Neonatal encephalopathy plasma metabolites are associated with neurodevelopmental outcomes

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.