Association of High-Dose Erythropoietin With Circulating Biomarkers and Neurodevelopmental Outcomes Among Neonates With Hypoxic Ischemic Encephalopathy
Authors: Juul Sandra E. , Voldal Emily , Comstock Bryan A. , Massaro An N. , Bammler Theo K. , Mayock Dennis E. , Heagerty Patrick J. , Wu Yvonne W. , Numis Adam L. ,   HEAL consortium, Ahmad Kaashif , Baserga Mariana , Bendel-Stenzel Ellen , Benninger Kristen , Chalak Lina , Chang Taeun , Flibotte John , Gonzalez Fernando , Lampland Andrea , Maitre Nathalie , Mathur Amit , Merhar Stephanie , Mietzsch Ulrike , Poindexter Brenda , Rao Rakesh , Riley David , Smyser Christopher , Sokol Gregory , Van Meurs Krisa , Weitkamp Joern-Hendrik , Wu Tai-Wei , Yanowitz Toby 
Published: July 2023

ImportanceThe ability to predict neurodevelopmental impairment (NDI) for infants diagnosed with hypoxic ischemic encephalopathy (HIE) is important for parental guidance and clinical treatment as well as for stratification of patients for future neurotherapeutic studies.ObjectivesTo examine the effect of erythropoietin on plasma inflammatory mediators in infants with moderate or severe HIE and to develop a panel of circulating biomarkers that improves the projection of 2-year NDI over and above the clinical data available at the time of birth.Design, Setting, and ParticipantsThis study is a preplanned secondary analysis of prospectively collected data from infants enrolled in the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which tested the efficacy of erythropoietin as an adjunctive neuroprotective therapy to therapeutic hypothermia. The study was conducted at 17 academic sites comprising 23 neonatal intensive care units in the United States between January 25, 2017, and October 9, 2019, with follow-up through October 2022. Overall, 500 infants born at 36 weeks’ gestation or later with moderate or severe HIE were included.InterventionErythropoietin treatment 1000 U/kg/dose on days 1, 2, 3, 4 and 7.Main Outcomes and MeasuresPlasma erythropoietin was measured in 444 infants (89%) within 24 hours after birth. A subset of 180 infants who had plasma samples available at baseline (day 0/1), day 2, and day 4 after birth and either died or had 2-year Bayley Scales of Infant Development III assessments completed were included in the biomarker analysis.ResultsThe 180 infants included in this substudy had a mean (SD) gestational age of 39.1 (1.5) weeks, and 83 (46%) were female. Infants who received erythropoietin had increased concentrations of erythropoietin at day 2 and day 4 compared with baseline. Erythropoietin treatment did not alter concentrations of other measured biomarkers (eg, difference in interleukin [IL] 6 between groups on day 4: −1.3 pg/mL; 95% CI, −4.8 to 2.0 pg/mL). After adjusting for multiple comparisons, we identified 6 plasma biomarkers (C5a, interleukin [IL] 6, and neuron-specific enolase at baseline; IL-8, tau, and ubiquitin carboxy-terminal hydrolase-L1 at day 4) that significantly improved estimations of death or NDI at 2 years compared with clinical data alone. However, the improvement was only modest, increasing the AUC from 0.73 (95% CI, 0.70-0.75) to 0.79 (95% CI, 0.77-0.81; P = .01), corresponding to a 16% (95% CI, 5%-44%) increase in correct classification of participant risk of death or NDI at 2 years.Conclusions and RelevanceIn this study, erythropoietin treatment did not reduce biomarkers of neuroinflammation or brain injury in infants with HIE. Circulating biomarkers modestly improved estimation of 2-year outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT02811263