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

Hannah C Glass; Courtney J Wusthoff; Bryan A Comstock; Adam L Numis; Fernando F Gonzalez; Nathalie Maitre; Shavonne L Massey; Dennis E Mayock; Ulrike Mietzsch; Niranjana Natarajan; Gregory M Sokol; Sonia L Bonifacio; Krisa P Van Meurs; Cameron Thomas; Kaashif A Ahmad; Patrick J Heagerty; Sandra E Juul; Yvonne W Wu

doi:10.1038/s41390-022-02398-w

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

Pediatr Res. 2023 Jul;94(1):252-259. doi: 10.1038/s41390-022-02398-w. Epub 2022 Dec 5.

Authors

Hannah C Glass^{1

2}, Courtney J Wusthoff^{3

4}, Bryan A Comstock⁵, Adam L Numis^{6

7}, Fernando F Gonzalez⁶, Nathalie Maitre⁸, Shavonne L Massey⁹, Dennis E Mayock¹⁰, Ulrike Mietzsch¹⁰, Niranjana Natarajan¹¹, Gregory M Sokol¹², Sonia L Bonifacio¹³, Krisa P Van Meurs¹³, Cameron Thomas^{14

15}, Kaashif A Ahmad¹⁶, Patrick J Heagerty⁵, Sandra E Juul¹⁰, Yvonne W Wu^{6

7}

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
² Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA. Hannah.Glass@ucsf.edu.
³ Department of Neurology, Stanford University, Palo Alto, CA, USA.
⁴ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University, Palo Alto, CA, USA.
⁵ Department Biostatistics, University of Washington, Seattle, WA, USA.
⁶ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Pediatrics, and Emory + Children's Pediatric Institute, Emory University, Atlanta, GA, USA.
⁹ Departments of Neurology and Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Pediatrics, Division of Neonatology, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, WA, USA.
¹¹ Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
¹² Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford, Palo Alto, CA, USA.
¹⁴ Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
¹⁵ Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁶ Pediatrix Neonatology of San Antonio, San Antonio, TX, USA.

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.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Asphyxia
Erythropoietin* / therapeutic use
Humans
Hypothermia* / therapy
Hypothermia, Induced* / methods
Hypoxia-Ischemia, Brain* / drug therapy
Hypoxia-Ischemia, Brain* / therapy
Infant, Newborn
Seizures / drug therapy

Substances

Erythropoietin

Abstract

Publication types

MeSH terms

Substances

Grants and funding