Moderate Hypoxic-ischemic Encephalopathy Research Articles

Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial

ObjectiveTo examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE).DesignDouble-blind pilot randomised controlled trial.SettingEight neonatal units in South Asia.PatientsNeonates (≥36 weeks) with moderate or severe...

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

ObjectiveTo evaluate associations between neurologic outcomes and early measurements of basal ganglia (BG) and thalamic (Th) perfusion using color Doppler ultrasonography (CDUS) in infants with hypoxic-ischemic encephalopathy (HIE). Study designProspective study of infants with mild (n=18), moderate (n=17), and severe HIE (n=14) and controls (n=17). Infants with moderate-severe HIE received therapeutic hypothermia (TH). CDUS was performed at 24-36h and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5 to 5 years. The primary outcome was the association between BG and Th perfusion and brain MRI injury. Secondary analyses focused on associations between perfusion measurements and admission neurologic examinations, MRI scores in infants treated with TH, and motor and sensory disability, or death. An exploratory analysis assessed the accuracy of BG and Th perfusion to predict brain MRI injury in infants treated with TH. ResultsIncreased BG and Th perfusion on CDUS was observed in infants with severe MRI scores and those with significant motor and neurosensory disability or death through 2.5 to 5 years (p<0.05). Infants with severe HIE showed increased BG and Th perfusion (p< .005) compared with infants with moderate HIE. No differences were identified between the between the control and mild HIE groups. Th perfusion ≥ 0.237 cm/sec (AUC of 0.824) correctly classified 80% of infants with severe MRI scores. ConclusionEarly dynamic CDUS of the BG and Th is a potential biomarker of severe brain injury in infants with HIE and may be a useful adjunct to currently used assessments.

Early Postnatal Administration of Erythropoietin and Its Association with Neurodevelopmental Outcomes and Incidence of Intraventricular Hemorrhage and Hypoxic-Ischemic Encephalopathy: A Four-Week Observational Study.

This study aimed to investigate the impact of early erythropoietin (EPO) administration on the neurodevelopment of newborns, specifically focusing on its effects on hypoxic-ischemic encephalopathy (HIE) and intraventricular hemorrhage (IVH). The primary objective was to determine whether early EPO administration could impact the short-term neurodevelopmental outcomes and provide safety in neonates at risk for neurodevelopmental disorders. Conducted at the "Louis Turcanu" Children's Emergency Clinical Hospital in Timisoara, Romania, this observational study included 121 neonates receiving EPO and 130 No EPO controls. EPO was administered within the first 48 h of life, with doses of 1000 U/kg that escalated to 2000 U/kg if necessary. Besides observing the occurrence of IVH and HIE, this study measured clinical and biochemical markers, including LDH, blood glucose, urea, creatinine, CPK, CRP, PCT, and erythropoietin levels alongside hematology and coagulation profiles. There were no significant differences in baseline characteristics between the groups. The EPO group showed significant reductions in LDH levels from days 1-3 to 7-10 (695.0 U/L to 442.0 U/L) and the APTT value (54.0 s) compared with the No EPO group (38.0 s). Notably, early EPO administration was associated with a significant decrease in HIE severity (beta coefficient: -0.38, p = 0.001). Additionally, lower gestational ages and hemoglobin levels correlated with increased severity of HIE. By week four, there was a significant reduction in moderate and severe HIE cases in the EPO group compared with controls (p = 0.001). Early administration of EPO in neonates significantly reduced the severity of IVH and HIE, suggesting its potential as a neuroprotective agent in neonatal care.

Incidence of encephalopathy and comorbidity in infants with perinatal asphyxia: a comparative prospective cohort study.

Programs that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life. An observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01-7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge. There were 9,537 births; 176 infants with ApH 7.01-7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01-7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01-7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated. Cord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01-7.10 cohort.

