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