Systematic review of terminology, definitions, and eligibility criteria in trials of neonatal encephalopathy, hypoxic-ischemic encephalopathy, and perinatal asphyxia

Authors

• Tim Hurley, Department of Pediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland.
• Fiona Quirke, Health Research Board Neonatal Encephalopathy PhD Training Network (NEPTuNE), Dublin, Ireland.
• Aoife Branagan, Department of Pediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland.
• Robert McCarthy, Department of Pediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland.
• Elaine Finucane, Evidence Synthesis Ireland, University of Galway, Galway, Ireland.
• Graham King, Department of Pediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland.
• Petek Eylul Taneri, Health Research Board - Trials Methodology Research Network (HRB-TMRN), University of Galway, Galway, Ireland.
• Mohamed El-Dib, Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
• Frank Harry Bloomfield, Liggins Institute, University of Auckland, Auckland, New Zealand.
• Beccy Maeso, James Lind Alliance, School of Healthcare Enterprise and Innovation, University of Southampton, Southampton, UK.
• Betsy Pilon, Hope for HIE, West Bloomfield, MI, USA.
• Sonia Bonifacio, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
• Courtney J. Wusthoff, Department of Neurology, University of California- Davis, Sacramento, CA, USA.
• Lina Chalak, Division of Neonatal-Perinatal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
• Cynthia F. Bearer, Division of Neonatology, Department of Pediatrics, Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
• Deirdre M. Murray, INFANT Research Centre, Cork, Ireland; Department of Pediatrics and Child Health, University College Cork, Cork, Ireland.
• Nadia Badawi, Cerebral Palsy Alliance Research Institute, Specialty of Child & Adolescent Health, Sydney Medical School, Faculty of Medicine & Health, The University of Sydney, Sydney, NSW, Australia.
• Suzann K. Campbell, Department of Physical Therapy, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL, USA.
• Sarah B. Mulkey, Prenatal Pediatrics Institute, Children's National Hospital, Washington DC, VA, USA.
• Pierre Gressens, Université Paris Cité, NeuroDiderot, Inserm, Paris, France.
• Donna M. Ferriero, Department of Pediatrics and Neurology, University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA, USA.
• Linda S. Vries, Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
• Karen Walker, Department of Newborn Care, Royal Prince Alfred Hospital, Sydney, Local Health District, Sydney, NSW, Australia.
• Sarah Kay, PEEPS-HIE, Manchester, UK.
• Geraldine B. Boylan, INFANT Research Centre, Cork, Ireland; Department of Pediatrics and Child Health, University College Cork, Cork, Ireland.
• Christopher Gale, Neonatal Medicine, School of Public Health, Faculty of Medicine, Chelsea and Westminster Campus, Centre for Paediatrics and Child Health, Imperial College London, London, UK.
• Nicola J. Robertson, Institute for Women's Health, University College London, London, UK.
• Mary D'Alton, Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.
• Tetyana H. Nesterenko, Department of Neonatology, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
• Ulrike Mietzsch, Division of Neonatology, Department of Pediatrics, University of Washington Medical School, Seattle Children's Hospital, Seattle, WA, USA.
• Alistair J. Gunn, Departments of Physiology and Paediatrics, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
• Karin B. Nelson, National Institutes of Health, National Institute of Neurological Diseases and Stroke, Bethesda, MD, USA.

Document Type

Journal Article

Publication Date

2-27-2026

Journal

Pediatric research

DOI

10.1038/s41390-025-04750-2

Abstract

BACKGROUND: Appropriate terminology and definitions of neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and perinatal asphyxia (PA) remain controversial. Participant criteria used in therapeutic hypothermia (TH) trials are frequently used as case definitions for NE/HIE/PA but studies are inconsistent. This review aims to assess variations in terminology and case participant criteria between trials for NE/HIE/PA. METHODS: Search strategy retrieved articles from databases (Embase, MEDLINE, CENTRAL, CDSR and WHO) for randomized controlled trials (RCTs) of interventions for NE/HIE/PA using any definition for NE/HIE/PA. Outcomes were a description of the terminology, definitions, and participant criteria. Two reviewers independently screened results. Qualitative results were synthesized in a narrative summary. RESULTS: The search provided 6768 results. 67 were included in the qualitative synthesis. HIE was the most frequently used term (56/67). NE was the least frequent (16/67). Some of the common inclusion criteria were Apgar scores (63/67), metabolic acidosis (58/67), and reduced level of consciousness (57/67). Most frequently employed exclusion criteria were prematurity (63/67), major congenital abnormalities (62/67), and identification beyond 6 h from birth (62/67). DISCUSSION: This review identified variations in terminology and in-trial participant criteria between studies. These results will inform a consensus process for developing a definition and case definition of NE/HIE/PA. IMPACT: Our article demonstrated significant variations in the terminology used to describe the condition of NE/HIE/PA, which demonstrates a need for more consistent definitions in terminology. A broad but meaningful definition of the condition would provide an inclusive approach while permitting subclassifications within the condition, and permitting comparisons and benchmarking across different settings. Developing consistency across these areas, as far as possible, would allow improved interpretation of interventions on long-term prognosis and greater generalizability of trial results.

APA Citation

Hurley, Tim; Quirke, Fiona; Branagan, Aoife; McCarthy, Robert; Finucane, Elaine; King, Graham; Taneri, Petek Eylul; El-Dib, Mohamed; Bloomfield, Frank Harry; Maeso, Beccy; Pilon, Betsy; Bonifacio, Sonia; Wusthoff, Courtney J.; Chalak, Lina; Bearer, Cynthia F.; Murray, Deirdre M.; Badawi, Nadia; Campbell, Suzann K.; Mulkey, Sarah B.; Gressens, Pierre; Ferriero, Donna M.; Vries, Linda S.; Walker, Karen; Kay, Sarah; Boylan, Geraldine B.; Gale, Christopher; Robertson, Nicola J.; D'Alton, Mary; Nesterenko, Tetyana H.; Mietzsch, Ulrike; Gunn, Alistair J.; and Nelson, Karin B., "Systematic review of terminology, definitions, and eligibility criteria in trials of neonatal encephalopathy, hypoxic-ischemic encephalopathy, and perinatal asphyxia" (2026). GW Authored Works. Paper 8660.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8660

Department

Neurology