Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review

doi:10.1016/j.earlhumdev.2018.02.007

Early Human Development

Volume 120, May 2018, Pages 80-87

https://doi.org/10.1016/j.earlhumdev.2018.02.007 Get rights and content

Abstract

Aims

Hypoxic ischaemic encephalopathy (HIE) remains a significant cause of long term neurodisability despite therapeutic hypothermia (TH). Infants with mild HIE, representing 50% of those with HIE, are perceived as low risk and are currently not eligible for TH [1]. This review examines the available evidence of outcome in term infants with mild HIE.

Methods

Medline, Embase and Cochrane Clinical Trials databases were searched in March 2017.

Studies with well-defined HIE grading at birth and standardised neurodevelopmental assessment at ≥18 months were included. Abnormal outcome was defined as death, cerebral palsy or standardised neurodevelopmental test score more than 1 standard deviation below the mean.

Result

Twenty studies were included. Abnormal outcome was reported in 86/341 (25%) of infants. There was insufficient evidence to examine the effect of TH on outcome.

Conclusion

A significant proportion of infants with mild HIE have abnormal outcome at follow up.

Section snippets

Background

Neonatal hypoxic ischaemic encephalopathy (HIE) remains one of the leading causes of neonatal mortality and long term disability worldwide occurring in 3–5 per 1000 live births [1]. Outcome depends on the severity of the initial insult, traditionally graded using the clinical Sarnat Grading system, where infants with a mild Sarnat grade are felt to have an excellent prognosis without long term disability [2]. For this reason, many studies do not examine mild HIE beyond the newborn period, and

Methods

Cochrane Systematic Review methods were used [6], adopting search strategies described by the Neonatal Cochrane Review Group [7]. However, since much of the literature on mild HIE outcome is inadvertently reported in studies with a broader focus, several scoping literature searches were made to identify key known reference papers prior to finalising the search strategy used for this review. An initial narrow search for HIE and outcome excluded many of the EEG, MRI and drug trials that did

Results

Twenty studies were included in this review. Quality assessment is presented in Supplementary S3 Table. 14 articles were rated high, 6 were rated medium quality with none yielding a low score.

Following this quality assessment, no articles were excluded leaving a total of 20 articles for systematic review. Two of the RCT's were multi-centre international trials and encompassed global recruitment. Eight studies were conducted in Europe, 7 in Asia, 2 in Australasia and 1 in North America. The

Discussion

We have shown that across the 16 available observation studies outcome was reported in 250 mild HIE infants. Of this group, 56 (22%) had an abnormal outcome at 18 months of age or older. By combining both RCT and non-RCT studies, outcome was reported in a total of 341 mild HIE infants, with one quarter having abnormal outcome. This review adds to the growing evidence that the outcome for infants outside cooling criteria, and with mild HIE is not normal. Disability may appear to be less severe

Conclusion and key guidelines

This review has shown that approximately one quarter of infants with mild HIE have an abnormal outcome defined as death, motor or developmental delay at follow up to 18 months. There is insufficient evidence to recommend induced hypothermia in this patient group.

Research directions

A well-constructed RCT of TH in mild HIE is urgently needed to give clinicians an evidence base to guide therapy in this neglected group.

This work has been supported by a Science Foundation Ireland Research Centre Award (INFANT – 12/RC/2272) and the Irish Health Research Board Award (HRB; CSA/2012/40).

Conflict of interest statement

The authors declare no conflict of interest.

