Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study

Authors

Lina F. Chalak, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
Athina Pappas, Department of Pediatrics, Wayne State University, Detroit, Michigan
Sylvia Tan, Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
Abhik Das, Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland
Pablo J. Sánchez, Department of Pediatrics, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus
Abbot R. Laptook, Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island
Krisa P. Van Meurs, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
Seetha Shankaran, Department of Pediatrics, Wayne State University, Detroit, Michigan
Edward F. Bell, Department of Pediatrics, University of Iowa, Iowa City
Alexis S. Davis, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
Roy J. Heyne, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas
Claudia Pedroza, Department of Pediatrics, University of Texas Medical School at Houston, Houston
Brenda B. Poindexter, Department of Pediatrics, Indiana University School of Medicine, Indianapolis; Emory University Hospital Midtown, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
Kurt Schibler, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Jon E. Tyson, Department of Pediatrics, University of Texas Medical School at Houston, Houston
M Bethany Ball, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
Rebecca Bara, Department of Pediatrics, Wayne State University, Detroit, Michigan
Cathy Grisby, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
Gregory M. Sokol, Department of Pediatrics, Indiana University School of Medicine, Indianapolis
Carl T. D'Angio, University of Rochester School of Medicine and Dentistry, Rochester, New York
Shannon E G Hamrick, Emory University Hospital Midtown, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
Kevin C. Dysart, Department of Pediatrics, University of Pennsylvania, Philadelphia
C Michael Cotten, Department of Pediatrics, Duke University, Durham, North Carolina
William E. Truog, Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri
Kristi L. Watterberg, University of New Mexico Health Sciences Center, Albuquerque
Christopher J. Timan, Department of Pediatrics, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus
Meena Garg, Department of Pediatrics, University of California, Los Angeles
Waldemar A. Carlo, Division of Neonatology, University of Alabama at Birmingham, Birmingham
Rosemary D. Higgins, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

Document Type

Article

Publication Date

12-1-2021

Abstract

Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce.

Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy.

Design, Setting, and Participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020.

Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity.

Main Outcomes and Measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes.

Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center.

Conclusions and Relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk.

Trial Registration: ClinicalTrials.gov Identifier: NCT01192776.

Publication Title

JAMA Neurol

ISSN

2168-6157

Volume

78

Issue

12

First Page

1484

Last Page

1493

DOI

10.1001/jamaneurol.2021.3723

Recommended Citation

Chalak LF, Pappas A, Tan S, Das A, Sánchez PJ, Laptook AR, Van Meurs KP, Shankaran S, Bell EF, Davis AS, Heyne RJ, Pedroza C, Poindexter BB, Schibler K, Tyson JE, Ball MB, Bara R, Grisby C, Sokol GM, D'Angio CT, Hamrick SEG, Dysart KC, Cotten CM, Truog WE, Watterberg KL, Timan CJ, Garg M, Carlo WA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study. JAMA Neurol. 2021 Dec 1;78(12):1484-1493. doi: 10.1001/jamaneurol.2021.3723. PMID: 34882200.