NICHD Magnetic Resonance Brain Imaging Score in Term Infants With Hypoxic-Ischemic Encephalopathy: A Secondary Analysis of a Randomized Clinical Trial

Seetha Shankaran; Abbot R Laptook; Carolina Guimaraes; Johnathan Murnick; Scott A McDonald; Abhik Das; Carolyn M Petrie Huitema; Athina Pappas; Rosemary D Higgins; Susan R Hintz; Kristin M Zaterka-Baxter; Krisa P Van Meurs; Gregory M Sokol; Lina F Chalak; Tarah T Colaizy; Uday Devaskar; Jon E Tyson; Anne Marie Reynolds; Sara B DeMauro; Pablo J Sánchez; Matthew M Laughon; Waldemar A Carlo; Kristi Watterberg; Karen M Puopolo; Anna Maria Hibbs; Shannon E G Hamrick; C Michael Cotten; John Barks; Brenda B Poindexter; William E Truog; Carl T D’Angio

doi:10.1001/jamapediatrics.2024.6209

. 2025 Feb 17;179(4):383–395. doi: 10.1001/jamapediatrics.2024.6209

NICHD Magnetic Resonance Brain Imaging Score in Term Infants With Hypoxic-Ischemic Encephalopathy

A Secondary Analysis of a Randomized Clinical Trial

Seetha Shankaran ^1,^✉, Abbot R Laptook ², Carolina Guimaraes ³, Johnathan Murnick ⁴, Scott A McDonald ⁵, Abhik Das ⁶, Carolyn M Petrie Huitema ⁶, Athina Pappas ¹, Rosemary D Higgins ^7,⁸, Susan R Hintz ⁹, Kristin M Zaterka-Baxter ⁵, Krisa P Van Meurs ⁹, Gregory M Sokol ¹⁰, Lina F Chalak ¹¹, Tarah T Colaizy ¹², Uday Devaskar ¹³, Jon E Tyson ¹⁴, Anne Marie Reynolds ¹⁵, Sara B DeMauro ^16,¹⁷, Pablo J Sánchez ¹⁸, Matthew M Laughon ³, Waldemar A Carlo ¹⁹, Kristi Watterberg ²⁰, Karen M Puopolo ^16,¹⁷, Anna Maria Hibbs ²¹, Shannon E G Hamrick ²², C Michael Cotten ²³, John Barks ²⁴, Brenda B Poindexter ²⁵, William E Truog ²⁶, Carl T D’Angio ²⁷, for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

¹Children’s Hospital of Michigan and Hutzel Women’s Hospital, Wayne State University, Detroit, Michigan

²Department of Pediatrics, Women & Infants Hospital, Brown University, Providence, Rhode Island

³University of North Carolina at Chapel Hill, Chapel Hill

⁴Children’s National Medical Center, Washington, DC

⁵Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina

⁶Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland

⁷Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland

⁸Research and Sponsored Programs, Florida Gulf Coast University, Fort Myers

⁹Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children’s Hospital, Palo Alto, California

¹⁰Department of Pediatrics, Indiana University School of Medicine, Indianapolis

¹¹Parkland Memorial Hospital, University of Texas Southwestern Medical Center, Dallas

¹²Department of Pediatrics, University of Iowa, Iowa City

¹³Department of Pediatrics, University of California, Los Angeles

¹⁴McGovern Medical School, The University of Texas Health Science Center at Houston, Houston

¹⁵Department of Pediatrics, University at Buffalo, Buffalo, New York

¹⁶Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia

¹⁷The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

¹⁸Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus

¹⁹Division of Neonatology, University of Alabama at Birmingham, Birmingham

²⁰University of New Mexico Health Sciences Center, Albuquerque

²¹Department of Pediatrics, Rainbow Babies & Children’s Hospital, Case Western Reserve University, Cleveland, Ohio

²²Department of Pediatrics, Children’s Healthcare of Atlanta, Grady Memorial Hospital and Emory University School of Medicine, Atlanta, Georgia

²³Department of Pediatrics, Duke University, Durham, North Carolina

²⁴Department of Pediatrics, University of Michigan, C.S. Mott Children’s Hospital, Ann Arbor

²⁵Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

²⁶Department of Pediatrics, Children’s Mercy Hospital and University of Missouri Kansas City School of Medicine, Kansas City

²⁷University of Rochester School of Medicine and Dentistry, Rochester, New York

Group Information: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network members appear in Supplement 3.

Accepted for Publication: November 7, 2024.

Published Online: February 17, 2025. doi:10.1001/jamapediatrics.2024.6209

^✉

Corresponding Author: Seetha Shankaran, MD, Children’s Hospital of Michigan and Hutzel Women’s Hospital, Wayne State University, 2523 Oxford Cir, Ann Arbor, MI 48103 (sshankar@med.wayne.edu).

Author Contributions: Mr McDonald and Dr Das had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Shankaran, Murnick, Higgins, Chalak, Colaizy, Hibbs, Truog.

Acquisition, analysis, or interpretation of data: Shankaran, Laptook, Guimaraes, Murnick, McDonald, Das, Petrie Huitema, Pappas, Higgins, Hintz, Zaterka-Baxter, Van Meurs, Sokol, Chalak, Devaskar, Tyson, Reynolds, DeMauro, Sánchez, Laughon, Carlo, Watterberg, Puopolo, Hibbs, Hamrick, Cotten, Barks, Poindexter, Truog, D’Angio.

Drafting of the manuscript: Shankaran, Chalak.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Shankaran, McDonald, Das, Tyson.

Obtained funding: Shankaran, Das, Sánchez, Hibbs, Poindexter, D’Angio.

Administrative, technical, or material support: Shankaran, Murnick, Petrie Huitema, Higgins, Hintz, Zaterka-Baxter, Van Meurs, Sokol, Devaskar, Tyson, Reynolds, Sánchez, Carlo, Hibbs, Hamrick, Poindexter, D’Angio.

Supervision: Shankaran, Guimaraes, Das, Higgins, Zaterka-Baxter, Van Meurs, Chalak, Hibbs, Cotten, Barks, Truog, D’Angio.

Conflict of Interest Disclosures: Dr Shankaran reported grants from Wayne State University School of Medicine and funding from NICHD during the conduct of the study. Dr Laptook reported grants from NICHD NRN during the conduct of the study. Dr Das reported grants from NICHD and the National Institutes of Health (NIH) during the conduct of the study. Ms Petrie Huitema reported grants from RTI International during the conduct of the study. Dr Pappas reported grants from NICHD NRN during the conduct of the study. Dr Hintz reported grants from NICHD NRN during the conduct of the study. Dr Van Meurs reported grants from NICHD during the conduct of the study. Dr Sokol reported grants from NIH during the conduct of the study. Dr Reynolds reported grants from NIH during the conduct of the study. Dr DeMauro reported grants from NIH during the conduct of the study; and grants from NIH outside the submitted work. Dr Sánchez reported grants from NICHD NRN during the conduct of the study. Dr Laughon reported grants from NIH during the conduct of the study; and grants from NIH and the US Food and Drug Administration outside the submitted work. Dr Watterberg reported grants from NICHD during the conduct of the study. Dr Hibbs reported grants from NICHD NRN and the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Cotten reported grants from NICHD during the conduct of the study; and personal fees from ReAlta Life Sciences and a patent for Cryo-Cell International with royalties paid from Duke University outside the submitted work. Dr Barks reported grants from Wayne State University as a subcontract from Wayne State University to the University of Michigan during the conduct of the study; and grants from NIH to the University of Michigan and grants from University College London as a grant subcontract to the University of Michigan outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by grants from NIH, NICHD, and the National Center for Advancing Translational Sciences for the NRN’s Optimizing Cooling trial through cooperative agreements.

Role of the Funder/Sponsor: NICHD staff had input into the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network members are listed in Supplement 3.

Disclaimer: The comments and views of the authors do not necessarily represent the views of NICHD, NIH, the US Department of Health and Human Services, or the US government.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study and were supported by the listed grants from NICHD:

NRN Steering Committee Chair: Richard A. Polin, MD, Division of Neonatology, College of Physicians and Surgeons, Columbia University (2011-2023)

Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (grant U10 HD27904): Martin Keszler, MD, William Oh, MD, Betty R. Vohr, MD, Angelita M. Hensman, PhD, RNC-NIC, Robert T. Burke, MD, MPH, Melinda Caskey, MD, Nicholas Guerina, MD, PhD, Andrea M. Knoll, Emilee Little, RN, BSN, Ross Sommers, MD, Birju A. Shah, MD, MPH, Elisa Vieira, RN, BSN, Barbara Alksninis, RNC, PNP, Mary Lenore Keszler, MD, Elisabeth C. McGowan, MD; Case Western Reserve University, Rainbow Babies & Children’s Hospital (grant U10 HD21364): Michele C. Walsh MD, MS, Nancy S. Newman, BA, RN, Bonnie S. Siner, RN, Eileen K. Stork, MD, Arlene Zadell, RN; Children’s Mercy Hospital, University of Missouri Kansas City School of Medicine (grant U10 HD68284): Eugenia K. Pallotto, MD, MSCE, Cheri Gauldin, RN, BSN, CCRC, Lisa Gaetano, MSN, RN, Anne M. Holmes, RN, MSN, MBA-HCM, CCRC, Kathy Johnson, RN, CCRC, Allison Scott, BSN, RNC-NIC; Cincinnati Children’s Hospital Medical Center, University of Cincinnati Medical Center, and Good Samaritan Hospital (grants U10 HD27853, UL1 TR77): Stephanie L. Merhar, MD, MS, Suhas G. Kallapur, MD, Kurt Schibler, MD, Cathy Grisby, BSN, CCRC, Barbara Alexander, RN, Lenora Jackson, CRC, Kristin Kirker, CRC, Teresa L. Gratton, PA, Greg Muthig, BA, Sandra Wuertz, RN, BSN, CLC, Kimberly Yolton, PhD; Duke University School of Medicine, University Hospital, University of North Carolina, and Duke Regional Hospital (grants U10 HD40492, UL1 TR1117): Ronald N. Goldberg, MD, Kimberley A. Fisher, PhD, FNP-BC, IBCLC, Joanne Probst, RN, JD, Sandra Grimes, RN, BSN, Ricki F. Goldstein, MD, Patricia L. Ashley, MD, PhD, William F. Malcolm, MD, Kathryn E. Gustafson, PhD, Carl L. Bose, MD, Janice Bernhardt, MS, RN, Cindy Clark, RN, Diane D. Warner, MD, MPH, Janice Wereszcsak, CPNP, Sofia Aliaga, MD, MPH; Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (grants U10 HD27851, UL1 TR454): Ravi M. Patel, MD, Barbara J. Stoll, MD, David P. Carlton, MD, Ellen C. Hale, RN, BS, CCRC, Yvonne Loggins, RN, Colleen Mackie, BS, RT, Diane I. Bottcher, MSN, RN; NICHD: Andrew A. Bremer, MD, PhD, Stephanie Wilson Archer, MA; Indiana University, Riley Hospital for Children and Methodist Hospital at Indiana University Health (grant U10 HD27856): Brenda B. Poindexter, MD, MS, Lu Ann Papile, MD, Abbey C. Hines, PsyD, Dianne E. Herron, RN, CCRC, Susan Gunn, NNP-BC, CCRC, Lucy C. Smiley, CCRC, Jeffery Joyce, CCRC (deceased); McGovern Medical School at The University of Texas Health Science Center at Houston, Children’s Memorial Hermann Hospital (grant U10 HD21373): Amir M. Khan, MD, Kathleen A. Kennedy, MD, MPH, Claudia Pedroza, PhD, Julie Arldt-McAlister, MSN, APRN, Katrina Burson, RN, BSN, Allison G. Dempsey, PhD, Andrea F. Duncan, MD, MSClinRes, Carmen Garcia, RN, BSN, Janice John, CPNP, Patrick M. Jones, MD, MA, M. Layne Lillie, RN, BSN, Sara Martin, RN, Georgia E. McDavid, RN, Saba Siddiki, MD, Daniel K. Sperry, RN, Patti L. Pierce Tate, RCP, Sharon L. Wright, MT (ASCP); Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center (grant U10 HD68278): Leif D. Nelin, MD, Sudarshan R. Jadcherla, MD, Patricia Luzader, RN, Christine A. Fortney, PhD, RN, Nehal A. Parikh, MD; RTI International (grant U10 HD36790): Dennis Wallace, PhD, Marie G. Gantz, PhD, Jeanette O’Donnell Auman, BS, Margaret M. Crawford, BS, CCRP, Jenna Gabrio, BS, CCRP, Jamie E. Newman, PhD, MPH, James W. Pickett II, BS, Annie M. VonLehmden, BS; Stanford University and Lucile Packard Children’s Hospital (grants U10 HD27880, UL1 TR93): Valerie Y. Chock, MD, MS Epi, David K. Stevenson, MD, M. Bethany Ball, BS, CCRC, Lynne C. Huffman, MD, Anne M. DeBattista, RN, PNP, PhD, Hali E. Weiss, MD, Maria Elena DeAnda, PhD, Casey E. Krueger, PhD, Melinda S. Proud, RCP; University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (grant U10 HD34216): Ambalavanan Namasivayam, MD, Monica V. Collins, RN, BSN, MaEd, Shirley S. Cosby, RN, BSN; University of California, Los Angeles, Mattel Children’s Hospital, Santa Monica Hospital, Los Robles Hospital and Medical Center, and Olive View Medical Center (grant U10 HD68270): Meena Garg, MD, Teresa Chanlaw, MPH, Rachel Geller, RN, BSN; University of Iowa and Mercy Medical Center (grants U10 HD53109, UL1 TR442): Edward F. Bell, MD, John A. Widness, MD, Karen J. Johnson, RN, BSN, Diane L. Eastman, RN, CPNP, MA, Jacky R. Walker, RN, Claire A. Lindauer, RN, Jonathan M. Klein, MD, Jeffrey L. Segar, MD, John M. Dagle, MD, PhD, Julie B. Lindower, MD, MPH, Steven J. McElroy, MD, Glenda K. Rabe, MD, Robert D. Roghair, MD, Lauritz R. Meyer, MD, Vipinchandra Bhavsar, MB, BS, Dan L. Ellsbury, MD, Donia B. Campbell, MS, ARNP, NNP-BC, Cary R. Murphy, MD; University of New Mexico Health Sciences Center (grants U10 HD53089, UL1TR41): Janell Fuller, MD, Robin K. Ohls, MD, Conra Backstrom Lacy, RN, Mary Ruffaner Hanson, RN, BSN, Sandra Sundquist Beauman, MSN, RNC, Carol H, Hartenberger, MPH, RN, Jean R. Lowe, PhD; University of Pennsylvania, Hospital of the University of Pennsylvania, Pennsylvania Hospital, and Children’s Hospital of Philadelphia (grant U10 HD68244): Eric C. Eichenwald, MD, Barbara Schmidt, MD, MSc, Haresh Kirpalani, MB, MSc, Kevin C. Dysart, MD, Soraya Abbasi, MD, Aasma S. Chaudhary, BS, RRT, Toni Mancini, RN, BSN, CCRC, Dara M. Cucinotta, RN, Judy C. Bernbaum, MD, Marsha Gerdes, PhD, Hallam Hurt, MD; University of Rochester Medical Center, Golisano Children’s Hospital, and the University of Buffalo Women’s and Children’s Hospital of Buffalo (grants U10 HD68263, UL1 TR42): Ronnie Guillet, MD, PhD, Satyan Lakshminrusimha, MD, Nirupama Laroia, MD, Gary J. Myers, MD, Kelley Yost, PhD, Stephanie Guilford, BS, Rosemary Jensen, Karen Wynn, NNP, RN, Osman Farooq, MD, Michael G. Sacilowski, MAT, Ann Marie Scorsone, MS, Holly I. M. Wadkins, MA, Ashley Williams, MS Ed, Joan Merzbach, LMSW; University of Texas Southwestern Medical Center, Parkland Health & Hospital System, and Children’s Medical Center Dallas (grant U10 HD40689): Myra H. Wyckoff, MD, Luc P. Brion, MD, Lijun Chen, PhD, RN, Diana M. Vasil, MSN, BSN, RNC-NIC, Sally S. Adams, MS, RN, CPNP, Catherine Twell Boatman, MS, CIMI, Alicia Guzman, Elizabeth T. Heyne, MS, MA, PA-C, PsyD, Roy Heyne, MD, Lizette E. Lee, RN, Linda A. Madden, BSN, RN, CPNP, Emma Ramon, RNC-NIC, RN, BSN; Wayne State University, University of Michigan, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (grant U10 HD21385): Beena G. Sood, MD, MS, Rebecca Bara, RN, BSN, Kirsten Childs, RN, BSN, Mary E. Johnson, RN, BSN, Bogdan Panaitescu, MD, Sanjay Chawla, MD, Jeannette E. Prentice, MD, Lilia C. De Jesus, MD, Eunice Hinz Woldt, RN, MSN, Girija Natarajan, MD, Monika Bajaj, MD, Mary Christensen, RT, Stephanie A. Wiggins, MS.

^✉

Corresponding author.

PMCID: PMC11833650 PMID: 39960680

Key Points

Question

What is the association of an expanded neonatal magnetic resonance brain injury score separating watershed and basal ganglia or thalamic injury with neurodevelopmental outcome in a trial of longer and deeper cooling for moderate or severe encephalopathy?

Findings

In this secondary study of 298 infants, the National Institute of Child Health and Human Development (NICHD) brain injury score was associated with death or disability among all infants and with disability in surviving infants. Outcomes following watershed injury did not differ from basal ganglia or thalamic injury.

Meaning

Similar outcomes following watershed and basal ganglia injury add refinement to magnetic resonance imaging as a biomarker of outcome following moderate or severe hypoxic-ischemic encephalopathy.

Abstract

Importance

The neonatal brain injury score on magnetic resonance imaging following moderate or severe hypoxic-ischemic encephalopathy developed by the National Institute of Child Health and Human Development Neonatal Research Network has been revised to separate watershed and basal ganglia or thalamic injury and their associated outcomes.

Objective

To evaluate the association of the injury score with outcomes of death or moderate or severe disability among all infants, and with neurodevelopment among survivors in a trial of deeper and longer cooling.

Design, Setting, and Participants

In this secondary analysis of a multicenter randomized clinical trial, brain imaging was obtained from infants between October 2010 and November 2013. Infants were followed up to 18 months of age, with follow-up completed in January 2016. Data analysis was performed from August 2021 to September 2024.

Interventions

Infants were assigned to 4 hypothermia groups based on depth and duration of cooling, stratified by center and level of encephalopathy in a 2 × 2 factorial design to cooling at 33.5 °C or 32.0 °C and to 72 or 120 hours. A 10-level brain injury score was examined.

Main Outcomes and Measures

The primary outcome was death or moderate or severe disability measured by the Bayley Scales of Infant and Toddler Development III, the Gross Motor Function Classification System level, vision, and hearing.

