A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy

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Abstract

Background and Objective

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE.

Methods

We included full articles and book chapters published in English on PubMed with references to “hypoxic ischemic encephalopathy”, “birth asphyxia”, “therapeutic hypothermia”, or “neonatal encephalopathy”. We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials.

Key Content and Findings

Despite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration.

Conclusions

TH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.

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Most cited references 207

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Sex and gender: modifiers of health, disease, and medicine

Franck Mauvais-Jarvis, Noel C Bairey Merz, Peter Barnes … (2020)

Summary Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.

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Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.

Li Liu, Hope L Johnson, Simon Cousens … (2012)

Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916-1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610-0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252-0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977-1·176), diarrhoea (9·9%; 0·751 million, 0·538-1·031), and malaria (7·4%; 0·564 million, 0·432-0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339-0·547], 0·363 million [0·283-0·419], and 0·359 million [0·215-0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. The Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Cooling for newborns with hypoxic ischaemic encephalopathy.

Susan Jacobs, Marie Berg, Rod Hunt … (2013)

Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

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Author and article information

Journal

Journal ID (nlm-ta): Transl Pediatr

Journal ID (iso-abbrev): Transl Pediatr

Journal ID (publisher-id): TP

Title: Translational Pediatrics

Publisher: AME Publishing Company

ISSN (Print): 2224-4336

ISSN (Electronic): 2224-4344

Publication date (Electronic): 22 August 2023

Publication date (Print): 30 August 2023

Volume: 12

Issue: 8

Pages: 1552-1571

Affiliations

[1 ]deptDepartment of Neurology , University of Texas McGovern Medical School , Houston, TX, USA;

[2 ]deptDepartment of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience , Baylor College of Medicine , Houston, TX, USA

Author notes

Contributions: (I) Conception and design: All authors; (II) Administrative support: LD McCullough; (III) Provision of study materials or patients: LD McCullough; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Viola Caretti, MD, PhD. Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, 6621 Fannin St, Houston, TX 77030, USA; Department of Neurology, University of Texas McGovern Medical School, Houston, TX 77030, USA. Email: Viola.Caretti@ 123456uth.tmc.edu .

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ORCID: Janelle M. Korf, 0000-0003-0246-6894; Louise D. McCullough, 0000-0002-8050-1686; Viola Caretti, 0000-0002-6702-1426.

Article

Publisher ID: tp-12-08-1552

DOI: 10.21037/tp-23-253

PMC ID: 10485647

PubMed ID: 37692539

SO-VID: 9c9d34c4-6f10-4c41-9c2b-d1888034a4c5

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

History

Date received : 22 April 2023

Date accepted : 08 August 2023

Funding

Funded by: American Heart Association

Award ID: No. 916595

Funded by: the American Heart Association

Award ID: 20MER-AQ15 IT35120410

Funded by: the NINDS

Award ID: R01 NS094543 and R37NS096493

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A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy

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Abstract

Background and Objective

Methods

Key Content and Findings

Conclusions

Related collections

Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 207

Sex and gender: modifiers of health, disease, and medicine

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.

Cooling for newborns with hypoxic ischaemic encephalopathy.

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Cited by 3

Most referenced authors 2,507