Abstract
<title>Abstract</title> <p>Background Metabolic signatures in newborns can serve as indicators of the intrauterine conditions to which they were exposed. Furthermore, they provide relevant information regarding metabolic status later in life. The aim of this study was to identify metabolic signatures in newborns exposed to gestational diabetes mellitus (GDM). Additionally, predictive models were developed and validated to identify offspring exposed to GDM. Methods This retrospective cohort study included 110 mother-infant dyads. GDM was diagnosed between 24 and 28 weeks of gestation using the criteria established by the International Association of Diabetes and Pregnancy Study Groups (IADPSG). Targeted metabolomics was used to determine circulating metabolites in blood samples obtained from the newborns' heels three days after birth. Results GDM-exposed girls had lower carnitine and valine, whereas exposed boys had lower dodecanoylcarnitine than unexposed peers. Across sexes, GDM exposure was associated with higher acetylcarnitine and propionylcarnitine. Pathway enrichment differed by sex, with lower lysine degradation, CoA/pantothenate biosynthesis, and valine pathways in exposed girls, and higher glycine, lipoic acid/porphyrin metabolism and primary bile acid biosynthesis in exposed boys. Exploratory ROC analyses showed that metabolite panels distinguished GDM-exposed from healthy infants with AUCs of 0.766 (95% CI: 0.532–0.917) in females and 0.810 (95% CI: 0.636–0.920) in males. Conclusion Our findings suggest that intrauterine exposure to GDM induces sex-specific metabolic programming, resulting in distinct neonatal metabolic signatures in male and female offspring. These metabolomic profiles may facilitate the identification of newborns exposed to GDM while highlighting the importance of considering fetal sex when evaluating the biological consequences of maternal hyperglycemia.</p>