Blood-Based Biomarkers Predict Cerebral Palsy and Cognitive Delay in Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of the HEAL Randomized Controlled Trial

OBJECTIVE: 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 HIE. STUDY DESIGN: A secondary analysis of the High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) 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; Bayley III cognitive/language scores <85 and, separately, <70 at 2 years. MRI of the brain was performed on day 4-6 of life. RESULTS: Mean gestational age was 39.0 weeks and 68 (44%) were female. After adjusting for multiple comparisons, 5 biomarkers: Tau, GFAP, VEGF, MIP-1b, and IL-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%, 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, UCH-L1, S100B, and NSE, 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%). CONCLUSIONS: 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.