Correlation analysis between the amniotic fluid contamination and clinical grading of neonatal hypoxic–ischemic encephalopathy and biomarkers of brain damage

BackgroundAmniotic fluid contamination (AFC) is a risk factor for neonatal hypoxic ischemic encephalopathy (HIE); however, the correlation between AFC level and the incidence and clinical grading of HIE, in addition to relevant biomarkers of brain damage, have not been assessed.MethodsThis single-center observational study included 75 neonates with moderate-to-severe HIE. The neonates with HIE were divided into four subgroups according to the AFC level: normal amniotic fluid with HIE group (NAF-HIE), I°AFC with HIE group (I°AFC-HIE), II°AFC with HIE group (II°AFC-HIE), and III°AFC with HIE group (III°AFC-HIE). The control groups consisted of 35 healthy neonates. The clinical grading of neonatal HIE was performed according to the criteria of Sarnat and Sarnat. Serum tau protein and S100B were detected by enzyme-linked immunosorbent assay kits. Correlations of serum tau protein and S100B were evaluated using the Pearson correlation analysis.Results(1) The incidence of neonatal HIE in the NAF-HIE group was 20 cases (26. 7%), I°AFC-HIE was 13 cases (17.3%), II°AFC-HIE was 10 cases (13.3%), and III°AFC-HIE was 32 cases (42. 7%). The incidence of moderate-to-severe HIE in the I°–III°AFC-HIE groups was 73.3% (55/75). (2) In 44 cases with severe HIE, 26 cases (59.1%) occurred in the III°AFC-HIE group, which had a significantly higher incidence of severe HIE than moderate HIE (p < 0.05). In NAF-HIE and I°AFC-HIE groups, the incidence of moderate HIE was 45.2% and 29.0%, respectively, which was higher than that of severe HIE (X2 = 9.2425, p < 0.05; X2 = 5.0472, p < 0.05, respectively). (3) Serum tau protein and S100B levels in the HIE groups were significantly higher than in the control group (all p < 0.05), and were significantly higher in the III°AFC-HIE group than in the NAF-HIE and I°AFC-HIE groups (all p < 0.05). (4) Serum tau protein and S100B levels in the severe HIE group were significantly higher in the moderate HIE group (all p < 0.05). (5) Serum tau protein and S100B levels were significantly positively correlated (r = 0.7703, p < 0.0001).ConclusionAmong children with severe HIE, the incidence of III°AFC was higher, and the levels of serum tau protein and S100B were increased. AFC level might be associated with HIE grading.

Prediction of underweight, short stature, and microcephaly based on brain diffusion-weighted imaging sequence in neonates with stage.2 of hypoxic-ischemic encephalopathy: A follow-up study.

Hypoxic-ischemic encephalopathy (HIE), caused due to reduced oxygenation and brain blood flow, occurs in 1-8 per 1000 live full-term births in developed countries and up to 26 per 1000 live in the developing world. The growth status of survivors of birth HIE has not been evaluated sufficiently. This study evaluated, the growth parameters (weight, height, and head circumference) of neonates with Sarnat stage.2 of HIE at 6, 10, and 12 months and its relationship with findings of neonatal brain diffusion-weighted imaging (DWI) sequence. Medical records and growth parameters of 35 neonates with gestational age 34 wk who were admitted with stage.2 of HIE in Neonatal Intensive Care Unit of Shahid Sadoughi hospital, Yazd, Iran from March 2021-March 2022, and its relationship with neonatal brain DWI sequence finding was evaluated. 15 girls and 20 boys with a mean birth weight of 2880.3 221.8 gr were evaluated. Conventional magnetic resonance imaging and DWI were found to be abnormal in 6 (17.1%) and 18 neonates (51.4%). The most abnormal finding of DWI was high signal in basal ganglia/thalamus in 9 neonates (25.7%). Abnormal DWI is more frequent in neonates with seizures and low birth weight. Hospital stay days were more prolonged in neonates with abnormal DWI. Microcephaly at 12 months was more frequent in children with abnormal DWI. In survivors of moderate neonatal HIE, abnormal brain DWI sequence might predict inappropriate head growth, and need close medical and nutritional interventions for growth improvement.

Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy

Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden. To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia. This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023. Whole-blood RNA that underwent next-generation sequencing. The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort. The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14). This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic–Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes

To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Networks of cortical activity show graded responses to perinatal asphyxia.

Perinatal asphyxia often leads to hypoxic-ischemic encephalopathy (HIE) with a high risk of neurodevelopmental consequences. While moderate and severe HIE link to high morbidity, less is known about brain effects of perinatal asphyxia with no or only mild HIE. Here, we test the hypothesis that cortical activity networks in the newborn infants show a dose-response to asphyxia. We performed EEG recordings for infants with perinatal asphyxia/HIE of varying severity (n = 52) and controls (n = 53) and examined well-established computational metrics of cortical network activity. We found graded alterations in cortical activity networks according to severity of asphyxia/HIE. Furthermore, our findings correlated with early clinical recovery measured by the time to attain full oral feeding. We show that both local and large-scale correlated cortical activity are affected by increasing severity of HIE after perinatal asphyxia, suggesting that HIE and perinatal asphyxia are better represented as a continuum rather than the currently used discreet categories. These findings imply that automated computational measures of cortical function may be useful in characterizing the dose effects of adversity in the neonatal brain; such metrics hold promise for benchmarking clinical trials via patient stratification or as early outcome measures. Perinatal asphyxia causes every fourth neonatal death worldwide and provides a diagnostic and prognostic challenge for the clinician. We report that infants with perinatal asphyxia show specific graded responses in cortical networks according to severity of asphyxia and ensuing hypoxic-ischaemic encephalopathy. Early EEG recording and automated computational measures of brain function have potential to help in clinical evaluation of infants with perinatal asphyxia.

Volumetric changes in brain MRI of infants with hypoxic-ischemic encephalopathy and abnormal neurodevelopment who underwent therapeutic hypothermia

BackgroundHypoxic-ischemic encephalopathy (HIE) is a severe neonatal complication that can result in 40–60 % of long-term morbidity. Magnetic Resonance Imaging (MRI) is a noninvasive method which is usually performed before discharge to visually assess acquired cerebral lesions associated with HIE and severity of lesions possibly providing a guide for detecting adverse outcomes. This study aims to evaluate the impact of HIE on brain volume changes observed in MRI scans performed at a mean 10 days of life, which can serve as a prognostic indicator for abnormal neurodevelopmental (ND) outcomes at 18–24 months among HIE infants. MethodsWe retrospectively identified a cohort of HIE patients between June 2013 and March 2017. The inclusion criteria for therapeutic hypothermia (TH) were a gestational age ≥35 weeks, a birth weight ≥1800 g, and the presence of ≥ moderate HIE. Brain MRI was performed at a mean 10 days of life and brain volumes (total brain volume, cerebral volume, cerebellar volume, brain stem volume, and ventricle volume) were measured for quantitative assessment. At 18–24 months, the infants returned for follow-up evaluations, during which their cognitive, language, and motor skills were assessed using the Bayley Scales of Infant and Toddler Development III. ResultsThe study recruited a total of 240 infants between 2013 and 2017 for volumetric brain MRI evaluation. Among these, 83 were normal control infants, 107 were TH-treated HIE infants and 37 were HIE infants who did not receive TH due to contraindications. Clinical evaluation was further proceeded. We compared the brain volumes between the normal control infants (n = 83) with normal ND but TH-treated HIE infants (n = 76), abnormal ND TH-treated HIE infants (n = 31), and the severe HIE MRI group with no TH (n = 37). The abnormal ND TH-treated HIE infants demonstrated a significant decrease in brainstem volume and an increase in ventricle size (p < 0.001) (Table 4). Lastly, the severe brain MRI group who did not receive TH showed significantly smaller brain stem (p = 0.006), cerebellar (p = 0.006) and cerebrum volumes (p = 0.027), accompanied by larger ventricular size (p = 0.013) compared to the normal control group (Table 5). ConclusionIn addition to assessing the location of brain injuries in MRI scans, the reduction in brain stem volume coupled with an increase in ventricular volume in HIE infants may serve as a biomarker indicating severe HIE and adverse long-term ND outcomes among HIE infants who either received therapeutic hypothermia (TH) treatment or not.

Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes

To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18months of age. Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P<.001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P<.001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P<.001). The present study shows the complementary utility of cUS in the first 48hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial

ObjectiveTo study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).DesignSecondary...

Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy

To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2years of age in infants with hypoxic-ischemic encephalopathy (HIE). Newborn infants ≥36weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4hours of age) or late (>4hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age2. Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n=211 [42%]) compared with the late TT group (n=289 [58%]) were more likely to be inborn (23% vs 13%; P<.001) and have severe HIE (28% vs 19%; P=.03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR,1.05; 95% CI,0.85-0.30; P=.62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI,-6.1 to 0.5], language -3.3 [95% CI,-7.4 to 0.8], and motor -3.5 [95% CI,-7.3 to 0.3]). In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta. gov/study/NCT02811263.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial

Introduction: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. Methods: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 to 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks’ gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1,000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern, and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. Results: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR: 4.5–5.8). The incidence of injury to the deep gray nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n = 414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. Conclusion: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Duration of birth depression and neurodevelopmental outcomes after whole-body hypothermia for hypoxic ischemic encephalopathy in India, Sri Lanka and Bangladesh – an exploratory analysis of the HELIX trial

Effect of duration of birth depression on neurodevelopmental outcomes in low- and middle-income countries (LMICs) is not known. We examined the association of birth depression with brain injury, neurodevelopmental outcomes, and hypothermia after hypoxic ischemic encephalopathy (HIE) in south Asia. We compared cerebral magnetic resonance (MR) at 2 weeks, and adverse outcomes (death or moderate or severe disability) at 18 months in 408 babies with moderate or severe HIE who had long birth depression (positive pressure ventilation (PPV)>10min or Apgar score<6at 10min or cord pH<7.0) and short birth depression (PPV for 5-10min or Apgar score<6at 5min, but ≥6at 10min). Long depression group (n=201) had more severe HIE (32.8% versus 6.8%), mortality (47.5% versus 26.4%), death or disability at 18 months (62.2% versus 35.4%) (all p<0.001), MR injury (Odds ratio; 95% CI) to basal ganglia (2.4 (1.3, 4.1); p=0.003), posterior limb of internal capsule (2.3 (1.3, 4.3); p<0.001) and white matter (1.7 (1.1, 2.7); p=0.021), and lower thalamic N-acetylaspartate levels (7.69±1.84 versus 8.29±1.60); p=0.031) than short depression group (n=207). Three babies had no heartbeat at 5min, of which 1 died and 2 survived with severe disability. No significant interaction between the duration of birth depression and whole-body hypothermia was seen for any of the MR biomarker or clinical outcomes. Long birth depression was associated with more brain injury and adverse outcomes than short depression. Effect of hypothermia was not modified by duration of birth depression. National Institute for Health Research.

Neuro-Specific and Immuno-Inflammatory Biomarkers in Umbilical Cord Blood in Neonatal Hypoxic-Ischemic Encephalopathy

