Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo

• Type of Material: Article
• Authors: Hannah C Glass, University of California San Francisco; Courtney J Wusthoff, Stanford University; Bryan A Comstock, University of Washington; Adam L Numis, University of California San Francisco; Fernando F Gonzalez, University of California San Francisco; Nathalie Maitre, Emory University; Shavonne L Massey, University of Pennsylvania; Dennis E Mayock, University of Washington; Ulrike Mietzsch, University of Washington; Niranjana Natarajan, University of Washington; Gregory M Sokol, Indiana University; Sonia L Bonifacio, Stanford University; Krisa P Van Meurs, Stanford University; Cameron Thomas, University of Cincinnati; Kaashif A Ahmad, Pediatrix Neonatol San Antonio; Patrick J Heagerty, University of Washington; Sandra E Juul, University of Washington; Yvonne W Wu, University of California San Francisco
• Language: English
• Date: 2022-12-05
• Publisher: SPRINGERNATURE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2024 Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41390-022-02398-w
• Title of Journal or Parent Work: PEDIATRIC RESEARCH
• Volume: 94
• Issue: 1
• Start Page: 252
• End Page: 259
• Grant/Funding Information: The study was funded by NIH/NINDS R01NS104322, U01NS092764, and U01NS092553. Adam L. Numis, MD, received grant support during the study period from NINDS K23NS105918.
• Keywords: Pediatrics; SAFETY; EXCITOTOXICITY; Science & Technology; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Epidemiology; Biology, Neuroscience; Biology, Biostatistics; Engineering, Biomedical

Abstract

Background: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. Methods: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. Results: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). Conclusion: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. Impact: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies.Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo).There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.