabolites Mediate the Association of Maternal Gestational Diabetes Mellitus with Offspring Neurodevelopment at 1 Year.

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Background/Objectives: We aimed to identify neonatal circulating metabolic alterations associated with maternal gestational diabetes mellitus (GDM) and to explore whether these altered metabolites could mediate the association of GDM with offspring neurodevelopment. Additionally, we investigated whether neonatal circulating metabolites could improve the prediction of offspring neurodevelopmental disorders over traditional risk factors. Methods: The retrospective cohort study enrolled 1228 mother-child dyads in South China. GDM was diagnosed at 24-28 weeks of gestation. Neonatal circulating amino acids and lipid metabolites (carnitines) were measured from newborn heel blood 3-7 days postpartum. Offspring neurodevelopment was assessed at age 1 year using the Children Neuropsychological and Behavioral Examination Scale. Neurodevelopmental disorders were defined as developmental delay in any domain of the scale. Results: Twenty-one metabolites associated with GDM were identified, consisting of seven amino acids and fourteen carnitines. Among these metabolites, five (glycine, myristicylcarnitine, palmitoylcarnitine, octadecadienoylcarnitine, and 3-hydroxypalmitylcarnitine) mediated the negative association of GDM with offspring neurodevelopment at 1 year (mediation proportions: 3.91-10.66%). Furthermore, six metabolites (glycine, methionine, malonylcarnitine, isovalerylcarnitine, palmitoylcarnitine, and octadecadienoylcarnitine) significantly increased the predictive performance for offspring neurodevelopmental disorders at 1 year over five traditional risk factors including GDM, parity, infant sex, birth weight, and feeding patterns (area under curve: 0.762 vs. 0.718, p = 0.012). Conclusions: GDM was associated with a variety of amino acid and lipid metabolic alterations in neonatal circulation, among which certain metabolites mediated the association of GDM with adverse neurodevelopmental outcomes in offspring. Moreover, some neonatal circulating metabolites may serve as potential biomarkers that improved the prediction of offspring neurodevelopmental disorders over GDM and other traditional risk factors.