The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy

Abstract

BackgroundHypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.Methods and FindingsThe injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at −80°C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.ConclusionThis study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.

Seizure burden and neurodevelopmental outcome in neonates with hypoxic–ischemic encephalopathy

“…We excluded neonates with evidence of perinatal infection, metabolic or congenital abnormalities. This study was a retrospective analysis of two cohorts of neonates prospectively recruited to cEEG studies of neonates at high risk of seizures 4, 15. The modified Sarnat score (Levene) for HIE was performed in all neonates at 24 hours after birth during recruitment of both studies.…”

Urinary gas chromatography mass spectrometry metabolomics in asphyxiated newborns undergoing hypothermia: from the birth to the first month of life

“…Emerging studies on animal model have highlighted the importance to recognize the metabolic fingerprint in perinatal anoxia-hypoxia (19)(20)(21). In newborns with perinatal asphyxia, a small number of metabolomics studies have been published in the literature (22)(23)(24)(25)(26)(27); each of them has depicted the metabolic snapshot of the disease. As recapitulated in a recent review (28), human metabolomics studies have found that the most impaired molecular pathway during perinatal asphyxia and TH are the TCA cycle and the osmoregulation system.…”

Metabolomics in Neonatology

“…Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (amino acids, acylcarnitines, and glycerophospholipids). A logistic regression model using five metabolites clearly delineates severity of asphyxia andclassifies HIE infants with area under the curve (AUC) = 0.92 [16].…”