Blood-Based Biomarkers Predict Cerebral Palsy and Cognitive Delay in Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of the High-Dose Erythropoietin for Asphyxia and Encephalopathy Randomized Controlled Trial.

Abstract

To determine whether blood-based biomarkers in the first days of life could specifically predict cerebral palsy (CP) and/or cognitive/language delay in infants with moderate-severe hypoxic-ischemic encephalopathy (HIE). A secondary analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which examined erythropoietin as an adjunct to therapeutic hypothermia for moderate-severe HIE. Recruitment took place in the United States from 2017-2019. Analysis focused on 180 infants with biomarker measurements performed at baseline, day 2, and day 4 of life. Outcomes assessed were: a diagnosis of CP at 2 years and Bayley III cognitive/language scores <85 and, separately, <70 at 2 years. Magnetic resonance imaging (MRI) of the brain was performed on day 4-6 of life. Mean gestational age was 39.0 weeks and 68 (44%) were female. After adjusting for multiple comparisons, 5 biomarkers: total tubulin-associated protein (Tau), glial fibrillary acidic protein, vascular endothelial growth factor, macrophage inflammatory protein 1b, and interleukin-13 were significantly altered in the CP group. On day 2 of life, Tau resulted in a receiver operating characteristic area under the curve (AUC) of 0.902 (95% CI: 0.812-0.992), specificity 91%, and sensitivity 88%, performing as well as detailed MRI scoring (AUC: 0.90 [95% CI: 0.80-1.0]). A different set of biomarkers showed altered expression in those with cognitive/language delay; Tau, ubiquitin carboxy-terminal hydrolase L1, S100 calcium-binding protein B, and neuron-specific enolase, with the best prediction seen with Tau on day 2 of life (AUC: 0.669 [95% CI: 0.564-0.774], sensitivity 40%, specificity 92%). Tau on day 2 of life demonstrated excellent prognostic value for CP in this cohort with moderate-severe HIE and gave similar prediction to detailed MRI score on day of life 4-6. Patterns of neurospecific biomarker perturbations were different for the prediction of cognitive/language delay, but Tau on day 2 remained the best performing biomarker. ClinicalTrials.gov NCT02811263.