Results

This study included 298 infants who had magnetic resonance imaging (MRI) and primary outcome data among 364 infants of the initial cohort (mean [SD] age at MRI, 9.18 [4.49] days). Death or moderate or severe disability occurred in 72 of 298 infants (24%), and disability occurred in 52 of 278 surviving infants (19%). Death or disability occurred in 12 of 28 infants (43%) with any or predominant watershed injury and in 17 of 46 (37%) of those with any or predominant basal ganglia or thalamic injury. Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. Injury scores of increasing severity were associated with death or disability among all infants (odds ratio, 13.66 [95% CI, 7.47-24.95]; area under the curve, 0.84 [95% CI, 0.78-0.90]) and with disability among surviving infants (odds ratio, 10.52 [95% CI, 5.46-20.28]; area under the curve, 0.80 [95% CI, 0.73-0.88]). There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or longer duration.

Conclusions

Among infants with hypoxic-ischemic encephalopathy, outcomes were similar between infants with watershed and basal ganglia injury. Higher imaging scores were associated with risk of death or disability among all infants and with neurodevelopmental disability among surviving infants.

Trial Registration

ClinicalTrials.gov Identifier: NCT01192776

This secondary analysis of a randomized clinical trial evaluates the association of the National Institute of Child Health and Human Development (NICHD) neonatal magnetic resonance brain injury score with outcomes of death, moderate or severe disability, and neurodevelopment.

Introduction

Hypothermia initiated within 6 hours of birth at 33 to 34 °C and continued for 72 hours among full-term infants with moderate or severe hypoxic-ischemic encephalopathy (HIE) has been shown to decrease death or disability and to increase disability-free survival among cooled infants at 18 months.^1,2,3,4,5 Three of the trials, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) trial,⁶ the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial,⁷ and the Infant Cooling Evaluation (ICE) trial,⁸ demonstrated less brain injury on magnetic resonance imaging (MRI) in cooled infants. The injury patterns were associated in infancy with death or moderate or severe disability. The NICHD NRN injury score was also associated with death or IQ less than 70 in childhood.⁹ A recent trial of erythropoietin among infants with HIE receiving hypothermia (High-Dose Erythropoietin for Asphyxia and Encephalopathy [HEAL] trial) noted that infants with mild or moderate MRI brain injury had similar neurodevelopmental scores in infancy as those with no injury.¹⁰

The NICHD brain injury score⁶ lacked detail in separating watershed (WS) injury from injury of the basal ganglia or thalamus (BGT) or the posterior limb of the internal capsule (PLIC). A subsequent NICHD NRN trial examining the effect of depth and duration of cooling on death or disability at 18 months provided the opportunity to refine the scoring system.¹¹ Infants with moderate or severe HIE were enrolled and received brain MRI. The first objective of the study was to evaluate the validity of the expanded injury score as a marker for death or disability among all infants and for disability among surviving infants. The second objective was to examine the association of the score comparing usual care (33.5 °C for 72 hours) vs longer and deeper cooling combined as 1 group since the impact of longer and/or deeper cooling on brain injury was not known.

Methods

Setting and Participants

This is a prognostic secondary study that was part of a randomized clinical trial that enrolled infants between October 2010 and November 2013. The trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. The trial protocol is available in Supplement 1. RTI International was the data coordinating center.¹¹ Infant follow-up was completed in January 2016.¹² The inclusion criteria were the same as the prior NICHD NRN trials of hypothermia for HIE.² Random assignment was stratified by center and level of encephalopathy in a 2 × 2 factorial design to cooling at 33.5 °C or 32.0 °C and to 72 or 120 hours. Data analysis for the current study was performed from August 2021 to September 2024. This secondary study was approved by the institutional review board of the NRN sites with waiver of consent due to the use of deidentified data; 3 sites without this waiver obtained consent from families. No additional data were collected for this study other than the date of the MRI.

Infants had brain MRI between 7 to 14 days, including T1 spin-echo and T1-weighted fluid-attenuated inversion recovery sequences at 1.5 or 3.0 T followed by T2-weighted fast spin-echo sequences. The age at MRI and the scanner specifics followed clinical practice in 2010 to 2013; data on diffusion-weighted imaging were not available at all centers. MRI studies were anonymized, stored on computer discs, and sent to the data center. The MRI central reader form gathered detailed information on the location, size, and signal characteristics of lesions in the cerebral hemispheres, intraventricular areas, cerebellar areas, BGT, PLIC, corona radiata, hippocampus, brainstem, corpus collosum, hypothalamus, and extra-axial areas. The expanded MRI injury score separated WS (area between vascular zones) injury from BGT or PLIC injury and included severity of injury and laterality of lesions. The score was as follows: 0 indicates normal; 1A, minimal cerebral injury; 1B, extensive cerebral lesions that were not WS or vascular in distribution; 2A1, WS or vascular infarction only; 2A2, BGT or PLIC injury only; 2A3, injury in both 2A1 and 2A2 areas; 2B1, WS or vascular infarction with additional cerebral lesions; 2B2, BGT or PLIC injury with cerebral lesions; 2B3, both 2B1 and 2B2; and 3, hemispheric devastation (the central reader form and scoring manual are available in eAppendix 1 and eAppendix 2 in Supplement 2).

Prior to reading MRI scans, interrater reliability was established; 30 MRIs performed between 7 and 14 days and ranging from normal to increasing brain injury based on site radiology readings were selected by study personnel (S.S. and A.R.L.). Fifteen MRIs were considered training MRIs and were read independently by the 2 pediatric neuroradiologists who served as central readers (C.G. and J.M.), followed by discussions to develop concordance between the readers. The second 15 MRIs were read independently by the 2 readers and the κ score for the NICHD NRN MRI injury score was calculated. Reading of additional sets of 10 MRIs was planned if the κ score was less than 0.70.

The central readers were aware of the age at which MRIs were obtained but not the clinical status or intervention group. After establishing interrater reliability, half the scans were sent to each central reader. Scans interpreted as normal by 1 reader (anticipated to be 52%)⁶ were not sent to the second reader; scans with any abnormalities by 1 reader were sent to the second reader for an independent reading, and adjudication sessions were conducted between the readers and the study working group (S.S., A.R.L., S.A.M., and C.M.P.H.) until consensus was reached regarding the final score and areas of injury.

Outcomes

The primary outcome was death or moderate or severe disability at 18 to 22 months. This outcome was selected because death prior to follow-up is a competing outcome for disability. Certified examiners, trained to reliability and unaware of study intervention status, performed the neurodevelopmental assessments. Severe disability was defined as any of the following: Bayley Scales of Infant and Toddler Development III cognitive composite score less than 70, a Gross Motor Function Classification System (GMFCS) level 3 to 5, profound hearing loss (inability to understand despite amplification), or bilateral blindness. Moderate disability was defined as having both (1) a cognitive score of 70 to 84 and (2) a GMFCS level 2, seizure disorder, or hearing deficit requiring amplification. Mild disability was defined as a cognitive score of 70 to 84 or as a cognitive score equal to or greater than 85 with any of the following: GMFCS level 1 or 2, seizure disorder, or hearing loss not requiring amplification. No disability was defined as having a normal cognitive score (≥85) and neurological examination findings, no seizures, and no sensory deficits. Predefined secondary outcomes included specific areas of brain injury and cognitive and neurological outcomes.

Statistical Analysis

To evaluate for bias, the maternal and neonatal characteristics of infants with MRI studies were compared with those of infants for whom MRIs were unavailable. The association between the patterns of injury and outcomes was assessed with unadjusted χ² tests and adjusted regression models. The NICHD NRN score was used as a categorical 10-level variable in a multivariable logistic regression model, controlling for severity of encephalopathy, maternal insurance, clinical site as a cluster effect, and age at MRI scan. The association with outcomes (odds ratio [OR] with 95% CI) was calculated using 2 separate regression models. The sensitivity, specificity, predictive values, and likelihood ratios of the MRI pattern of injury and outcome of death or disability were assessed. The area under the curve (AUC) of the receiver operating characteristic curve was compared for models with nonneuroimaging clinical variables that are known to be associated with adverse outcome vs those with neuroimaging included. Unadjusted analyses were performed comparing the following: (1) the 2 depths of cooling, 33.5 °C vs 32.0 °C, (2) the 2 durations of cooling, 72 vs 120 hours, and (3) the usual care group (33.5 °C for 72 hours of cooling), with the longer and deeper cooling groups combined as 1 group. No adjustment was made for multiple comparisons or type I error for the primary outcome or prespecified secondary outcomes. Two-tailed P < .05 was considered statistically significant. SAS statistical software version 9.4 (SAS Institute Inc) was used to conduct all statistical analyses.

Results

The trial was closed to recruitment because of increased mortality rates in the deeper and longer cooling arms of the trial after 364 infants had been enrolled.¹¹ MRI scans were available among 315 infants. The κ score for concordance between the 2 central readers was 0.75 after the first session examining 30 MRI studies. The mean (SD) age at MRI for all infants was 9.18 (4.49) days, while the mean (SD) age at 30 randomly chosen MRIs was 9 (5) days. The maternal and neonatal characteristics at random assignment were comparable between infants with and without available MRI scans, except infants without an MRI were more likely to have a 10-minute Apgar score of 5 or lower, more severe encephalopathy and inotropic support, and a higher mortality rate (eTable 1 in Supplement 2). Among infants with an MRI, primary outcome data were available for 298 of 364 infants (82%), constituting the study cohort (eFigure in Supplement 2).

MRI findings by region and pattern of injury among all infants and by the 4 hypothermia groups are noted in Table 1. Among the 298 infants, 129 (43%) received the MRI within 7 days, although there was a difference in age at MRI in the 4 groups. MRI findings among infants in the usual care group when compared with the other 3 groups combined are noted in Table 2; fewer infants among the usual care group had a normal WS area compared with the other 3 groups. No significant differences were observed in MRI findings between the 2 cooling depths and the 2 cooling durations (eTable 2 in Supplement 2) except for fewer temporal, parietal, and occipital lesions and less white matter injury in the longer duration compared with the usual duration of cooling.

Table 1. Brain Injury on MRI Among Study Participants by Treatment Group.

