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Cognitive outcomes in late childhood and adolescence of neonatal hypoxic-ischemic encephalopathy.

ABSTRACT: Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal encephalopathy with a global incidence of approximately 1 to 8 per 1,000 live births. Neonatal encephalopathy can cause neurodevelopmental and cognitive impairments in survivors of hypoxic-ischemic insults with and without functional motor deficits. Normal neurodevelopmental outcomes in early childhood do not preclude cognitive and behavioral difficulties in late childhood and adolescence because cognitive functions are not yet fully developed at this early age. Therapeutic hypothermia has been shown to significantly reduced death and severe disabilities in term newborns with HIE. However, children treated with hypothermia therapy remain at risk for cognitive impairments and follow-up is necessary throughout late childhood and adolescence. Novel adjunctive neuroprotective therapies combined with therapeutic hypothermia may enhance the survival and neurodevelopmental outcomes of infants with HIE. The extent and severity of brain injury on magnetic resonance imaging might predict neurodevelopmental outcomes and lead to targeted interven tions in children with a history of neonatal encephalopathy. We provide a summary of the long-term cognitive outcomes in late childhood and adolescence in children with a history of HIE and the association between pattern of brain injury and neurodevelopmental outcomes.

SUBMITTER: Lee BL

PROVIDER: S-EPMC8650814 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy.

Project description:Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future.

| S-EPMC4613313 | biostudies-literature

Association between sedation-analgesia and neurodevelopment outcomes in neonatal hypoxic-ischemic encephalopathy.

Project description:OBJECTIVE:To evaluate the association between sedation-analgesia (SA) during initial 72?h and death/disability at 18 months of age in neonatal hypoxic-ischemic encephalopathy (HIE). DESIGN:This was a secondary analysis of the NICHD therapeutic hypothermia (TH) randomized controlled trial in moderate or severe HIE. Receipt of SA and anticonvulsant medications at five time points were considered: prior to and at baseline, 24, 48, and 72?h of TH or normothermia. Disability was defined as mental developmental index <85, cerebral palsy, blindness, hearing impairment, or Gross Motor Function Classification System 2-5. RESULTS:Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the five time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only, and 69 (33%) received both SA and anticonvulsants. SA category drugs were not administered in 57% of infants while 18% received SA at ?3 time points; 72% infants received anticonvulsants during 72?h of intervention. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with (48 and 65%) or without (37 and 58%) SA, compared to groups with no exposure (14 and 34%) or SA (13 and 32%) alone. Severe HIE (aOR 3.60; 1.59-8.13), anticonvulsant receipt (aOR 2.48; 1.05-5.88), and mechanical ventilation (aOR 7.36; 3.15-17.20) were independently associated with 18-month death/disability, whereas TH (aOR 0.28; 0.13-0.60) was protective. SA exposure showed no association with outcome. CONCLUSIONS:The risk benefits of SA in HIE need further investigation.

| S-EPMC6092226 | biostudies-literature

Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy.

Project description:ObjectiveWe aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes.Study designAmong 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site.Result321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56).ConclusionPlacental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.

| S-EPMC10711751 | biostudies-literature

Language in children with neonatal hypoxic-ischemic encephalopathy.

Project description:Introduction Neonatal hypoxic-ischemic encephalopathy (NHIE) is a common neurologic injury, and it may compromise the child's language and cognition. Understanding the process of language acquisition becomes possible with concise knowledge about children's global development. Objective The aim of this study was to observe if language acquisition and development are impaired in children with NHIE. Methods Seventy children with NHIE from 1 to 24 months old were analyzed in a Pediatric Neurology Service of Hospital of Porto Alegre, South of Brazil using the Brunet-Lezine Scale. Statistical analysis used SPSS 13.0 software. Results Twenty-four (60%) of the subjects were boys, with mean gestational age of 35.8 weeks (standard deviation of 4.6) and mean Apgar score of 6.0 at 1 minute and 7.1 at 5 minutes. The variables age versus language showed significant inverse correlation (r = - 0.566; p = 0.028). As the subjects aged, language tasks became more specific and dependent on the subject's direct action, rather than the subjective interpretation of their guardian. This correlation seems to be closely associated with scale configuration and with consequences of neurologic disorder, evincing the delays in language development. Conclusion This study achieved the goals proposed and highlights the necessity of greater attention by professionals to language skills during the initial period of child development.

| S-EPMC4297029 | biostudies-other

Vitamin D insufficiency in neonatal hypoxic-ischemic encephalopathy.