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Neonatal hypoxia impairs serotonin release and cognitive functions in adult mice
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Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT_1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT_1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.
Blockade of connexin hemichannels with tonabersat protects against mild hypoxic ischemic brain injury in neonatal rats
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There is growing evidence that infants with mild hypoxic-ischemic (HI) encephalopathy have increased risk of brain injury and adverse neurodevelopmental outcomes. Currently, there is no approved treatment for these infants. It was previously shown that blocking connexin 43 hemichannels is neuroprotective in models of moderate to severe HI injury. However, it is yet to be established whether these channels play a role in the evolution of mild HI brain injury, and whether blocking these channels after mild HI is neuroprotective.
HI was induced in postnatal day 10 rats of both sexes by right carotid artery ligation followed by 80 min of hypoxia in 8% oxygen. Pups receiving HI were randomised to receive intraperitoneal injections of either saline, vehicle (2-hydroxypropyl-beta-cyclodextrin polyethylene glycol-400), or tonabersat (2 mg/kg), at 60 min, 24 h, and 48 h after hypoxia. Seven days after HI, brains were harvested for measurement of volume loss and histological analysis.
HI resulted in a significant reduction in hemispheric, hippocampal, and white matter volumes, which were significantly attenuated after treatment with tonabersat. HI was also associated with a significant reduction in numbers of neurons in the CA1 and CA3 hippocampal regions, a reduction in the numbers of oligodendrocytes in the corpus callosum, and an increase in the number of astrocytes in both regions, which were significantly attenuated by tonabersat treatment. There were no differences in rectal temperatures between tonabersat- and vehicle-treated rat pups.
Blockade of connexin hemichannels with tonabersat significantly reduced mild HI injury in the hippocampus and white matter, without causing hypothermia.
Neonatal cortical activity organizes into transient network states that are affected by vigilance states and brain injury
2023, NeuroImage
Early neurodevelopment is critically dependent on the structure and dynamics of spontaneous neuronal activity; however, the natural organization of newborn cortical networks is poorly understood. Recent adult studies suggest that spontaneous cortical activity exhibits discrete network states with physiological correlates. Here, we studied newborn cortical activity during sleep using hidden Markov modeling to determine the presence of such discrete neonatal cortical states (NCS) in 107 newborn infants, with 47 of them presenting with a perinatal brain injury. Our results show that neonatal cortical activity organizes into four discrete NCSs that are present in both cardinal sleep states of a newborn infant, active and quiet sleep, respectively. These NCSs exhibit state-specific spectral and functional network characteristics. The sleep states exhibit different NCS dynamics, with quiet sleep presenting higher fronto-temporal activity and a stronger brain-wide neuronal coupling. Brain injury was associated with prolonged lifetimes of the transient NCSs, suggesting lowered dynamics, or flexibility, in the cortical networks. Taken together, the findings suggest that spontaneously occurring transient network states are already present at birth, with significant physiological and pathological correlates; this NCS analysis framework can be fully automatized, and it holds promise for offering an objective, global level measure of early brain function for benchmarking neurodevelopmental or clinical research.
Ten years since the introduction of therapeutic hypothermia in neonates with perinatal hypoxic-ischaemic encephalopathy in Spain
2023, Neurologia
Se cumple ahora más de una década del inicio de la hipotermia terapéutica (HT) en España, la única intervención neuroprotectora que ha venido a ser práctica estándar en el tratamiento de la encefalopatía hipóxico-isquémica perinatal (EHI). El objetivo de este artículo es ofrecer un panorama actual y presentar las controversias surgidas alrededor de la aplicación de esta terapia.
En esta década se ha implantado con éxito la HT en la gran mayoría de los hospitales terciarios de España y más del 85% de los recién nacidos con EHI moderada-grave reciben esta terapia. Entre los aspectos que pueden mejorar la eficacia de la HT están su inicio precoz dentro de las primeras 6 h de vida y el control de factores comórbidos asociados a la asfixia perinatal. En los pacientes con EHI moderada el inicio después de las 6 h parece mantener cierta eficacia neuroprotectora. Una duración de la HT mayor de 72 horas o un enfriamiento más profundo no ofrecen mayor eficacia neuroprotectora y aumentan el riesgo de efectos adversos. Aspectos no bien aclarados aún son la sedación durante la HT y la aplicación de esta intervención a los neonatos con EHI leve y en otros escenarios. La información pronóstica y su marco temporal es uno de los aspectos más desafiantes.
La HT es universal en países con recursos económicos, aunque existen puntos de controversia no resueltos. Si bien es un tratamiento generalizado en nuestro país, falta disponer de dispositivos para el traslado de estos pacientes y su centralización.
More than a decade has passed since therapeutic hypothermia (TH) was introduced in Spain; this is the only neuroprotective intervention that has become standard practice in the treatment of perinatal hypoxic-ischaemic encephalopathy (HIE). This article aims to provide a current picture of the technique and to address the controversies surrounding its use.
In the last 10 years, TH has been successfully implemented in the vast majority of tertiary hospitals in Spain, and more than 85% of newborns with moderate or severe HIE currently receive the treatment. The factors that can improve the efficacy of TH include early treatment onset (first 6 hours of life) and the control of comorbid factors associated with perinatal asphyxia. In patients with moderate HIE, treatment onset after 6 hours seems to have some neuroprotective efficacy. TH duration longer than 72 hours or deeper hypothermia do not offer greater neuroprotective efficacy, but instead increase the risk of adverse effects. Unclarified aspects are the sedation of patients during TH, the application of the treatment in infants with mild HIE, and its application in other scenarios. Prognostic information and time frame are one of the most challenging aspects.
TH is universal in countries with sufficient economic resources, although certain unresolved controversies remain. While the treatment is widespread in Spain, there is a need for cooling devices for the transfer of these patients and their centralisation.
Hypoxic-Ischemic Encephalopathy: Changing Outcomes Across the Spectrum
2023, Clinics in Perinatology
Brain Injury in Infants Evaluated for, But Not Treated with, Therapeutic Hypothermia
2023, Journal of Pediatrics

View all citing articles on Scopus

View full text

Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome - A systematic review

Abstract

Aims

Methods

Result

Conclusion

Section snippets

Background

Methods

Results

Discussion

Conclusion and key guidelines

Research directions

Conflict of interest statement

J. Pediatr.

J. Pediatr.

Pediatr. Neurol.

Pediatr. Neurol.

Eur. J. Paediatr. Neurol.

Eur. J. Paediatr. Neurol.

Eur. J. Paediatr. Neurol.

Pediatr. Neurol.

Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990

Pediatr. Res.

Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study

Arch. Neurol.

Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy

Pediatrics

Serial MRI and neurodevelopmental outcome in 9- to 10-year-old children with neonatal encephalopathy

J. Pediatr.

The frequency and severity of magnetic resonance imaging abnormalities in infants with mild neonatal encephalopathy

J. Pediatr.

Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [Updated March 2011]

Review Manager (RevMan)

ENDNOTE™ [Internet]

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

PLoS Med.

CONSORT Guidelines

Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy