Biomarkers of hypoxic-ischemic encephalopathy: a systematic review

Abstract

Background: Current diagnostic criteria for hypoxic-ischemic encephalopathy in the early hours lack objective measurement tools. Therefore, this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice (PROSPERO ID: CRD42021272610).

Data sources: Searches were performed in PubMed, Web of Science, and Science Direct databases until November 2020. English original papers analyzing samples from newborns > 36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included. Bias was assessed by the Newcastle-Ottawa Scale. The search and data extraction were verified by two authors separately.

Results: From 373 papers, 30 met the inclusion criteria. Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia. In addition, the levels of glial fibrillary acidic protein, ubiquitin carboxyl terminal hydrolase isozyme-L1, glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with hypoxic-ischemic encephalopathy. Moreover, pathway analysis revealed insulin-like growth factor signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult.

Conclusions: Neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of hypoxic-ischemic encephalopathy newborns. However, more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.

Keywords: Biomarker; Hypoxic–ischemic encephalopathy; Neonatal brain injury; Neuron-specific enolase; Newborn; S100-calcium-binding protein-B.

Fig. 1

Database search results and summary of population characteristics. a PRISMA 2020 flow diagram. Only English manuscripts that analyzed human samples collected within 72 h (excluding CSF) and studied biochemical biomarkers associated with HIE were included. In addition, selected studies had to match at least two ACOG diagnosis criteria or present neuroimaging evidence of acute brain ischemia. b Common articles between PubMed, Web of Science, and Science Direct. Only 12 articles were common between the three databases. c and d Concerning population characteristics, the majority of selected studies were performed in Europe and America and published after 2014. f, g Almost all studies applied whole-body hypothermia and had MRI data available. h Studies lacked uniformity in comparison groups, but the severity was preferably assessed by the Sarnat scoring system. e, j Technique most prevalently used is ELISA, while plasma was the fluid with more identifications. k Summary of NOS scoring. CSF cerebrospinal fluid, ACOG American College of Obstetricians and Gynecologists, DBS dried blood spots, ELISA enzyme linked immunosorbent assay, miRNA microRNA, NIRS near-infrared spectroscopy, MRS magnetic resonance spectroscopy, FDNIRS–DCS frequency-domain near-infrared spectroscopy–diffuse correlation spectroscopy, MS mass spectrometer, GC–MS gas chromatography–mass spectrometer, ESI–MS electro spray ionization MS, ILMA immunoluminometric assay, SIMOA single molecular array, Epo erythropoietin, RT–PCR reverse transcription–polymerase chain reaction, MRI magnetic resonance imaging, EEG electroencephalogram, PET positron emission computed tomography, CRP C-reactive protein, NOS Newcastle–Ottawa scale

Fig. 2

Proteins and metabolites identified as potential biomarkers. a Representation of biomarkers that were present in more than one fluid and/or more than one study. Green, red and yellow triangles represent studies with evidence of significantly increased, decreased, or altered levels of the molecule in the HIE group. Blue circles represent molecules without significant differences, and on gray squares, no comparison was performed. Plasma and serum samples were then combined for pathway analysis. b, c Gene ontology analysis of proteins, namely, biological process and molecular function. Altered pathways were identified using a metabolite enrichment analysis (d) and a combined approach of protein and metabolite analysis (mixomics approach) (e). f Alterations in the alanine, aspartate and glutamate pathways were identified, where metabolites are highlighted in green and proteins in blue. Balls represent metabolites, and squares represent proteins. S100B S100-calcium-binding protein-B, DBS dried blood spots, GFAP glial fibrillary acidic protein, UCHL-1 ubiquitin C-terminal hydrolase L1, NSE neuron-specific enolase, IL interleukin, CRP C-reactive protein, VEGF vascular endothelial growth factor, ALT alanine aminotransferase, AST aspartate aminotransferase, TNF-α tumor necrosis factor α, GO Gene Ontology