MRI result	No. (%)
	All infants (n = 298)^a	33.5 °C		32.0 °C
	All infants (n = 298)^a	For 72 h (n = 82)	For 120 h (n = 80)	For 72 h (n = 75)	For 120 h (n = 61)
Overall diagnosis
Normal	115 (39)	33 (40)	28 (35)	24 (32)	30 (49)
Abnormal	169 (57)	47 (57)	47 (59)	48 (64)	27 (44)
Normal with other findings	14 (5)	2 (2)	5 (6)	3 (4)	4 (7)
Total hemispheric devastation
No	266 (89)	72 (88)	76 (95)	64 (85)	54 (89)
Yes	32 (11)	10 (12)	4 (5)	11 (15)	7 (11)
Laterality
Left and right equally	29 (91)	10	2	11	6
Right greater than left	2 (6)	0	1	0	1
Left greater than right	1 (3)	0	1	0	0
Edema	43 (14)	16 (20)	13 (16)	12 (16)	2 (3)
Cerebral lesions
Any frontal	93 (31)	25 (30)	21 (26)	31 (41)	16 (26)
Any temporal	72 (24)	21 (26)	17 (21)	26 (35)	8 (13)
Any parietal	109 (37)	36 (44)	28 (35)	30 (40)	15 (25)
Any occipital	70 (23)	23 (28)	14 (18)	22 (29)	11 (18)
Any frontal, temporal, parietal, or occipital	129 (43)	39 (48)	35 (44)	35 (47)	20 (33)
Other cerebral lesions^b	91 (31)	26 (32)	23 (29)	27 (36)	15 (25)
Any frontal, temporal, parietal, occipital or other cerebral lesions	158 (53)	45 (55)	43 (54)	44 (59)	26 (43)
BGT classification^c
Normal	215 (72)	59 (72)	56 (70)	53 (71)	47 (77)
Mild	28 (9)	7 (9)	9 (11)	7 (9)	5 (8)
Moderate	16 (5)	3 (4)	9 (11)	2 (3)	2 (3)
Severe	39 (13)	13 (16)	6 (8)	13 (17)	7 (11)
PLIC classification^d
Normal	235 (79)	64 (78)	65 (81)	55 (73)	51 (84)
Equivocal	8 (3)	3 (4)	3 (4)	2 (3)	0
Abnormal	55 (18)	15 (18)	12 (15)	18 (24)	10 (16)
WS area^e
Normal	235 (79)	60 (73)	71 (89)	55 (73)	49 (80)
Mild	4 (1)	0	1 (1)	2 (3)	1 (2)
Moderate	19 (6)	11 (13)	2 (3)	3 (4)	3 (5)
Severe	40 (13)	11 (13)	6 (8)	15 (20)	8 (13)
White matter injury^f
None	182 (61)	47 (57)	49 (61)	40 (53)	46 (75)
Mild	41 (14)	13 (16)	16 (20)	7 (9)	5 (8)
Moderate	28 (9)	8 (10)	8 (10)	10 (13)	2 (3)
Severe	47 (16)	14 (17)	7 (9)	18 (24)	8 (13)
Hemorrhage	98 (33)	27 (33)	24 (30)	29 (39)	18 (30)
Cerebral atrophy	15/297 (5)^g	5 (6)	3/79 (4)^g	3 (4)	4 (7)
Localized	2	1	0	0	1
Global	13	4	3	3	3
Corpus callosum thinning
None	284 (95)	80 (98)	75 (94)	71 (95)	58 (95)
Mild	10 (3)	1 (1)	5 (6)	3 (4)	1 (2)
Moderate	4 (1)	1 (1)	0	1 (1)	2 (3)
Severe	0	0	0	0	0
Ventricular dilatation^h
None	274 (92)	78 (95)	72 (90)	66 (88)	58 (95)
Mild	13 (4)	2 (2)	3 (4)	8 (11)	0
Moderate	6 (2)	1 (1)	4 (5)	0	1 (2)
Severe	4 (1)	1 (1)	0	1 (1)	2 (3)
Shunted	1 (0.3)	0	1 (1)	0	0
NICHD pattern of injury
0	129 (43)	35 (43)	33 (41)	27 (36)	34 (56)
1A	43 (14)	10 (12)	15 (19)	9 (12)	9 (15)
1B	18 (6)	3 (4)	6 (8)	9 (12)	0
2A1	9 (3)	6 (7)	0	2 (3)	1 (2)
2A2	11 (4)	2 (2)	4 (5)	4 (5)	1 (2)
2A3	3 (1)	1 (1)	1 (1)	0	1 (2)
2B1	15 (5)	5 (6)	2 (3)	5 (7)	3 (5)
2B2	32 (11)	10 (12)	11 (14)	6 (8)	5 (8)
2B3	6 (2)	0	4 (5)	2 (3)	0
3	32 (11)	10 (12)	4 (5)	11 (15)	7 (11)
Extentⁱ
Normal pattern, no extent	129	35	33	27	34
Abnormal pattern	169	47	47	48	27
Mild	73 (43)	18 (38)	22 (47)	18 (38)	15 (56)
Moderate	47 (28)	14 (30)	17 (36)	12 (25)	4 (15)
Extensive	17 (10)	5 (11)	4 (9)	7 (15)	1 (4)
Hemispheric devastation	32 (19)	10 (21)	4 (9)	11 (23)	7 (26)
Laterality^j
Normal pattern, no laterality	129	35	33	27	34
Abnormal pattern	169	47	47	48	27
Right only	18 (11)	6 (13)	6 (13)	5 (10)	1 (4)
Left only	25 (15)	8 (17)	8 (17)	5 (10)	4 (15)
Right greater than left	19 (11)	1 (2)	7 (15)	5 (10)	6 (22)
Left greater than right	28 (17)	10 (21)	8 (17)	4 (8)	6 (22)
Right and left equally	79 (47)	22 (47)	18 (38)	29 (60)	10 (37)
Details of signal abnormalities
Frontoparietal	52 (17)	14 (17)	10 (13)	18 (24)	10 (16)
Parietal-temporal	40 (13)	14 (17)	7 (9)	12 (16)	7 (11)
Parietal-occipital	46 (15)	16 (20)	6 (8)	15 (20)	9 (15)
Temporal-occipital	38 (13)	12 (15)	6 (8)	13 (17)	7 (11)
Parasagittal	23 (8)	9 (11)	4 (5)	7 (9)	3 (5)
Perirolandic	22 (7)	10 (12)	5 (6)	3 (4)	4 (7)
Perisylvian	6 (2)	2 (2)	0	2 (3)	2 (3)
Insular	33 (11)	7 (9)	8 (10)	12 (16)	6 (10)
Intraventricular	43 (14)	8 (10)	11 (14)	15 (20)	9 (15)
Cerebellar	22 (7)	8 (10)	5 (6)	6 (8)	3 (5)
Corona radiata	13 (4)	5 (6)	3 (4)	5 (7)	0
Hippocampus	0	0	0	0	0
Brainstem	2 (0.7)	0	1 (1)	1 (1)	0
Pituitary	0	0	0	0	0
Hypothalamus	4 (1)	0	1 (1)	2 (3)	1 (2)
Optic chiasma	0	0	0	0	0
Extra-axial	34 (11)	9 (11)	8 (10)	10 (13)	7 (11)
Scalp	0	0	0	0	0
Basal ganglia	48 (16)	12 (15)	19 (24)	11 (15)	6 (10)
Thalamus	30 (10)	8 (10)	13 (16)	5 (7)	4 (7)
Corpus callosum	3 (1)	0	2 (3)	1 (1)	0
Vascular	3 (1)	0	3 (4)	0	0
Other	0	0	0	0	0
Age at MRI, mean (SD), d^k	9.18 (4.49)	8.27 (3.96)	9.24 (4.40)	8.93 (4.95)	10.64 (4.41)

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Abbreviations: BGT, basal ganglia or thalamus; MRI, magnetic resonance imaging; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; PLIC, posterior limb of the internal capsule; WS, watershed.

^{^a}

Among the 364 infants of the original cohort, 49 were excluded due to lack of MRI of adequate quality, 16 due to missing primary outcome, and 1 due to genetic abnormality.

^{^b}

Other cerebral lesions include any of the following: parasagittal, perirolandic, perisylvian, insular, intraventricular, corona radiata, hippocampus, corpus collosum, pituitary, hypothalamus, optic chiasma, or brainstem.

^{^c}

BGT injury was classified as mild (focal abnormalities), moderate (focal abnormalities including posterior lentiform nuclei and ventrolateral nuclei of the thalami), or severe (widespread abnormalities in all regions of the BGT).

^{^d}

PLIC injury was described as abnormal if there was partial to complete absence of normal high signal on T1 imaging and loss of normal low intensity on T2 imaging.

^{^e}

WS injury (between vascular zones) was described as mild (no extension into overlying cortical region), moderate (involvement of overlying cortical region), or severe (more extensive involvement).

^{^f}

White matter injury was described as mild (≤3 punctate lesions), moderate (4-12 punctate lesions or 1 that is 4-15 mm), or severe (>12 punctate lesions or ≥1 that is >15 mm).

^{^g}

Values are expressed as number/total number (percentage).

^{^h}

Indicates worse finding between right and left.

^ⁱ

The extent of injury was described as mild (less than one-third involved), moderate (one-third to two-thirds involved), or severe (two-thirds or greater involvement). Lesions were described as cystic, noncystic, hemorrhagic, mineralization, gliosis, or edema.

^{^j}

Laterality of injury was described as right or left if unilateral, or if bilateral, as right greater than left, left greater than right, or left equal to right.

^{^k}

P = .002 for age at MRI in the 4 groups.

Table 2. MRI Findings Comparing Usual Care vs Other 3 Treatment Groups.

