Whole-Body Hypothermia for Neonatal Encephalopathy in Preterm Infants 33 to 35 Weeks’ Gestation
Authors: Roger G. Faix, Abbot R. Laptook, Seetha Shankaran, Barry Eggleston, Dhuly Chowdhury, Roy J. Heyne, Abhik Das, Claudia Pedroza, Jon E. Tyson, Courtney Wusthoff, Sonia L. Bonifacio, Pablo J. Sánchez, Bradley A. Yoder, Matthew M. Laughon, Diana M. Vasil, Krisa P. Van Meurs, Margaret M. Crawford, Rosemary D. Higgins, Brenda B. Poindexter, Tarah T. Colaizy, Shannon E. G. Hamrick, Lina F. Chalak, Robin K. Ohls, Michele E. Hartley-McAndrew, Kevin Dysart, Carl T. D’Angio, Ronnie Guillet, Stephen D. Kicklighter, Waldemar A. Carlo, Gregory M. Sokol, Sara B. DeMauro, Anna Maria Hibbs, C. Michael Cotten, Stephanie L. Merhar, Roopali V. Bapat, Heidi M. Harmon, Elizabeth Sewell, Sarah Winter, Girija Natarajan, Ricardo Mosquera, Susan R. Hintz, Nathalie L. Maitre, Kristen L. Benninger, Myriam Peralta-Carcelen, Abbey C. Hines, Andrea F. Duncan, Deanne E. Wilson-Costello, Andrea Trembath, William F. Malcolm, Michele C. Walsh, Namasivayam Ambalavanan, Kirstin J. Bailey, Fred J. Biasini (deceased), Waldemar A. Carlo, Stephanie A. Chopko, Monica V. Collins, Shirley S. Cosby, Kristy A. Domnanovich, Samuel J. Gentle, Chantel J. Jno-Finn, Morissa Ladinsky, Tara E. McNair, Mary Beth Moses, Myriam Peralta-Carcelen, Vivien A. Phillips, Julie Preskitt, Richard V. Rector, Kimberlly Stringer, Colm P. Travers, Sally Whitley, Sheree York Chapman, Barbara Alksninis, Adam Czynski, Nicholas Guerina, Angelita M. Hensman, Martin Keszler, Mary Lenore Keszler, Andrea M. Knoll, Abbot R. Laptook, Theresa M. Leach, Elizabeth C. McGowan, Lucille St. Pierre, Elisa Vieira, Betty R. Vohr, Victoria E. Watson, Kelly R. Coleman, Stephanie Guilford, Michelle E. Hartley-McAndrew, Emily Li, Anne Marie Reynolds, William A. Zorn, Anna Maria Hibbs, Nancy S. Newman, Elizabeth Roth, Bonnie S. Siner, Deanne E. Wilson-Costello, Traci Beiersdorfer, Tanya E. Cahill, Juanita Dudley, Cathy Grisby, Devan Hayes, Lisa Henkes, Kristin Kirker, Stephanie L. Merhar, Greg Muthig, Brenda B. Poindexter, David Russell, Kurt Schibler, Sara Stacey, Julia Thompson, Sandra Wuertz, Richard A. Polin, Sally S. Adams, Luc P. Brion, Lina F. Chalak, Maria M. De Leon, Joanne Duran, Frances Eubanks, Alicia Guzman, Michelle Harrod, Elizabeth T. Heyne, Roy J. Heyne, Lizette E. Lee, Natalia Lopez, E. Rebecca McDougald, #REF! #REF!, Lara Pavageau, Anna E. Puentez, Emma Ramon, Pollieanna Sepulveda, Kristine Tolentino-Plata, Catherine Twell Boatman, Diana M. Vasil, Azucena Vera, Jillian Waterbury, Myra H. Wyckoff, Patricia L. Ashley, C. Michael Cotten, Kimberley A. Fisher, Ronald N. Goldberg, Kathryn E. Gustafson, Deesha Mago-Shah, William F. Malcolm, Joanne Probst, Mollie Warren, Ryan Moore, Ira Adams-Chapman (deceased), Diane I. Bottcher, David P. Carlton, Sheena L. Carter, Shannon E. G. Hamrick, Salathiel Kendrick-Allwood, Judith Laursen, Yvonne C. Loggins, Colleen Mackie, Nathalie L. Maitre, Maureen Mulligan LaRossa, Ravi M. Patel, Amy Sanders, Elizabeth Sewell, Gloria V. Smikle, Lynn Wineski, Nora I. Alaniz, Elizabeth Allain, Julie Arldt-McAlister, Fatima