Amino Acid Profile Alterations in the Mother-Fetus System in Gestational Diabetes Mellitus and Macrosomia

: Gestational diabetes mellitus (GDM) is a growing global health concern, driving the need for novel diagnostic and prognostic approaches. This non-targeted metabolomic study investigated amino acid profiles in the mother-fetus system to identify biomarkers linked to GDM and fetal macrosomia. Using HPLC-MS/MS, we analyzed serum from maternal venous and umbilical cord blood, along with amniotic fluid, across 94 mother-fetus pairs (53 GDM, 41 controls). Machine learning and metabolic pathway analysis revealed significant alterations in 19 amino acids. In GDM, maternal serum showed elevated 5-OH-lysine and homocitrulline, while cord blood had higher isoleucine, serine, and threonine. Amniotic fluid exhibited increased leucine, isoleucine, threonine, serine, arginine, and ornithine. Conversely, histidine, glutamine, alanine, asparagine, β-/γ-aminobutyric acids, phenylalanine, ornithine, and citrulline were reduced. Histidine, glutamine, and asparagine inversely correlated with blood glucose (|R| < 0.4, *p* < 0.05) and were lower in GDM. These findings highlight three key metabolic loci in GDM pathogenesis, with glutamine, histidine, and asparagine emerging as potential maternal blood biomarkers for early macrosomia prediction. However, given confounding factors in metabolomic studies, further large-scale validation is essential.