MRI result	No. (%)		χ² P value
MRI result	33.5 °C for 72 h (n = 82)	Other 3 groups (n = 216)^a	χ² P value
Overall diagnosis
Normal	33 (40)	82 (38)	.52
Abnormal	47 (57)	122 (56)
Normal with other findings	2 (2)	12 (6)
Total hemispheric devastation
No	72 (88)	194 (90)	.62
Yes	10 (12)	22 (10)	.62
Laterality
Left and right equally	10	19
Right greater than left	0	2
Left greater than right	0	1
Edema	16 (20)	27 (13)	.12
Cerebral lesions
Any frontal	25 (30)	68 (31)	.87
Any temporal	21 (26)	51 (24)	.72
Any parietal	36 (44)	73 (34)	.11
Any occipital	23 (28)	47 (22)	.25
Any frontal, temporal, parietal, or occipital	39 (48)	90 (42)	.36
Other cerebral lesions^b	26 (32)	65 (30)	.79
Any frontal, temporal, parietal, occipital, or other cerebral lesions	45 (55)	113 (52)	.69
BGT classification^c
Normal	59 (72)	156 (72)	.71
Mild	7 (9)	21 (10)
Moderate	3 (4)	13 (6)
Severe^c	13 (16)	26 (12)
PLIC classification^d
Normal	64 (78)	171 (79)	.81
Equivocal	3 (4)	5 (2)
Abnormal	15 (18)	40 (19)
WS area^e
Normal	60 (73)	175 (81)	.02^f
Mild	0	4 (2)
Moderate	11 (13)	8 (4)
Severe	11 (13)	29 (13)
White matter injury^g
None	47 (57)	135 (63)	.86
Mild	13 (16)	28 (13)
Moderate	8 (10)	20 (9)
Severe	14 (17)	33 (15)
Cerebral atrophy	5 (6)	10/215 (5)^h	.57^f
Localized	1	1
Global	4	9
Corpus callosum thinning
None	80 (98)	204 (94)	.43^f
Mild	1 (1)	9 (4)
Moderate	1 (1)	3 (1)
Severe	0	0
Ventricular dilatationⁱ
None	78 (95)	196 (91)	.91^f
Mild	2 (2)	11 (5)
Moderate	1 (1)	5 (2)
Severe	1 (1)	3 (1)
Shunted	0	1 (0.5)
NICHD pattern of injury
0	35 (43)	94 (44)	.68^f
1A	10 (12)	33 (15)
1B	3 (4)	15 (7)
2A1	6 (7)	3 (1)
2A2	2 (2)	9 (4)
2A3	1 (1)	2 (0.9)
2B1	5 (6)	10 (5)
2B2	10 (12)	22 (10)
2B3	0	6 (3)
3	10 (12)	22 (10)
Extent^j
Normal pattern, no extent	35	94
Abnormal pattern	47	122
Mild	18 (38)	55 (45)	.88
Moderate	14 (30)	33 (27)
Extensive	5 (11)	12 (10)
Hemispheric devastation	10 (21)	22 (18)
Laterality^k
Normal pattern, no laterality	35	94
Abnormal pattern	47	122
Right only	6 (13)	12 (10)	.19
Left only	8 (17)	17 (14)
Right greater than left	1 (2)	18 (15)
Left greater than right	10 (21)	18 (15)
Right and left equally	22 (47)	57 (47)
Details of signal abnormalities
Frontoparietal	14 (17)	38 (18)	.92
Parietal-temporal	14 (17)	26 (12)	.25
Parietal-occipital	16 (20)	30 (14)	.23
Temporal-occipital	12 (15)	26 (12)	.55
Parasagittal	9 (11)	14 (6)	.19
Perirolandic	10 (12)	12 (6)	.05
Perisylvian	2 (2)	4 (2)	.67^f
Insular	7 (9)	26 (12)	.39
Intraventricular	8 (10)	35 (16)	.16
Cerebellar	8 (10)	14 (6)	.33
Corona radiata	5 (6)	8 (4)	.36^f
Hippocampus	0	0	NA
Brainstem	0	2 (0.9)	>.99^f
Pituitary	0	0	NA
Hypothalamus	0	4 (2)	.58^f
Optic chiasma	0	0	NA
Extra-axial	9 (11)	25 (12)	.88
Scalp	0	0	NA
Basal ganglia	12 (15)	36 (17)	.67
Thalamus	8 (10)	22 (10)	.91
Corpus callosum	0	3 (1)	.56^f
Vascular	0	3 (1)	.56^f
Other	0	0	NA

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Abbreviations: BGT, basal ganglia or thalamus; MRI, magnetic resonance imaging; NA, not applicable; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; PLIC, posterior limb of the internal capsule; WS, watershed.

^{^a}

The other 3 treatment groups were 33.5 °C for 120 hours, 32.0 °C for 72 hours, and 32.0 °C for 120 hours.

^{^b}

^{^c}

^{^d}

PLIC injury was described as abnormal if there was partial to complete absence of normal high signal on T1 imaging and loss of normal low intensity on T2 imaging.

^{^e}

WS injury (between vascular zones) was described as mild (no extension into overlying cortical region), moderate (involvement of overlying cortical region), or severe (more extensive involvement).

^{^f}

Fisher exact test.

^{^g}

White matter injury was described as mild (≤3 punctate lesions), moderate (4-12 punctate lesions or 1 that is 4-15 mm), or severe (>12 punctate lesions or ≥1 that is >15 mm).

^{^h}

Values are expressed as number/total number (percentage).

^ⁱ

Indicates worse finding between right and left.

^{^j}

^{^k}

Laterality of injury was described as right or left if unilateral, or if bilateral, as right greater than left, left greater than right, or left equal to right.

The primary outcome of death or moderate or severe disability was present in 72 of 298 infants (24%), death among 20 of 298 infants (7%), and moderate or severe disability among 52 of 278 surviving infants (19%). Among the 32 infants with hemispheric devastation, 30 (94%) had death or disability, and 17 (89%) survived with moderate or severe disability. The association between the NICHD NRN MRI score and outcome of death or disability among all infants or disability among survivors is noted in Table 3. Injury scores of 2A1 or greater, vs less than 2, were associated with death or disability among all infants and with disability among surviving infants (eTable 3 in Supplement 2). MRI scores 2 or greater, compared with those less than 2, were associated with the primary outcome, with an OR of 13.66 (95% CI, 7.47-24.95) and an AUC of 0.84 (95% CI, 0.78-0.90), the latter indicating high ability for this cutoff to discriminate between 2 levels of the primary outcome. Similarly, the OR between scores of 2 or greater vs less than 2 for disability among survivors was 10.52 (95% CI, 5.46-20.28) with an AUC of 0.80 (95% CI, 0.73-0.88). The association of an abnormal MRI finding and death or disability had a sensitivity of 0.89, specificity of 0.54, positive predictive value of 0.38, negative predictive value of 0.94, and positive likelihood ratio of 1.91; the corresponding values for moderate or severe disability among surviving infants were 0.85, 0.54, 0.30, 0.94, and 1.82, respectively.

Table 3. Association Between Magnetic Resonance Imaging Patterns of Injury and Outcome^a.

NICHD pattern of injury	Infants, No.	Death or moderate or severe disability		Moderate or severe disability among survivors		Survival with mild or no disability
NICHD pattern of injury	Infants, No.	No. (%)	OR (95% CI)	No. (%)	OR (95% CI)	No. (%)	OR (95% CI)
0	129	8 (6)	NA	8 (6)	NA	121 (94)	NA
1A	43	1 (2)	0.34 (0.04-2.95)	1 (2)	0.33 (0.04-2.93)	42 (98)	2.94 (0.34-25.45)
1B	18	3 (17)	2.54 (0.67-9.60)	3 (17)	2.44 (0.63-9.49)	15 (83)	0.39 (0.10-1.49)
2A1	9	2 (22)	4.28 (1.12-16.28)	2 (22)	4.36 (1.12-16.98)	7 (78)	0.23 (0.06-0.89)
2A2	11	6 (55)	17.95 (3.42-94.19)	6 (55)	18.25 (3.41-97.55)	5 (45)	0.06 (0.01-0.29)
2A3	3	1 (33)	8.71 (1.82-41.80)	1 (33)	8.61 (1.80-41.15)	2 (67)	0.11 (0.02-0.55)
2B1	15	7 (47)	11.27 (2.89-43.90)	5 (38)	7.91 (2.18-28.77)	8 (53)	0.09 (0.02-0.35)
2B2	32	9 (28)	4.81 (2.07-11.17)	8 (26)	4.54 (1.90-10.84)	23 (72)	0.21 (0.09-0.48)
2B3	6	5 (83)	41.71 (12.04-144.48)	1 (50)	10.63 (5.05-22.37)	1 (17)	0.02 (0.007-0.08)
3	32	30 (94)	161.99 (20.63-1271.89)	17 (89)	102.79 (11.63-908.89)	2 (6)	0.006 (0.0008-0.05)

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Abbreviations: NA, not applicable; NICHD, Eunice Kennedy Shriver National Institute of Child Health and Human Development; OR, odds ratio.

^{^a}

Multivariable logistic regression models controlling for severity of encephalopathy, maternal public insurance, age at magnetic resonance imaging, and site (as a cluster effect). Four infants are missing data on maternal public insurance.

Among 74 of the 298 infants (25%) with injury in WS and/or BGT or PLIC areas, infants with any or predominant WS injury were less acidotic and had a lower frequency of seizures at random assignment and none were born following uterine rupture compared with those with any BGT or PLIC injury (exploratory analysis, eTable 4 in Supplement 2). Infants with any or predominant WS injury had numerically but not statistically significantly higher in-hospital mortality, while those with any or predominant BGT or PLIC injury had a significantly higher frequency of moderate or severe cerebral palsy (Table 4); cognitive and motor scores were not different. Compared with an injury score of 0, death or disability occurred in 12 of 28 infants (43%) with any or predominant WS injury (OR, 9.61; 95% CI, 3.60-25.65) and in 17 of 46 infants (37%) with any or predominant BGT or PLIC injury (OR, 7.23; 95% CI, 2.83-18.50) (eTable 5 in Supplement 2).

