A longitudinal 1H-NMR metabolomics analysis of urine from newborns with hypoxic-ischemic encephalopathy undergoing hypothermia therapy. Clinical and medical legal insights.

Emanuela Locci,Ernesto D'Aloja,Cristina Dalmazzo,Melania Puddu,Roberto Demontis,Paolo Gancia,Giulia Pomero,Antonio Delogu,Antonio Noto,Vassilios Fanos

doi:10.1371/journal.pone.0194267

Abstract

Perinatal asphyxia is an event affecting around four million newborns worldwide. The 0.5 to 2 per 1000 of full term asphyxiated newborns suffer from hypoxic-ischemic encephalopathy (HIE), which is a frequent cause of death or severe disability and, as consequence, the most common birth injury claim for obstetrics, gynaecologists, and paediatricians. Perinatal asphyxia results from a compromised gas exchange that leads to hypoxemia, hypercapnia, and metabolic acidosis. In this work, we applied a metabolomics approach to investigate the metabolic profiles of urine samples collected from full term asphyxiated newborns with HIE undergoing therapeutic hypothermia (TH), with the aim of identifying a pattern of metabolites associated with HIE and to follow their modifications over time. Urine samples were collected from 10 HIE newborns at birth, during hypothermia (48 hours), at the end of the therapeutic treatment (72 hours), at 1 month of life, and compared with a matched control population of 16 healthy full term newborns. The metabolic profiles were investigated by 1H NMR spectroscopy coupled with multivariate statistical methods such as principal component analysis and orthogonal partial least square discriminant analysis. Multivariate analysis indicated significant differences between the urine samples of HIE and healthy newborns at birth. The altered metabolic patterns, mainly originated from the depletion of cellular energy and homeostasis, seem to constitute a characteristic of perinatal asphyxia. The HIE urine metabolome changes over time reflected either the effects of TH and the physiological growth of the newborns. Of interest, the urine metabolic profiles of the HIE non-surviving babies, characterized by the increased excretion of lactate, resulted significantly different from the rest of HIE population.

Highlights

Perinatal asphyxia is an event that occurs at a frequency of 1 to 6 per 1000 in countries with high levels of socio-economic development [1]
The American Academy of Pediatrics (AAP) and the American College of Obstetricians and Gynecologists (ACOG) stated that hypoxic-ischemic encephalopathy (HIE) is considered as a cause of cerebral palsy (CP) if the following four essential criteria are met: umbilical artery blood metabolic acidosis, moderate to severe neonatal encephalopathy, outcome in spastic or dyskinetic tetraparesis, and absence of other causes of CP [2]
All the collected urine samples were analysed by 1H NMR spectroscopy

Summary

Introduction

Perinatal asphyxia is an event that occurs at a frequency of 1 to 6 per 1000 in countries with high levels of socio-economic development [1]. The hypoxic-ischemic encephalopathy (HIE) has an incidence of 0.5 to 2 per 1000; it is a frequent cause of death and severe disability in survivors. 12 mmol/L), moderate to severe neonatal encephalopathy, outcome in spastic or dyskinetic tetraparesis, and absence of other causes of CP [2]. Following these criteria, about 14% of children with CP has been exposed to an hypoxic-ischemic brain damage during labour [3]. Much progress has been made in preventing anoxic event through the centralization of high-risk pregnancies in level III care centres, the accurate monitoring of pregnancies, and the application by trained personnel of the modern techniques of neonatal resuscitation, leading to a more specialized approach to the problem of asphyxia as a whole. Besides brain damage, muscle, liver, kidney, and heart dysfunction can lead to death even in 50% of cases [5]

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