Associations of neonatal birth outcomes with amino acids and acylcarnitines: an observational study of over 3.3 million newborns in China

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BACKGROUND: Birth outcomes are linked to postnatal metabolic adaptation and long-term health, but their associations with neonatal metabolite profiles remain poorly understood. This study aimed to delineate the associations of key birth outcomes with a panel of 11 amino acids and 27 acylcarnitines in a large-scale newborn population. METHODS: This cross-sectional study analyzed data from 3,398,012 neonates across 14 regions in China from April 2013 to May 2019. We compared metabolite levels between preterm and full-term infants using the Wilcoxon rank-sum test, and among low, normal, and high birth weight groups using the Kruskal-Wallis test with Dunn's post hoc analysis. Multivariable linear regression was used to examine the associations of gestational age and sex-specific birth weight for gestational age z-scores (BWZ) with metabolite concentrations. Restricted cubic splines were employed to model potential nonlinear relationships. Pathway enrichment analysis was conducted to identify implicated metabolic pathways. Finally, we performed several sensitivity analyses to test the robustness of the findings. RESULTS: The cohort comprised 52.8% males, with 5.2% preterm births. The prevalence of low, normal, and high birth weight was 3.4%, 91.1%, and 5.6%, respectively. Small, appropriate, and large for gestational age accounted for 1.6%, 89.2%, and 9.2% of neonates. All 38 measured metabolites differed significantly across gestational age and birth weight categories (all P < 0.05). Gestational age was significantly associated with all metabolites, including alanine (β = 0.308; 95% CI, 0.306 to 0.310) and C3 (β = - 0.139; 95% CI, - 0.140 to - 0.137). Similarly, BWZ was associated with all metabolites, such as proline (β = - 0.026; 95% CI, - 0.026 to - 0.026) and C0 (β = - 0.030; 95% CI, - 0.030 to - 0.029). Most of these associations were linear and varied by neonatal age and sex. Pathway analysis implicated the urea cycle, phenylalanine and tyrosine metabolism, arginine and proline metabolism, and β-oxidation of very long-chain fatty acids. CONCLUSIONS: Neonatal amino acid and acylcarnitine profiles are profoundly associated with birth outcomes, highlighting the importance of developing targeted early screening and intervention strategies.

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