Objective: To determine the association of gestational age (GA) and day of life (DOL) with the circulating serum concentration of six brain injury-associated biomarkers in non-brain injured neonates born between 23–41 weeks’ GA. Methods: In a multicenter prospective observational cohort study, serum CNS-insult, inflammatory and trophic proteins concentrations were measured daily in the first 7 DOL. Results: 3232 serum samples were analyzed from 745 enrollees, median GA 32.3 weeks. BDNF increased 3.7% and IL-8 increased 8.9% each week of gestation. VEGF, IL-6, and IL-10 showed no relationship with GA. VEGF increased 10.8% and IL-8 18.9%, each DOL. IL-6 decreased by 15.8% each DOL. IL-10 decreased by 81.4% each DOL for DOL 0–3. BDNF did not change with DOL. Only 49.67% of samples had detectable GFAP and 33.15% had detectable NRGN. The odds of having detectable GFAP and NRGN increased by 53% and 11%, respectively, each week after 36 weeks’ GA. The odds of having detectable GFAP and NRGN decreased by 15% and 8%, respectively, each DOL. Conclusion: BDNF and IL-8 serum concentrations vary with GA. VEGF and interleukin concentrations are dynamic in the first week of life, suggesting circulating levels should be adjusted for GA and DOL for clinically relevant assessment of brain injury.

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Background: To investigate mechanisms of injury and recovery in neonatal encephalopathy (NE), we performed targeted metabolomic analysis of plasma using LC/MS/MS from healthy term neonates or neonates with NE. Methods: Plasma samples from the NE (n=45, day of life 0–1) or healthy neonatal (n=30, ≥36 weeks’ gestation) cohorts had LC/MS/MS metabolomic profiling with a 193-plex targeted metabolite assay covering >366 metabolic pathways. Metabolite levels were compared to two-year neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development III (Bayley-III). Results: 57/193 metabolites met pre-defined quality control criteria for analysis. Significant (after FDR correction) KEGG pathways included aminoacyl-tRNA biosynthesis, arginine biosynthesis, and metabolism of multiple amino acids. Significant disease pathways included seizures. In regression models, histidine and C6 sugar amine were significantly associated with cognitive, motor, and language and betaine with cognitive and motor Bayley-III composite scores. Addition of histidine, C6 sugar amine, and betaine to a Sarnat score based clinical regression model significantly improved model performance (AIC and adjusted r 2 ) for Bayley-III cognitive, motor, and language scores. Conclusion: Plasma metabolites may help to predict neurological outcomes in neonatal brain injury and enhance current clinical predictors.