Table 4. Outcomes With Any or Predominant WS vs BGT or PLIC Injury.

Outcome	No. (%)^a		P value^b
Outcome	WS (n = 28)	BGT or PLIC (n = 46)	P value^b
Primary
Death or moderate or severe disability	12 (43)	17 (37)	.61
Secondary
Death
In NICU	3 (11)	0	.05^c
Through follow-up	3 (11)	3 (7)	.67^c
Among survivors
No.	25	43
Disability
Moderate or severe	9 (36)	14 (33)	.77
Mild or none	16 (64)	29 (67)	.77
Impairment
Visual	0	2 (5)	.53^c
Hearing	4 (16)	4 (9)	.45
Cerebral palsy
Any	5 (20)	18 (42)	.07
Moderate or severe	2 (8)	14 (33)	.02
Bayley Scales of Infant and Toddler Development III score
Cognitive
No.	25	43
Median (IQR)	90 (80-95)	85 (60-100)	.43^d
≥85	17 (68)	27 (63)	.62
70-84	4 (16)	5 (12)
<70	4 (16)	11 (26)
Motor
No.	25	42
Median (IQR)	88 (76-91)	85 (55-94)	.73^d
≥85	15 (60)	23 (55)	.11
70-84	6 (24)	4 (10)
<70	4 (16)	15 (36)
Language
No.	23	42
Median (IQR)	86 (74-100)	83 (71-91)	.11^d
≥85	15 (65)	19 (44)	.25
70-84	4 (17)	14 (33)
<70	4 (17)	10 (23)

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Abbreviations: BGT, basal ganglia or thalamus; NICU, neonatal intensive care unit; PLIC, posterior limb of the internal capsule; WS, watershed.

^{^a}

The WS group includes infants with 2A1, 2B1, and 2A3 or 2B3 Eunice Kennedy Shriver National Institute of Child Health and Human Development patterns of injury if WS injury was more severe than BGT injury. The BGT or PLIC group includes infants with 2A2, 2B2, and 2A3 or 2B3 patterns of injury if BGT injury was more severe than WS injury. Two infants (1 with the 2A3 pattern and 1 with the 2B3 pattern) could not be assigned to the WS group or the BGT or PLIC group due to no predominant finding between WS and BGT.

^{^b}

P values are from χ² test except as noted.

^{^c}

P value from Fisher exact test.

^{^d}

P value from nonparametric median test.

The associations of clinical variables at random assignment into the trial with the MRI injury score and death or disability are shown in Table 5. Severe encephalopathy, presence of acute perinatal events, a 10-minute Apgar score less than 5, seizures, and a higher brain injury score were all associated with death or disability.

Table 5. Association Between Baseline Variables and Pattern of Injury With Outcome^a.

Variable	Death or disability
Variable	No./total No. (%)	OR (95% CI)^b
Level of HIE
Moderate	40/240 (17)	1 [Reference]
Severe	32/58 (55)	6.15 (3.31-11.43)
Perinatal sentinel events^c
Yes	69/266 (26)	4.90 (1.14-21.13)
No	2/30 (7)	1 [Reference]
Public insurance
Yes	32/153 (21)	0.69 (0.40-1.18)
No	39/141 (28)	1 [Reference]
10-min Apgar score <5
Yes	48/130 (37)	3.84 (2.08-7.07)
No	18/136 (13)	1 [Reference]
Acidosis^d
Yes	49/187 (26)	1.36 (0.77-2.39)
No	23/111 (21)	1 [Reference]
Neonatal seizures
Yes	28/86 (33)	1.84 (1.05-3.23)
No	44/212 (21)	1 [Reference]
Maternal education
<HS	12/59 (20)	0.61 (0.29-1.27)
HS	13/72 (18)	0.53 (0.26-1.07)
>HS	39/132 (30)	1 [Reference]
MRI injury pattern
0	8/129 (6)	1 [Reference]
1A	1/43 (2)	0.36 (0.04-2.97)
1B	3/18 (17)	3.03 (0.72-12.66)
2A1	2/9 (22)	4.32 (0.77-24.30)
2A2	6/11 (55)	18.15 (4.54-72.56)
2A3	1/3 (33)	7.56 (0.62-92.58)
2B1	7/15 (47)	13.23 (3.82-45.79)
2B2	9/32 (28)	5.92 (2.07-16.94)
2B3	5/6 (83)	75.63 (7.87-726.98)
3	30/32 (94)	226.88 (45.80-1123.97)

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Abbreviations: HIE, hypoxic-ischemic encephalopathy; HS, high school; MRI, magnetic resonance imaging.

^{^a}

Missing data from 2 infants for perinatal sentinel events, 32 infants for 10-minute Apgar score less than 5, 35 infants for maternal education, and 4 infants for public insurance.

^{^b}

Odds ratios are from unadjusted logistic regression models.

^{^c}

Perinatal sentinel events include any of the following: decelerations or loss of fetal heart tones, cord mishap, uterine rupture, shoulder dystocia, placental problems, maternal hemorrhage, maternal trauma, maternal cardiorespiratory arrest, and maternal seizures.

^{^d}

Acidosis is defined as pH of 7 or less, using cord blood gas if available or first postnatal blood gas if not.

Discussion

This study demonstrated that the expanded NICHD NRN MRI brain injury score 2A or greater was associated with death or disability among all infants and with disability among surviving infants, after controlling for severity of encephalopathy, in the trial evaluating effect of depth and duration of cooling on outcomes at age 18 months. There were no differences in the injury score between infants undergoing usual care cooling and those cooled to a greater depth or for a longer duration. We have previously demonstrated that cooling to lower than 33.5 °C, cooling for longer than 72 hours, or both did not reduce death or moderate or severe disability.¹² The expanded NICHD NRN score separated any or predominant WS from any or predominant BGT or PLIC injury, and infants with BGT or PLIC injury had similar outcomes compared with infants with WS injury, but cerebral palsy rates were higher. Other investigators evaluating gray matter injury have previously noted association of BGT or PLIC injury and cerebral palsy.^13,14,15 We observed that infants without an MRI had higher rates of severe HIE and higher mortality than those who had an MRI, findings similar to the HEAL imaging study results.¹⁰ In clinical practice, the MRI is performed after the rewarming phase; hence, the extent of brain injury among infants undergoing imaging with moderate or severe HIE may be underestimated.

From earlier trials of hypothermia for HIE, the TOBY trial⁷ noted a reduction in BGT or PLIC and white matter lesions among infants in the hypothermia group compared with those in the control group, with good correlation of MRI and outcome in both groups.⁷ In our trial of whole-body hypothermia for moderate or severe HIE, the brain injury score was associated with outcome; each point increase in the severity of the score was associated with more than a 2-fold increase in the odds of death or disability.⁶ The ICE trial⁸ found a reduction in areas of gray and white matter injury in the cooled group compared with the control group, with abnormal MRI findings and diffusion abnormalities in the BGT or PLIC correlating with adverse outcomes at 24 months. In the HEAL trial,¹⁰ among 451 of 500 trial participants (90%) with neuroimaging at less than 8 days, MRI injury and spectroscopy findings were associated with outcomes of neurodevelopmental impairment or death at 2 years. However, infants with mild or moderate MRI injury had Bayley Scales of Infant and Toddler Development III cognitive, language, and motor scores similar to those of infants with no injury. The differences between the HEAL trial’s findings and our data may be due to earlier age at MRI in HEAL, different MRI scoring systems,¹⁶ and different definitions of outcome.

In an observational study, Weeke et al¹⁵ assessed infants following hypothermia therapy (Netherlands, n = 97; Sweden, n = 76), including those with mild encephalopathy, using 3 MRI subscores for deep gray matter, white matter or cortex, and cerebellum.¹⁵ The gray matter subscore was associated with adverse outcome at 2 years and at school age. Bach et al¹⁷ evaluated 434 infants at 30 months of age, including 138 with mild encephalopathy; 204 received hypothermia and 317 had MRI assessed by the Barkovich scoring system.¹⁸ The predictive accuracy of the MRI score for motor disability and/or death was similar between hypothermia-treated and untreated infants. In the present study of infants with moderate or severe HIE, we noted an association of the brain injury score among all infants, those with any or predominant BGT or PLIC injury or WS injury, and those with death or disability or survival with disability.

The assessment of brain injury among infants with HIE may be influenced by the timing of the MRI.⁷ The differences between imaging prior to and after 7 days among infants with imaging at both periods was examined among 94 infants with varying stages of HIE who received hypothermia.¹⁹ Eighteen infants (19%) had changes between the early and late imaging; however, neurodevelopmental outcome data were unavailable. A recent meta-analysis has suggested that the predictive value of MRI decreases beyond the first week of age.²⁰ In the current study, MRI was obtained between 7 and 14 days of age based on clinical practice at the time of the study.

MRI injury scoring systems have been compared in recent articles. Among 161 infants receiving hypothermia, Langeslag et al²¹ compared 4 MRI scoring systems^7,9,10,22 and found all to reliably predict adverse outcomes at 24 months of age. Another study²³ of 40 infants comparing 4 scoring systems^7,9,15,18 noted correlations between the scoring systems and cognitive outcome, with the studies by Weeke et al¹⁵ and Rutherford et al⁷ having the strongest correlation. A study by Ní Bhroin et al²⁴ comparing the NICHD NRN score and the scores by Barkovich et al¹⁸ and Weeke et al¹⁵ found that all 3 scores correlated with cognitive and motor outcomes, while the score from Weeke et al was also associated with the language score in infancy. In a meta-analysis of the prognostic value of the neonatal MRI in HIE, Sánchez Fernández et al²⁵ noted MRI as a good biomarker of outcome beyond infancy. Interrater reliability was excellent in another recent study for scoring systems assessed among 2 central readers examining neonates with varying stages of HIE.²⁶ In our study, the expanded MRI score of brain injury has demonstrated correlation with death or disability among all infants and with disability among surviving infants; comparing our expanded MRI score with other scores is beyond the scope of the current study.

We found that when predictive ability of early clinical variables and MRI injury scores were examined, low 10-minute Apgar scores, acute perinatal events, severe HIE, seizures, and the MRI score were predictive of death or disability at 18 months of age. Thoresen et al²⁷ and Peeples et al²⁸ have noted that addition of clinical variables improved the predictive ability of the MRI injury score in evaluating death or disability in infancy.

Strengths and Limitations

The strengths of this study include the large sample size, high follow-up rate, comparison between groups with and without an MRI, and the procedure used to obtain concordance between the 2 central readers. The limitations of this study include the age at MRI being later than current age at imaging in infants with HIE, the use of 1.5-T scanners, and the lack of diffusion-weighted imaging. These limitations may be sources of bias and confounding in this study.

Conclusions

Among neonates of at least 36 weeks’ gestation with moderate or severe HIE, the expanded neonatal NICHD NRN MRI brain injury score was a marker for death or disability as well as disability among surviving infants, after controlling for severity of encephalopathy. These results help with counseling families and may have implications for the design of future neuroprotective trials.

Supplement 1.

Trial Protocol

jamapediatr-e246209-s001.pdf^{(917.5KB, pdf)}

Supplement 2.

eTable 1. Infants With MRI and Those for Whom MRI Studies Were Unavailable

eTable 2. MRI Findings Among Study Subjects by Depth of Cooling and Duration of Cooling

eTable 3. Outcomes Among Infants With NICHD Score 2A or Greater vs NICHD Score <2A

eTable 4. Baseline Characteristics for Infants With Injury in Any/Predominant Watershed vs Any/Predominant BGT/PLIC Injury

eTable 5. The Relationship Between the Any/Predominant WS or BGT/PLIC Groups and Outcome

eFigure. CONSORT Flow Diagram

eAppendix 1. Optimizing Cooling MRI Secondary Central MRI Reading Form

eAppendix 2. Optimizing Cooling MRI Secondary Scoring Manual

jamapediatr-e246209-s002.pdf^{(1.2MB, pdf)}

Supplement 3.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Members

jamapediatr-e246209-s003.pdf^{(234.1KB, pdf)}

Supplement 4.

Data Sharing Statement

jamapediatr-e246209-s004.pdf^{(16.4KB, pdf)}

References

1.Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663-670. doi: 10.1016/S0140-6736(05)17946-X [DOI] [PubMed] [Google Scholar]
2.Shankaran S, Laptook AR, Ehrenkranz RA, et al. ; National Institute of Child Health and Human Development Neonatal Research Network . Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi: 10.1056/NEJMcps050929 [DOI] [PubMed] [Google Scholar]
3.Azzopardi DV, Strohm B, Edwards AD, et al. ; TOBY Study Group . Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349-1358. doi: 10.1056/NEJMoa0900854 [DOI] [PubMed] [Google Scholar]
4.Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants . Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126(4):e771-e778. doi: 10.1542/peds.2009-2441 [DOI] [PubMed] [Google Scholar]
5.Jacobs SE, Morley CJ, Inder TE, et al. ; Infant Cooling Evaluation Collaboration . Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165(8):692-700. doi: 10.1001/archpediatrics.2011.43 [DOI] [PubMed] [Google Scholar]
6.Shankaran S, Barnes PD, Hintz SR, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F398-F404. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010;9(1):39-45. doi: 10.1016/S1474-4422(09)70295-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Cheong JLY, Coleman L, Hunt RW, et al. ; Infant Cooling Evaluation Collaboration . Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med. 2012;166(7):634-640. doi: 10.1001/archpediatrics.2012.284 [DOI] [PubMed] [Google Scholar]
9.Shankaran S, McDonald SA, Laptook AR, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Neonatal magnetic resonance imaging pattern of brain injury as a biomarker of childhood outcomes following a trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2015;167(5):987-993.e3. doi: 10.1016/j.jpeds.2015.08.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Wu YW, Monsell SE, Glass HC, et al. How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy? Pediatr Res. 2023;94(3):1018-1025. doi: 10.1038/s41390-023-02510-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Shankaran S, Laptook AR, Pappas A, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312(24):2629-2639. doi: 10.1001/jama.2014.16058 [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Shankaran S, Laptook AR, Pappas A, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: randomized clinical trial. JAMA. 2017;318(1):57-67. doi: 10.1001/jama.2017.7218 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Rutherford M, Biarge MM, Allsop J, Counsell S, Cowan F. MRI of perinatal brain injury. Pediatr Radiol. 2010;40(6):819-833. doi: 10.1007/s00247-010-1620-z [DOI] [PubMed] [Google Scholar]
14.de Vries LS, Groenendaal F. Patterns of neonatal hypoxic-ischaemic brain injury. Neuroradiology. 2010;52(6):555-566. doi: 10.1007/s00234-010-0674-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Weeke LC, Groenendaal F, Mudigonda K, et al. A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. J Pediatr. 2018;192:33-40.e2. doi: 10.1016/j.jpeds.2017.09.043 [DOI] [PMC free article] [PubMed] [Google Scholar]
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17.Bach AM, Fang AY, Bonifacio S, et al. Early magnetic resonance imaging predicts 30-month outcomes after therapeutic hypothermia for neonatal encephalopathy. J Pediatr. 2021;238(e1):94-101.e1. doi: 10.1016/j.jpeds.2021.07.003 [DOI] [PubMed] [Google Scholar]
18.Barkovich AJ, Hajnal BL, Vigneron D, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998;19(1):143-149. [PMC free article] [PubMed] [Google Scholar]
19.Garvey AA, El-Shibiny H, Yang E, Inder TE, El-Dib M. Differences between early and late MRI in infants with neonatal encephalopathy following therapeutic hypothermia. Pediatr Res. 2023;94(3):1011-1017. doi: 10.1038/s41390-023-02580-8 [DOI] [PubMed] [Google Scholar]
20.Ouwehand S, Smidt LCA, Dudink J, et al. Predictors of outcomes in hypoxic-ischemic encephalopathy following hypothermia: a meta-analysis. Neonatology. 2020;117(4):411-427. doi: 10.1159/000505519 [DOI] [PubMed] [Google Scholar]
21.Langeslag JF, Groenendaal F, Roosendaal SD, et al. ; PharmaCool Study Group . Outcome prediction and inter-rater comparison of four brain magnetic resonance imaging scoring systems of infants with perinatal asphyxia and therapeutic hypothermia. Neonatology. 2022;119(3):311-319. doi: 10.1159/000522629 [DOI] [PubMed] [Google Scholar]
22.Trivedi SB, Vesoulis ZA, Rao R, et al. A validated clinical MRI injury scoring system in neonatal hypoxic-ischemic encephalopathy. Pediatr Radiol. 2017;47(11):1491-1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Kang OH, Jahn P, Eichhorn JG, Dresbach T, Müller A, Sabir H. Correlation of different MRI scoring systems with long-term cognitive outcome in cooled asphyxiated newborns. Children (Basel). 2023;10(8):1295. doi: 10.3390/children10081295 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Ní Bhroin M, Kelly L, Sweetman D, et al. Relationship between MRI scoring systems and neurodevelopmental outcome at two years in infants with neonatal encephalopathy. Pediatr Neurol. 2022;126:35-42. doi: 10.1016/j.pediatrneurol.2021.10.005 [DOI] [PubMed] [Google Scholar]
25.Sánchez Fernández I, Morales-Quezada JL, Law S, Kim P. Prognostic value of brain magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2017;32(13):1065-1073. doi: 10.1177/0883073817726681 [DOI] [PubMed] [Google Scholar]
26.Machie M, Weeke L, de Vries LS, Rollins N, Brown L, Chalak L. MRI score ability to detect abnormalities in mild hypoxic-ischemic encephalopathy. Pediatr Neurol. 2021;116:32-38. doi: 10.1016/j.pediatrneurol.2020.11.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Thoresen M, Jary S, Walløe L, et al. MRI combined with early clinical variables are excellent outcome predictors for newborn infants undergoing therapeutic hypothermia after perinatal asphyxia. EClinicalMedicine. 2021;36:100885. doi: 10.1016/j.eclinm.2021.100885 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Peeples ES, Rao R, Dizon MLV, et al. ; Children’s Hospitals Neonatal Consortium Hypoxic-Ischemic Encephalopathy Focus Group . Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2021;147(2):e2020022962. doi: 10.1542/peds.2020-022962 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol

jamapediatr-e246209-s001.pdf^{(917.5KB, pdf)}

Supplement 2.

eTable 1. Infants With MRI and Those for Whom MRI Studies Were Unavailable

eTable 2. MRI Findings Among Study Subjects by Depth of Cooling and Duration of Cooling

eTable 3. Outcomes Among Infants With NICHD Score 2A or Greater vs NICHD Score <2A

eTable 4. Baseline Characteristics for Infants With Injury in Any/Predominant Watershed vs Any/Predominant BGT/PLIC Injury

eTable 5. The Relationship Between the Any/Predominant WS or BGT/PLIC Groups and Outcome

eFigure. CONSORT Flow Diagram

eAppendix 1. Optimizing Cooling MRI Secondary Central MRI Reading Form

eAppendix 2. Optimizing Cooling MRI Secondary Scoring Manual

jamapediatr-e246209-s002.pdf^{(1.2MB, pdf)}

Supplement 3.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Members

jamapediatr-e246209-s003.pdf^{(234.1KB, pdf)}

Supplement 4.

