Temporal profile of serum orexin-A in neonatal hypoxic-ischemic encephalopathy: a prospective longitudinal study

No serum biomarker has yet been validated for clinical use in neonatal hypoxic-ischemic encephalopathy (HIE). Orexin-A is a hypothalamic neuropeptide that has demonstrated neuroprotective effects in experimental models of cerebral hypoxia-ischemia. We aimed to describe the early temporal profile of serum orexin-A in neonates with HIE, to compare its longitudinal change according to therapeutic hypothermia (TH) exposure, and to examine its relationship with clinical severity, electrophysiological findings and brain imaging.

This prospective longitudinal observational study enrolled 41 neonates born at ≥ 36 weeks' gestation in whom HIE was diagnosed within the first 6 postnatal hours. Serum orexin-A was measured at 6-12 h and at 72-96 h after birth. Longitudinal changes were compared between neonates who received TH and those managed without TH, and were examined against clinical severity, amplitude-integrated and video electroencephalography (EEG), brain magnetic resonance imaging (MRI) and routine metabolic indices.

Twenty-two neonates received TH and 19 were managed without TH. Orexin-A concentrations did not differ between groups at either time point (6-12 h, p = 0.078; 72-96 h, p = 0.082). The within-subject change from 6-12 h to 72-96 h did differ, with relative preservation under TH and a decline without it (median + 31.2 vs. -54.5 pg/mL; p = 0.002), and more neonates in the TH group had a higher value at the second measurement (p = 0.012). Orexin-A fell significantly over time in the normothermia group (p = 0.005). The change also differed by amplitude-integrated EEG background (p = 0.010), although abnormal tracings were almost confined to the TH group. Neither concentration nor change was related to video EEG findings, MRI abnormality or metabolic indices. Higher 72-96 h concentrations tracked clinical severity only in outlier-sensitive analyses.

Serum orexin-A followed different early trajectories in neonates managed with and without hypothermia, and the clinical signal lay in the direction of change rather than in any single concentration. Because treatment allocation was inseparable from disease severity, these trajectories cannot be attributed to cooling itself. Orexin-A behaves as a marker of functional state rather than of tissue injury, and serial sampling in larger, severity-matched cohorts with neurodevelopmental follow-up is required before any clinical role can be defined.