Boricha, Allison G. Dempsey, Andrea F. Duncan, Donna J. Hall, Janice John, Kathleen A. Kennedy, Amir M. Khan, Karen Martin, Georgia Elaine McDavid, Shannon L. McKee, Ricardo A. Mosquera, Tina Reddy, Kimberly Rennie, Matthew A. Rysavy, Debasree Sana Boral, Daniel K. Sperry, Emily K. Stephens, Barbara J. Stoll, Jon E. Tyson, Michelle White, Sharon L. Wright, Dinorah Zanger, Susan Gunn, Dianne E. Herron, Abbey C. Hines, Jeffery Joyce (deceased), Gregory M. Sokol, Donna Watkins, Edward F. Bell, Jane E. Brumbaugh, Tarah T. Colaizy, Diane L. Eastman, Claire A. Goeke, Heidi M. Harmon, Karen J. Johnson, Mendi L. Schmelzel, Bailey M. Schrimper, Jacky R. Walker, Dan L. Ellsbury, Tracy L. Tud, Roopali Bapat, Nancy Batterson, Hallie Baugher, Demi R. Beckford, Kristin L. Benninger, Stephanie Burkhardt, Helen Carey, Erna Clark, Chelsea Cobe, Brittany DeSantis, Eduardo Finol Mark, Jennifer L. Grothause, Julie Gutentag, Sudarshan R. Jadcherla, Jordan Knox, Katelyn Levengood, Patricia Luzader, Laura Marzec, Jacqueline McCool, Bethany Miller, Leif D. Nelin, Mary Ann Nelin, Julia Newton, Courtney Park, Lindsay Pietruszewski, Jessica Purnell, Pablo J. Sánchez, Jessica Schiering, Kelly Schmidt, Julie C. Shadd, Jonathan L. Slaughter, Laurel A. Slaughter, Kristi L. Small, Melanie Stein, Rox Ann Sullivan, Abbie M. Tice, Christopher J. Timan, Kyrstin Warnimont, Andrew A. Bremer, Rosemary D. Higgins, Michele C. Walsh, Stephanie Wilson Archer, Soraya Abbasi, Aasma S. Chaudhary, Dara M. Cucinotta, Sara B. DeMauro, Megan A. Dhawan, Kevin C. Dysart, Eric C. Eichenwald, John Flibotte, Sarvin Ghavam, Haresh Kirpalani, Toni Mancini, Karen M. Puopolo, Barbara Schmidt, Jonathan M. Snyder, Kristina Ziolkowski, Kyle Binion, Elizabeth Boylin, Brenna Cavanaugh, Carl T. D'Angio, Osman Farooq, Ronnie Guillet, Cassandra A. Horihan, Rosemary L. Jensen, Rachel Jones, Jennifer Kachelmeyer, Alison Kent, Nirupama Laroira, Corinne Leach, Deanna Maffett, Kimberly G. McKee, Joan Merzbach, Gary J. Myers, Constance Orme, Premini Sabaratnam, Ann Marie Scorsone, Kelley Yost, Carla M. Bann, Annie M. Bayard, Margaret M. Crawford, Abhik Das, Barry Eggleston, David Leblond, Amanda Lewis, Brae McVoy, Jamie E. Newman, Jeanette O’Donnell Auman, Lindsay Parlberg, Carolyn M. Petrie Huitema, Kristin M. Zaterka-Baxter, Michelle L. Baack, Megan Broadbent, Chelsey Elenkiwich, Megan M. Henning, Laurie A. Hogden, Sarah Van Muyden, Dona Bahmani, M. Bethany Ball, Barbara Bentley, Sonia Lomeli Bonifacio, Valerie Y. Chock, Maria Elena DeAnda, Anne M. DeBattista, Beth A. Earhart, Susan R. Hintz, Lynne C. Huffman, Casey E. Krueger, Ryan E. Lucash, Melinda S. Proud, Barbara P. Recine, Elizabeth N. Reichert, Lilia Rutkowska, David K. Stevenson, Heather L. Taylor, Krisa P. Van Meurs, Hali E. Weiss, R. Jordan Williams, Janice Bernhardt, Carl L. Bose, Gennie Bose, Cynthia L. Clark, Matthew Maxwell Laughon, Jennifer Talbert, Andrea Trembath, Janice Kay Wereszczak, John Barks, Martha D. Carlson, Diane F. White, Shawna Baker, Mariana Baserga, Susan Christensen, Laura Cole Bledsoe, Sean D. Cunningham, Jennifer O. Elmont, Roger G. Faix, Erick B. Gerday, Trisha Marchant, Earl