Data Sharing Statement

jamapediatr-e246209-s004.pdf^{(16.4KB, pdf)}

[poi240110r1] 1.Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005;365(9460):663-670. doi: 10.1016/S0140-6736(05)17946-X [DOI] [PubMed] [Google Scholar]

[poi240110r2] 2.Shankaran S, Laptook AR, Ehrenkranz RA, et al. ; National Institute of Child Health and Human Development Neonatal Research Network . Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi: 10.1056/NEJMcps050929 [DOI] [PubMed] [Google Scholar]

[poi240110r3] 3.Azzopardi DV, Strohm B, Edwards AD, et al. ; TOBY Study Group . Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009;361(14):1349-1358. doi: 10.1056/NEJMoa0900854 [DOI] [PubMed] [Google Scholar]

[poi240110r4] 4.Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants . Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126(4):e771-e778. doi: 10.1542/peds.2009-2441 [DOI] [PubMed] [Google Scholar]

[poi240110r5] 5.Jacobs SE, Morley CJ, Inder TE, et al. ; Infant Cooling Evaluation Collaboration . Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011;165(8):692-700. doi: 10.1001/archpediatrics.2011.43 [DOI] [PubMed] [Google Scholar]

[poi240110r6] 6.Shankaran S, Barnes PD, Hintz SR, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F398-F404. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r7] 7.Rutherford M, Ramenghi LA, Edwards AD, et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial. Lancet Neurol. 2010;9(1):39-45. doi: 10.1016/S1474-4422(09)70295-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r8] 8.Cheong JLY, Coleman L, Hunt RW, et al. ; Infant Cooling Evaluation Collaboration . Prognostic utility of magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: substudy of a randomized trial. Arch Pediatr Adolesc Med. 2012;166(7):634-640. doi: 10.1001/archpediatrics.2012.284 [DOI] [PubMed] [Google Scholar]

[poi240110r9] 9.Shankaran S, McDonald SA, Laptook AR, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Neonatal magnetic resonance imaging pattern of brain injury as a biomarker of childhood outcomes following a trial of hypothermia for neonatal hypoxic-ischemic encephalopathy. J Pediatr. 2015;167(5):987-993.e3. doi: 10.1016/j.jpeds.2015.08.013 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r10] 10.Wu YW, Monsell SE, Glass HC, et al. How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy? Pediatr Res. 2023;94(3):1018-1025. doi: 10.1038/s41390-023-02510-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r11] 11.Shankaran S, Laptook AR, Pappas A, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial. JAMA. 2014;312(24):2629-2639. doi: 10.1001/jama.2014.16058 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r12] 12.Shankaran S, Laptook AR, Pappas A, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: randomized clinical trial. JAMA. 2017;318(1):57-67. doi: 10.1001/jama.2017.7218 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r13] 13.Rutherford M, Biarge MM, Allsop J, Counsell S, Cowan F. MRI of perinatal brain injury. Pediatr Radiol. 2010;40(6):819-833. doi: 10.1007/s00247-010-1620-z [DOI] [PubMed] [Google Scholar]

[poi240110r14] 14.de Vries LS, Groenendaal F. Patterns of neonatal hypoxic-ischaemic brain injury. Neuroradiology. 2010;52(6):555-566. doi: 10.1007/s00234-010-0674-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r15] 15.Weeke LC, Groenendaal F, Mudigonda K, et al. A novel magnetic resonance imaging score predicts neurodevelopmental outcome after perinatal asphyxia and therapeutic hypothermia. J Pediatr. 2018;192:33-40.e2. doi: 10.1016/j.jpeds.2017.09.043 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r16] 16.Cizmeci MN, Martinez-Biarge M, Cowan FM. The predictive role of brain magnetic resonance imaging in neonates with hypoxic-ischemic encephalopathy. Pediatr Res. 2024;95(3):601-602. doi: 10.1038/s41390-023-02732-w [DOI] [PubMed] [Google Scholar]

[poi240110r17] 17.Bach AM, Fang AY, Bonifacio S, et al. Early magnetic resonance imaging predicts 30-month outcomes after therapeutic hypothermia for neonatal encephalopathy. J Pediatr. 2021;238(e1):94-101.e1. doi: 10.1016/j.jpeds.2021.07.003 [DOI] [PubMed] [Google Scholar]

[poi240110r18] 18.Barkovich AJ, Hajnal BL, Vigneron D, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998;19(1):143-149. [PMC free article] [PubMed] [Google Scholar]

[poi240110r19] 19.Garvey AA, El-Shibiny H, Yang E, Inder TE, El-Dib M. Differences between early and late MRI in infants with neonatal encephalopathy following therapeutic hypothermia. Pediatr Res. 2023;94(3):1011-1017. doi: 10.1038/s41390-023-02580-8 [DOI] [PubMed] [Google Scholar]

[poi240110r20] 20.Ouwehand S, Smidt LCA, Dudink J, et al. Predictors of outcomes in hypoxic-ischemic encephalopathy following hypothermia: a meta-analysis. Neonatology. 2020;117(4):411-427. doi: 10.1159/000505519 [DOI] [PubMed] [Google Scholar]

[poi240110r21] 21.Langeslag JF, Groenendaal F, Roosendaal SD, et al. ; PharmaCool Study Group . Outcome prediction and inter-rater comparison of four brain magnetic resonance imaging scoring systems of infants with perinatal asphyxia and therapeutic hypothermia. Neonatology. 2022;119(3):311-319. doi: 10.1159/000522629 [DOI] [PubMed] [Google Scholar]

[poi240110r22] 22.Trivedi SB, Vesoulis ZA, Rao R, et al. A validated clinical MRI injury scoring system in neonatal hypoxic-ischemic encephalopathy. Pediatr Radiol. 2017;47(11):1491-1499. [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r23] 23.Kang OH, Jahn P, Eichhorn JG, Dresbach T, Müller A, Sabir H. Correlation of different MRI scoring systems with long-term cognitive outcome in cooled asphyxiated newborns. Children (Basel). 2023;10(8):1295. doi: 10.3390/children10081295 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r24] 24.Ní Bhroin M, Kelly L, Sweetman D, et al. Relationship between MRI scoring systems and neurodevelopmental outcome at two years in infants with neonatal encephalopathy. Pediatr Neurol. 2022;126:35-42. doi: 10.1016/j.pediatrneurol.2021.10.005 [DOI] [PubMed] [Google Scholar]

[poi240110r25] 25.Sánchez Fernández I, Morales-Quezada JL, Law S, Kim P. Prognostic value of brain magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2017;32(13):1065-1073. doi: 10.1177/0883073817726681 [DOI] [PubMed] [Google Scholar]

[poi240110r26] 26.Machie M, Weeke L, de Vries LS, Rollins N, Brown L, Chalak L. MRI score ability to detect abnormalities in mild hypoxic-ischemic encephalopathy. Pediatr Neurol. 2021;116:32-38. doi: 10.1016/j.pediatrneurol.2020.11.015 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r27] 27.Thoresen M, Jary S, Walløe L, et al. MRI combined with early clinical variables are excellent outcome predictors for newborn infants undergoing therapeutic hypothermia after perinatal asphyxia. EClinicalMedicine. 2021;36:100885. doi: 10.1016/j.eclinm.2021.100885 [DOI] [PMC free article] [PubMed] [Google Scholar]

[poi240110r28] 28.Peeples ES, Rao R, Dizon MLV, et al. ; Children’s Hospitals Neonatal Consortium Hypoxic-Ischemic Encephalopathy Focus Group . Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy. Pediatrics. 2021;147(2):e2020022962. doi: 10.1542/peds.2020-022962 [DOI] [PubMed] [Google Scholar]

PERMALINK

NICHD Magnetic Resonance Brain Imaging Score in Term Infants With Hypoxic-Ischemic Encephalopathy

Seetha Shankaran, MD

Abbot R Laptook, MD

Carolina Guimaraes, MD

Johnathan Murnick, MD

Scott A McDonald, BS

Abhik Das, PhD

Carolyn M Petrie Huitema, MS, CCRP

Athina Pappas, MD

Rosemary D Higgins, MD

Susan R Hintz, MD, MS Epi

Kristin M Zaterka-Baxter, RN, BSN, CCRP

Krisa P Van Meurs, MD

Gregory M Sokol, MD

Lina F Chalak, MD

Tarah T Colaizy, MD, MPH

Uday Devaskar, MD

Jon E Tyson, MD, MPH

Anne Marie Reynolds, MD, MPH

Sara B DeMauro, MD, MSCE

Pablo J Sánchez, MD

Matthew M Laughon, MD, MPH

Waldemar A Carlo, MD

Kristi Watterberg, MD

Karen M Puopolo, MD, PhD

Anna Maria Hibbs, MD, MSCE

Shannon E G Hamrick, MD

C Michael Cotten, MD, MHS

John Barks, MD

Brenda B Poindexter, MD, MS

William E Truog, MD

Carl T D’Angio, MD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions

Trial Registration

Introduction

Methods

Setting and Participants

Outcomes

Statistical Analysis

Results

Table 1. Brain Injury on MRI Among Study Participants by Treatment Group.

Table 2. MRI Findings Comparing Usual Care vs Other 3 Treatment Groups.

Table 3. Association Between Magnetic Resonance Imaging Patterns of Injury and Outcomea.

Table 4. Outcomes With Any or Predominant WS vs BGT or PLIC Injury.

Table 5. Association Between Baseline Variables and Pattern of Injury With Outcomea.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Table 3. Association Between Magnetic Resonance Imaging Patterns of Injury and Outcome^a.

Table 5. Association Between Baseline Variables and Pattern of Injury With Outcome^a.