Metabolic maturity patterns in neonates: dissecting the interactive effects of gestational age and birth weight on metabolic profiles

Background Newborn screening (NBS) based on tandem mass spectrometry (MS/MS) is essential for the early identification of inherited metabolic disorders. However, physiological immaturity in preterm and low-birth-weight (LBW) infants frequently alters metabolite concentrations, thereby increasing the risk of false-positive results. Objective This study aimed to clarify the independent and interactive effects of gestational age (GA) and birth weight (BW) on neonatal amino acid and acylcarnitine profiles, with the goal of improving screening precision in vulnerable populations. Methods We conducted a retrospective analysis of 147,643 neonates screened in Hunan Province, China. The cohort was stratified into seven GA groups and five BW groups. One-way and two-way analyses of variance (ANOVA), together with principal component analysis (PCA), were used to characterize main effects, interaction effects, and global metabolic clustering. Results Metabolic profiles followed distinct developmental trajectories. Preterm infants (<37 weeks) showed significantly elevated amino acid concentrations (e.g., tyrosine and arginine) but relative attenuation of long-chain acylcarnitine levels, suggesting an altered balance between protein turnover and fatty acid oxidation. Importantly, significant GA × BW interactions were detected for multiple markers, indicating that the metabolic impact of birth weight varied according to gestational maturity. Conclusion Neonatal metabolic maturity is shaped by the synergistic interplay between intrauterine duration and fetal growth. The characteristic “high amino acid/low long-chain acylcarnitine” pattern observed in preterm infants, especially in those with lower birth weight, supports the need for individualized reference intervals in newborn screening.