Project description:BackgroundVitamin D has neuroprotective and immunomodulatory properties, and deficiency is associated with worse stroke outcomes. Little is known about effects of hypoxia-ischemia or hypothermia treatment on vitamin D status in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized vitamin D metabolism would be dysregulated in neonatal HIE altering specific cytokines involved in Th17 activation, which might be mitigated by hypothermia.MethodsWe analyzed short-term relationships between 25(OH) and 1,25(OH)2 vitamin D, vitamin D binding protein, and cytokines related to Th17 function in serum samples from a multicenter randomized controlled trial of hypothermia 33 °C for 48 h after HIE birth vs. normothermia in 50 infants with moderate to severe HIE.ResultsInsufficiency of 25(OH) vitamin D was observed after birth in 70% of infants, with further decline over the first 72 h, regardless of treatment. 25(OH) vitamin D positively correlated with anti-inflammatory cytokine IL-17E in all HIE infants. However, Th17 cytokine suppressor IL-27 was significantly increased by hypothermia, negating the IL-27 correlation with vitamin D observed in normothermic HIE infants.ConclusionSerum 25(OH) vitamin D insufficiency is present in the majority of term HIE neonates and is related to lower circulating anti-inflammatory IL-17E. Hypothermia does not mitigate vitamin D deficiency in HIE.

| S-EPMC5509506 | biostudies-literature

Emerging therapeutic strategies in hypoxic-ischemic encephalopathy: a focus on cognitive outcomes.

Project description:Perinatal hypoxia-ischemia represents a significant risk to CNS development, leading to high mortality rates, diverse damages, and persistent neurological deficits. Despite advances in neonatal medicine in recent decades, the incidence of HIE remains substantial. Motor deficits can manifest early, while cognitive impairments may be diagnosed later, emphasizing the need for extended follow-up. This review aims to explore potential candidates for therapeutic interventions for hypoxic-ischemic encephalopathy (HIE), with a focus on cognitive deficits. We searched randomized clinical trials (RCT) that tested drug treatments for HIE and evaluated cognitive outcomes. The results included studies on erythropoietin, melatonin, magnesium sulfate, topiramate, and a combination of vitamin C and ibuprofen. Although there are several indications of the efficacy of these drugs among animal models, considering neuroprotective properties, the RCTs failed to provide complete effectiveness in the context of cognitive impairments derived from HIE. More robust RCTs are still needed to advance our knowledge and to establish standardized treatments for HIE.

| S-EPMC10925695 | biostudies-literature

Evolution of encephalopathy during whole body hypothermia for neonatal hypoxic-ischemic encephalopathy.

Project description:To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability.On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability.

| S-EPMC3299861 | biostudies-other

Different antecedents and neonatal condition in neonatal arterial ischemic stroke and hypoxic-ischemic neonatal encephalopathy.

Project description:ObjectiveTo define similarities and differences between neonatal arterial ischemic stroke (NAIS) and hypoxic-ischemic neonatal encephalopathy (HINE).MethodsA retrospective case-control study was conducted of neonates born at 35 weeks or more and weighing 1800 g or more at a tertiary care university hospital, between 2005 and 2016, with NAIS (group A), perinatal asphyxia (PA) with Stage II-III HINE (group B), and PA with or without Stage I HINE (group C). Ante- and intrapartum data, neonatal characteristics, and placental histopathology were compared.ResultsEleven neonates were identified in group A, 10 in group B, and 227 in group C. Sentinel events occurred exclusively in groups B (80%) and C (41.4%). Umbilical cord blood gas values and Apgar score were worse in groups B and C compared to group A. No group A neonates required resuscitation at birth, whereas all group B and one-third of group C neonates did. Seizures developed only in neonates in groups A and B. One neonatal death occurred in group A. There were no significant differences in placental histopathology.ConclusionNAIS and PA/HINE cases have different intrapartum and neonatal features. PA does not seem necessary for the occurrence of NAIS. More research is needed regarding associated placental abnormalities.

| S-EPMC9290624 | biostudies-literature

Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

Project description:To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy.Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed.Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%.The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age.ClinicalTrials.gov: NCT00005772.

| S-EPMC4700815 | biostudies-literature

Mood disorders in children following neonatal hypoxic-ischemic encephalopathy.

Project description:BackgroundFew studies on the consequences following newborn hypoxic-ischemic encephalopathy (NHIE) assess the risk of mood disorders (MD), although these are prevalent after ischemic brain injury in adults.ObjectiveTo study the presence of MD in children survivors of NHIE.Methods14 children survivors of NHIE treated with hypothermia and without cerebral palsy and 15 healthy children without perinatal complications were studied aged three to six years for developmental status (Ages and Stages Questionnaire 3 [ASQ-3]) and for socio-emotional status (Preschool Symptom Self-Report [PRESS] and Child Behavior Checklist [CBCL] 1.5-5 tests). Maternal depression was assessed using Montgomery-Asberg Depression Rating Scale (MADRS). Socio-economic factors such as parental educational level or monthly income were also studied.ResultsNHIE children did not present delay but scored worse than healthy children for all ASQ3 items. NHIE children showed higher scores than healthy children for PRESS as well as for anxious/depressive symptoms and aggressive behavior items of CBCL. In addition, in three NHIE children the CBCL anxious/depressive symptoms item score exceeded the cutoff value for frank pathology (P = 0.04 vs healthy children). There were no differences in the other CBCL items as well as in maternal MADRS or parental educational level or monthly income. Neither ASQ3 scores nor MADRS score or socio-economic factors correlated with PRESS or CBCL scores.ConclusionsIn this exploratory study children survivors of NHIE showed increased risk of developing mood disturbances, in accordance with that reported for adults after brain ischemic insults. Considering the potential consequences, such a possibility warrants further research.

| S-EPMC8797213 | biostudies-literature

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