# Urinary metabolome at birth in patients with hypoxic–ischemic encephalopathy treated with therapeutic hypothermia and long-term neurodevelopmental outcomes: a 7-year follow up

## TL;DR

This study explores how the urinary metabolome at birth can predict long-term brain development in babies with hypoxic-ischemic encephalopathy treated with cooling therapy.

## Contribution

This is the first study linking neonatal urinary metabolites to long-term neurodevelopmental outcomes in HIE patients treated with therapeutic hypothermia.

## Key findings

- 21 metabolites were identified that distinguish neonates with favorable versus adverse long-term outcomes.
- Brain MRI had 67% positive and 96% negative predictive value for adverse outcomes.
- Metabolites like γ-butyrolactone and Aldosterone are linked to neuromodulation and neuronal damage susceptibility.

## Abstract

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and morbidity, yet no validated biomarkers currently exist to predict long-term outcomes. We investigated the potential of the neonatal urinary metabolomic profile as a predictor of long-term neurodevelopmental outcomes in HIE newborns treated with therapeutic hypothermia (TH).

We conducted a longitudinal study in neonates with HIE undergoing TH. Urine samples collected during TH were analyzed using untargeted metabolomics via mass spectrometry. Based on long-term follow-up outcomes, patients were categorized into two groups: the adverse outcome (AO) group, defined by perinatal death, cerebral palsy, and/or an intelligence quotient (IQ) < 70, and the favourable outcome (FO) group, defined as absence of CP and IQ ≥ 70. Additionally, we assessed the predictive value of early neonatal brain magnetic resonance imaging (MRI) in relation to the aforementioned outcomes.

Among 53 newborns treated with TH for HIE, long-term follow-up outcomes were available for 40; 29 were classified as FO and 11 as AO group. To mitigate bias, 11 FO patients were matched with 11 AO patients based on similar perinatal characteristics. Metabolomic analysis identified 21 metabolites distinguishing the two groups, with γ-butyrolactone, N-acetyl-galactosamine/glucosamine, Aldosterone, and Creatinine showing independent discriminative capability among groups. Brain MRI demonstrated a 67% positive and 96% negative predictive value for adverse outcomes.

The identified metabolites are implicated in neuromodulation and neuronal susceptibility to damage, suggesting their potential as prognostic markers for long-term outcomes in HIE and warranting further investigation. This is the first study linking the acute-phase metabolomic profile with long-term neurodevelopmental outcomes in HIE neonates, supporting its prognostic potential.

The online version contains supplementary material available at 10.1186/s12967-025-06714-w.