Predictors of death or severe impairment in neonates with hypoxic-ischemic encephalopathy
Open accessAbstract
Importance: Outcomes after hypoxic-ischemic encephalopathy (HIE) are variable. Predicting death or severe neurodevelopmental impairment (NDI) in affected neonates is crucial for guiding management and parent communication. Objective: To predict death or severe NDI in neonates who receive hypothermia for HIE. Design, Setting, and Participants: This prognostic study included participants enrolled in a large US clinical trial conducted in US neonatal intensive care units who were born between January 2017 and October 2019 and followed up to age 2 years. Eligible participants were neonates with moderate-severe HIE born at 36 weeks or more gestation and with 2-year outcome data. Data were analyzed June 2023. External validation was performed with a UK cohort. Exposure: Clinical, electroencephalography (EEG), and magnetic resonance imaging (MRI) variables were curated and examined at 24 hours and following cooling. Main Outcome and Measures: Death or severe NDI at age 2 years. Severe NDI was defined as Bayley Scales of Infant Toddler Development cognitive score below 70, Gross Motor Function Classification System score of 3 or higher, or quadriparesis. Model performance metrics were derived from training, internal, and external validation datasets. Results: Among 424 neonates (mean [SD] gestational age, 39.1 [1.4] weeks; 192 female [45.3%]; 28 Asian [6.6%], 50 Black [11.8%], 311 White [73.3%]), 105 (24.7%) had severe encephalopathy at enrollment. Overall, 59 (13.9%) died and 46 (10.8%) had severe NDI. In the 24-hour model, the combined presence of 3 clinical characteristics-(1) severely abnormal EEG, (2) pH level of 7.11 or below, and (3) 5-minute Apgar score of 0-had a specificity of 99.6% (95% CI, 97.5%-100%) and a positive predictive value (PPV) of 95.2% (95% CI, 73.2%-99.3%). Validation model metrics were 97.9% (95% CI, 92.7%-99.8%) for internal specificity, with a PPV of 77.8% (95% CI, 43.4%-94.1%), and 97.6% (95% CI, 95.1%-99.0%) for external specificity, with a PPV of 46.2% (95% CI, 23.3%-70.8%). In the postcooling model, specificity for T1, T2, or diffusion-weighted imaging (DWI) abnormality in at least 2 of 3 deep gray regions (ie, thalamus, caudate, putamen and/or globus pallidus) plus a severely abnormal EEG within the first 24 hours was 99.1% (95% CI, 96.8%-99.9%), with a PPV of 91.7% (95% CI, 72.8%-97.8%). Internal specificity in this model was 98.9% (95% CI, 94.1%-100%), with a PPV of 92.9% (95% CI, 64.2%-99.0%); external specificity was 98.6% (95% CI, 96.5%-99.6%), with a PPV of 83.3% (95% CI, 64.1%-93.4%). Conclusions and Relevance: In this prognostic study of neonates with moderate or severe HIE who were treated with therapeutic hypothermia, simple models using readily available clinical, EEG, and MRI results during the hospital admission had high specificity and PPV for death or severe NDI at age 2 years.
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Outcome uncertainty remains for a majority of HIE patients even with the availability of magnetic resonance imaging (MRI).
“outcome uncertainty remains for a majority of HIE patients even with the availability of magnetic resonance imaging (MRI).”
From Association of the neonatal sequential organ failure assessment score with neurological outcomes in infants diagnosed with hypoxic-ischemic encephalopathy (2026) · cites this paper as [8]
The Discussion’s Limitations section (page not available) says the model’s high-specificity approach limits counseling about outcomes for children without its identified risk factors, even though MRI results provide some guidance. The Results’ Postcooling Model section reports 349 infants with MRI who were not predicted to have death or severe impairment, but it does not establish that outcomes remained uncertain for a majority of all HIE patients. (LLM, conf=0.78)
Experimental — accuracy not yet measuredProgress has been made in the detection of death or severe impairment.
“Progress has been made in the detection of death or severe impairment (7, 8)”
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Lagnese, K., Sheth, S., Vice, S., Rajderkar, D., Roig, J. C., Weiss, M., & Wynn, J. L. (2026) · Frontiers in Pediatrics · doi:10.3389/fped.2026.1844058
“Progress has been made in the detection of death or severe impairment (7, 8) and outcome uncertainty remains for a majority of HIE patients even with the availability of magnetic resonance imaging (MRI).”
Rieger, B., Iqbal, S., Garavatti, E., Shen, J., Morphew, T., & Inder, T. E. (2026) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2026.115148
- Authors
- Glass, H. C., Wood, T. R., Comstock, B. A., Numis, A. L., Bonifacio, S. L., Cornet, M.-C., Gonzalez, F. F., Morell, A., Kolnik, S. E., Li, Y., Mathur, A., Mietzsch, U., Wu, T.-W., Wusthoff, C. J., Thoresen, M., Heagerty, P. J., Juul, S. E., & Wu, Y. W.
- Affiliations
- University of California, San Francisco (US)
- Seattle Children's Hospital (US)
- University of Washington (US)
- Stanford University (US)
- Saint Louis University (US)
- University of Southern California (US)
- University of Oslo (NO)
- Corresponding author
- Glass, Hannah C.
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2024-12-05
- Volume
- 7
- Issue
- 12
- Pages
- e2449188
- ISSN
- 2574-3805 (ISSN-L)
- OpenAlex
- W4405062672
- Cited by
- 37
- References
- 63
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 1
- FWCI
- 25.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS104322, U01NS092553, U01NS092764)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Infant Development and Preterm Care
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Keywords
- hypoxic-ischemic encephalopathy, neonatal hypothermia, neurodevelopmental impairment, neonatal death, prognostic model, EEG, blood pH, Apgar score, magnetic resonance imaging, external validation, Gross Motor Function Classification System, tetraparesis, neonatal intensive care, term and near-term neonates, parental communication
- MeSH terms
- Child, Preschool, Electroencephalography, Female, Humans, Hypothermia, Induced, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Prognosis, Severity of Illness Index, Hypoxia-Ischemia, Brain, Neurodevelopmental Disorders
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