Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up
Authors: Lina F. Chalak, Athina Pappas, Sylvia Tan, Abhik Das, Pablo J. Sánchez, Abbot R. Laptook, Krisa P. Van Meurs, Seetha Shankaran, Edward F. Bell, Alexis S. Davis, Roy J. Heyne, Claudia Pedroza, Brenda B. Poindexter, Kurt Schibler, Jon E. Tyson, M. Bethany Ball, Rebecca Bara, Cathy Grisby, Gregory M. Sokol, Carl T. D’Angio, Shannon E. G. Hamrick, Kevin C. Dysart, C. Michael Cotten, William E. Truog, Kristi L. Watterberg, Christopher J. Timan, Meena Garg, Waldemar A. Carlo, Rosemary D. Higgins, Namasivayam Ambalavanan, Monica V. Collins, Shirley S. Cosby, Myriam Peralta-Carcelen, Vivien A. Phillips, David A. Randolph, Barbara Alksninis, Robert T. Burke, Melinda Caskey, Nicholas Guerina, Angelita M. Hensman, Martin Keszler, Mary Lenore Keszler, Andrea M. Knoll, Emilee Little, Elizabeth C. McGowan, William Oh, Birju A. Shah, Ross Sommers, Elisa Vieira, Betty R. Vohr, Stephanie Guilford, Satyan Lakshminrusimha, Anne Marie Reynolds, Michael G. Sacilowski, Ashley Williams, Karen Wynn, Anna Maria Hibbs, Nancy S. Newman, Bonnie S. Siner, Eileen K. Stork, Michele C. Walsh, Arlene Zadell, Michael S. Caplan, Richard A. Polin, Sally S. Adams, Luc P. Brion, Lijun Chen, Alicia Guzman, Elizabeth T. Heyne, Lizette E. Lee, Linda A. Madden, Emma Ramon, Pablo J. Sánchez, Catherine Twell Boatman, Diana M. Vasil, Myra H. Wyckoff, Patricia L. Ashley, Joanne Finkle, Kimberley A. Fisher, Ronald N. Goldberg, Ricki F. Goldstein, Sandra Grimes, Kathryn E. Gustafson, William F. Malcolm, Ira Adams-Chapman (deceased), Diane I. Bottcher, David P. Carlton, Sheena L. Carter, Ellen C. Hale, Yvonne C. Loggins, Colleen Mackie, Ravi M. Patel, Barbara J. Stoll, Lynn Wineski, Susan Gunn, Heidi M. Harmon, Dianne E. Herron, Abbey C. Hines, Jeffery Joyce, Carolyn Lytle, Lucy C. Miller, Heike M. Minnich, Lu-Ann Papile, Brenda B. Poindexter, Leslie Richard, Lucy C. Smiley, Leslie Dawn Wilson, Michael J. Acarregui, Vipinchandra Bhavsar, Jane E. Brumbaugh, Tarah T. Colaizy, John M. Dagle, Diane L. Eastman, Karen J. Johnson, Jonathan M. Klein, Julie B. Lindower, Steven J. McElroy, Cary R. Murphy, Glenda K. Rabe, Robert D. Roghair, Jeffrey L. Segar, Jacky R. Walker, John A. Widness, Dan L. Ellsbury, Cheri Gauldin, Anne M. Holmes, Kathy Johnson, Howard W. Kilbride, Eugenia K. Pallotto, Allison Scott, Roopali Bapat, Thomas Bartman, Elizabeth Bonachea, Helen Carey, Michelle Chao, Louis G. Chicoine, Bronte Clifford, Marliese Dion Nist, Erin Fearns, Christine A. Fortney, Aubry Fowler, Jennifer Fuller, Jennifer L. Grothause, Ish Gulati, Julie Gutentag, Cole D. Hague, Krista Haines, Brandon Hart, Michael Hokenson, Sudarshan R. Jadcherla, Marissa E. Jones, Sarah A. Keim, Patricia Luzader, Nathalie L. Maitre, Sarah McGregor, Pamela Moorehead, Leif D. Nelin, Mary Ann Nelin, Nehal A. Parikh, Elizabeth Rodgers, Ruth Seabrook, Tiffany Sharp, Edward G. Shepherd, Jonathan L. Slaughter, Melanie Stein, Rox Ann Sullivan, Jodi A. Ulloa, Jon Wispe, Tara Wolfe, Keith O. Yeates, Lina Yossef-Salameh, Nahla Zaghoul, Stephanie Wilson Archer, Soraya Abbasi, Judy C. Bernbaum, Aasma S. Chaudhary, Dara M. Cucinotta, Sara B. DeMauro, Marsha Gerdes, Hallam Hurt, Haresh Kirpalani, Toni Mancini, Barbara Schmidt, Kyle Binion, Patrick Conway, Osman Farooq, Ronnie Guillet, Cassandra A. Horihan, Rosemary L. Jensen, Nirupama Laroira, Joan Merzbach, Gary J. Myers, Premini Sabaratnam, Ann Marie Scorsone, Holly I.M. Wadkins, Kelley Yost, Carla M. Bann, Margaret M. Crawford, Jenna Gabrio, Marie G. Gantz, Scott A. McDonald, Jamie E. Newman, Jeanette O’Donnell Auman, Carolyn M. Petrie Huitema, James W. Pickett, Annie M. VonLehmden, Dennis Wallace, Kristin M. Zaterka-Baxter, Valerie Y. Chock, Maria Elena DeAnda, Anne M. DeBattista, Lynne C. Huffman, Casey E. Krueger, Ryan E. Lucash, Melinda S. Proud, David K. Stevenson, Heather L. Taylor, Hali E. Weiss, Teresa Chanlaw, Uday Devaskar, Rachel Geller, Isabell B. Purdy, Sofia Aliaga, Janice Bernhardt, Carl L. Bose, Cynthia L. Clark, Matthew Maxwell Laughon, Diane D. Warner, Janice Kay Wereszczak, Conra Backstrom Lacy, Andrea F. Duncan, Janell Fuller, Carol H. Hartenberger, Jean R. Lowe, Robin K. Ohls, Sandra Sundquist Beauman, John Barks, Mary K. Christensen, Stephanie A. Wiggins, Monika Bajaj, Sanjay Chawla, Kirsten Childs, Lilia C. De Jesus, Eunice Hinz Woldt, Mary E. Johnson, Girija Natarajan, Bogdan Panaitescu, Jeannette E. Prentice, Beena G. Sood
Journal: JAMA Neurology (2021)

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. 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. 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. 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. 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. 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. 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. ClinicalTrials.gov Identifier: NCT01192776.