Maxson, Kandace M. McGrath, Hena G. Mickelsen, Stephen D. Minton, Galina Morshedzadeh, Robin K. Ohls, D. Melody Parry, Carrie A. Rau, Brixen A. Reich, Susan T. Schaefer, Mark J. Sheffield, Kelly Stout, Ashley L. Stuart, Katherine Tice, Kimberlee Weaver-Lewis, Sarah Winter, Kathryn D. Woodbury, Bradley A. Yoder, Alexandra Bentley, Laura Edwards, Stephen D. Kicklighter, Ginger Rhodes-Ryan, Donna White, Prashant Agarwal, Monika Bajaj, Rebecca Bara, Sanjay Chawla, Kirsten Childs, Melissa February, Laura A. Goldston, Eunice Hinz Woldt, Girija Natarajan, Bogdan Panaitescu, Seetha Shankaran
Journal: JAMA Pediatrics (2025)

Importance Hypothermia begun less than 6 hours after birth reduces death or disability in infants with encephalopathy due to hypoxia-ischemia at 36 or more weeks’ gestation. Trials of hypothermia for infants younger than 36 weeks’ gestation are lacking. Objective To assess the probability that hypothermia at less than 6 hours after birth decreases death or disability in infants 33 to 35 weeks’ gestation with moderate or severe hypoxic-ischemic encephalopathy. Design, Setting, and Participants This randomized clinical trial was conducted between July 2015 and December 2022 for infants 33 to 35 weeks’ gestation with moderate or severe hypoxic-ischemic encephalopathy at less than 6 hours after birth. Bayesian and intention-to-treat analyses were prespecified. The setting included 19 US Neonatal Research Network centers. Data were analyzed from March 2023 to November 2024. Interventions Infants received unblinded targeted esophageal temperature management. Infants with hypothermia were maintained at 33.5 °C (acceptable 33-34 °C) for 72 hours and then rewarmed. Infants with normothermia were to be maintained at 37 °C (acceptable 36.5-37.3 °C). Main Outcomes and Measures Composite of death or disability (moderate or severe) at 18 to 22 months’ corrected age adjusted for level of encephalopathy and center. Results A total of 168 infants with hypothermia and normothermia were preterm (mean [SD] age, 34.0 [0.8] weeks’ gestation and 34.1 [0.8] weeks’ gestation, respectively), while 46 of 88 (52%) and 45 of 80 (56%) were male, respectively. Randomization occurred at mean (SD) 4.5 (1.2) hours and 4.5 (1.3) hours for the groups with hypothermia and normothermia, respectively. The primary outcome occurred in 29 of 83 infants (35%) with hypothermia and 20 of 69 infants (29%) with normothermia (adjusted relative risk [hypothermic/normothermic], 1.11; 95% credibility interval, 0.74-2.00), and death occurred in 18 of 88 infants (20%) with hypothermia and 9 of 78 infants (12%) with normothermia (adjusted relative risk, 1.38; 95% credibility interval, 0.79-2.85). Bayesian analysis with neutral prior indicated 74% probability of increased death or disability and 87% probability of increased death with hypothermia. Conclusions and Relevance Among infants 33 to 35 weeks’ gestation with hypoxic-ischemic encephalopathy, hypothermia at less than 6 hours’ age did not reduce death or disability at 18 to 22 months’ corrected age. Trial Registration ClinicalTrials.gov Identifier: NCT01793129