Objectives: The aim of the study was to evaluate neuronal injury and immuno-inflammatory biomarkers in umbilical cord blood (UCB) at birth, in cases with perinatal asphyxia with or without hypoxic-ischemic encephalopathy (HIE), compared with healthy controls and to assess their ability to predict HIE. Study Design: In this case-control study, term infants with perinatal asphyxia were recruited at birth. UCB was stored at delivery for batch analysis. HIE was diagnosed by clinical Sarnat staging at 24 h. Glial fibrillary acidic protein (GFAP), the neuronal biomarkers tau and neurofilament light protein (NFL), and a panel of cytokines were analyzed in a total of 150 term neonates: 50 with HIE, 50 with asphyxia without HIE (PA), and 50 controls. GFAP, tau, and NFL concentrations were measured using ultrasensitive single-molecule array (Simoa) assays, and a cytokine screening panel was applied to analyze the immuno-inflammatory and infectious markers. Results: GFAP, tau, NFL, and several cytokines were significantly higher in newborns with moderate and severe HIE compared to a control group and provided moderate prediction of HIE II/III (AUC: 0.681–0.827). Furthermore, the levels of GFAP, tau, interleukin-6 (IL-6), and interleukin-8 (IL-8) were higher in HIE II/III cases compared with cases with PA/HIE I. IL-6 was also higher in HIE II/III compared with HIE I cases. Conclusions: Biomarkers of brain injury and inflammation were increased in umbilical blood in cases with asphyxia. Several biomarkers were higher in HIE II/III versus those with no HIE or HIE I, suggesting that they could assist in the prediction of HIE II/III.

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

Objective: We 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 Design: Among 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. Result: 321/500 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). Conclusion: Placental 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.

Early Glycemic State and Outcomes of Neonates With Hypoxic-Ischemic Encephalopathy.

In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR). Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI. Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months.

5 Years Analysis of Therapeutic Hypothermia for HIE Neonates in NICUs of Ain Shams University

Background Therapeutic hypothermia (TH) is a standard of care for neonatal Hypoxic Ischemic Encephalopathy (HIE) in developed countries. Most data come from High income countries (HIC). Recently, experts suggest that the safety and efficacy data on cooling from HIC should not be extrapolated to Low and Middle Income Countries (LMIC). Aim of the Work Evaluation of the outcome of neonates with HIE treated with TH as a neuroprotective treatment who were admitted to NICUs of Ain Shams University from 1/2016 to 12/2020. Patients and Methods All HIE babies who were treated with TH were included. Retrospectively, patients’ medical paper notes of included babies were reviewed, recorded, and analyzed. Survived neonates were approached by telephone interview regarding parental views on their neurodevelopment and were offered a formal neurodevelopmental assessment for their babies using Bayley Scales III. Results A total 37 neonates (17 survived and 20 died) were included: 2 mild HIE (survived), 13 severe HIE (all died) and 22 moderate HIE (15 survived and 7 died) (mortality 54.1%). The most common causes of death are pulmonary hemorrhage (24.3%) and shock (18.9%). Of the 17 survivors, 6 patients couldn’t be reached while 9 patients had satisfactory neurodevelopmental progression as per their parents while 2 patients had poor outcome. Bayley III was done for only 3 babies: All had normal cognitive and language development. 2 of them had normal motor development while 1 patient had mild to moderate motor delay. Conclusion TH might not improve outcome of sever HIE but of great value on outcome of moderate HIE. Prospective RCTs are recommended to assess the role of TH as a neuroprotective agent for neonates with HIE in a low resource setting.

Evolution of Feeding and Developmental Outcomes in Infants With Moderate Hypoxic-Ischemic Encephalopathy: A Pilot Study.

The purpose of the study was to describe the evolution of outcomes among full-term infants with moderate hypoxic-ischemic encephalopathy (HIE); from their early swallowing and feeding abilities during hospitalization, to their later developmental outcomes at 6 and 12 months. Four participants with moderate HIE were recruited. Early feeding and swallowing were assessed using the Neonatal Feeding Assessment Scale and video fluoroscopic swallow studies. Developmental assessments were conducted at 6 and 12 months using the Rossetti Infant-Toddler Language Scale and Vineland-3 Scale. All participants displayed atypical outcomes throughout the study, including oropharyngeal dysphagia initially during hospitalization. All participants were discharged on oral feeds but some breastfeeding difficulties persisted. Variable but pervasive developmental delays were found among all participants at 6 and 12 months. This study emphasizes the need for consistent early intervention from the neonatal period onward, for all infants with moderate HIE. Future studies should use larger cohorts, longer follow-up, and correlational designs.