Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 2;7(12):e2449188.
doi: 10.1001/jamanetworkopen.2024.49188.

Predictors of Death or Severe Impairment in Neonates With Hypoxic-Ischemic Encephalopathy

Hannah C Glass  1   2   3 , Thomas R Wood  4 , Bryan A Comstock  5 , Adam L Numis  1   2 , Sonia L Bonifacio  6 , Marie-Coralie Cornet  2 , Fernando F Gonzalez  2 , Adriana Morell  1   2 , Sarah E Kolnik  4 , Yi Li  7 , Amit Mathur  8 , Ulrike Mietzsch  4 , Tai-Wei Wu  9 , Courtney J Wusthoff  10 , Marianne Thoresen  11   12 , Patrick J Heagerty  5 , Sandra E Juul  4 , Yvonne W Wu  1   2
Affiliations

Predictors of Death or Severe Impairment in Neonates With Hypoxic-Ischemic Encephalopathy

Hannah C Glass et al. JAMA Netw Open. .

Erratum in

  • Errors in Figures.
    [No authors listed] [No authors listed] JAMA Netw Open. 2025 Jan 2;8(1):e2459716. doi: 10.1001/jamanetworkopen.2024.59716. JAMA Netw Open. 2025. PMID: 39786781 Free PMC article. No abstract available.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Glass reported grants from National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS); she received personal fees for serving as a medicolegal expert witness and holding shares from Elemeno Health during the conduct of the study. Dr Numis reported grants from NINDS during the conduct of the study; he reported receiving medicolegal consulting fees outside the submitted work. Dr Cornet reported grants from National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr Li reported acting as an expert witness for medicolegal cases. Dr Mietzsch reported service on the medical advisory board for Hope for HIE. Dr Wusthoff reported receiving funding from her institution from NIH/NINDS and Medicure; she reported acting as an expert witness for medicolegal cases, receiving royalties from Cambridge Publishing for editing a textbook, receiving a stipend as Associate Editor for Neurology, and service on Data Safety Monitoring Board/Data Monitoring Committee for ICON plc and the University of Utah. Dr Heagerty reported receiving grants from NIH during the conduct of the study. Dr Juul reported receiving grants from NINDS and NICHD during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Models Predicting Death or Severe Neurodevelopmental Impairment (NDI) at Age 2 Years With Hypoxic-Ischemic Encephalopathy
DWI indicates diffusion-weighted imaging; EEG, electroencephalogram.
Figure 2.
Figure 2.. Neurodevelopmental Outcome Among the Neonates Not Predicted to Sustain Death or Severe Neurodevelopmental Impairment (NDI) and for the Full Cohort
In panel A, a total of 349 neonates who were alive after cooling and magnetic resonance imaging and not predicted to sustain death or severe NDI by number of deep gray regions (thalamus, caudate, globus pallidus/putamen) with injury on T1, T2, or diffusion-weighted imaging; B, includes the full cohort and adds 24-hour electroencephalogram (EEG) background results.
Figure 3.
Figure 3.. Neurodevelopment Among Neonates Not Predicted to Sustain Death or Severe Neurodevelopmental Disability (NDI) by Electroencephalography (EEG) Throughout Cooling
A total of 117 neonates are included in the cohort not predicted to sustain death or severe NDI.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Wu Y. Clinical features, diagnosis, and treatment of neonatal encephalopathy. UpToDate. Updated January 30, 2024. Accessed July 29, 2024. https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatm...
    1. Calabrese E, Wu Y, Scheffler AW, et al. . Correlating quantitative MRI-based apparent diffusion coefficient metrics with 24-month neurodevelopmental outcomes in neonates from the HEAL Trial. Radiology. 2023;308(3):e223262. doi:10.1148/radiol.223262 - DOI - PMC - PubMed
    1. Temko A, Doyle O, Murray D, Lightbody G, Boylan G, Marnane W. Multimodal predictor of neurodevelopmental outcome in newborns with hypoxic-ischaemic encephalopathy. Comput Biol Med. 2015;63:169-177. doi:10.1016/j.compbiomed.2015.05.017 - DOI - PubMed
    1. O’Sullivan MP, Looney AM, Moloney GM, et al. . Validation of altered umbilical cord blood microRNA expression in neonatal hypoxic-ischemic encephalopathy. JAMA Neurol. 2019;76(3):333-341. doi:10.1001/jamaneurol.2018.4182 - DOI - PMC - PubMed
    1. Juul SE, Voldal E, Comstock BA, et al. ; HEAL consortium . Association of high-dose erythropoietin with circulating biomarkers and neurodevelopmental outcomes among neonates with hypoxic ischemic encephalopathy: a secondary analysis of the HEAL randomized clinical trial. JAMA Netw Open. 2023;6(7):e2322131. doi:10.1001/jamanetworkopen.2023.22131 - DOI - PMC - PubMed

Publication types