Causes and Terminology in Neonatal Encephalopathy: What is in a Name? Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy or Perinatal Asphyxia.

Neurologic depression in term/near-term neonates (neonatal encephalopathy, NE) is uncommon with modern obstetric care. Asphyxial birth, with or without co-factors, accounts for a minority of NE, while maldevelopment (congenital malformations, growth aberrations, genetic, metabolic and placental abnormalities) plays an enlarging role in identifying etiologic subgroups of NE. The terms NE and hypoxic-ischemic encephalopathy (HIE) have not been employed uniformly, hampering research and clinical care. The authors propose the term NE as an early working-diagnosis, to be supplemented by a diagnosis of NE due to HIE or to other factors, as a final diagnosis once workup is complete.

Advances in Electroencephalographic Biomarkers of Neonatal Hypoxic Ischemic Encephalopathy.

Electroencephalography (EEG) is a key objective biomarker of newborn brain function, delivering critical, cotside insights to aid the management of encephalopathy. Access to continuous EEG is limited, forcing reliance on subjective clinical assessments. In hypoxia ischaemia, the primary cause of encephalopathy, alterations in EEG patterns correlate with. injury severity and evolution. As HIE evolves, causing secondary neuronal death, EEG can track injury progression, informing neuroprotective strategies, seizure management and prognosis. Despite its value, challenges with interpretation and lack of on site expertise has limited its broader adoption. Technological advances, particularly in digital EEG and machine learning, are enhancing real-time analysis. This will allow EEG to expand its role in HIE diagnosis, management and outcome prediction.

Key Inflammatory Biomarkers in Perinatal Asphyxia: A Comprehensive Review.

This article summarizes the current evidence regarding inflammatory biomarkers (placental and postnatal) and provides a comprehensive understanding of their roles: (1) diagnostic accuracy to predict the severity of hypoxic-ischemia encephalopathy (HIE), (2) value in assessing treatment responses, and (3) prediction of both short- and long-term neurodevelopmental outcomes. In the early critical stages of perinatal asphyxia, inflammatory biomarkers may guide clinical decision-making. Additional research is required to increase our understanding of the optimal utility of biomarkers to predict the severity, evolution, and developmental outcomes after exposure to HIE.

Amplitude-Integrated EEG in Infants at Risk of Hypoxic-Ischemic Encephalopathy: A Feasibility Study in Road and Air Transport in Western Australia.

Infants at risk of HIE require early identification and initiation of therapeutic hypothermia (TH). Earlier treatment with TH is associated with better outcomes. aEEG is frequently used when making the decision whether to commence TH. As this is often limited to tertiary centers, TH may be delayed if the infant requires transport to a center that provides it. We aimed to provide a method for the application of amplitude-integrated electroencephalogram (aEEG) and to determine the feasibility of acquiring clinically meaningful information during transport. All infants ≥35 weeks, at risk of HIE at referral, were eligible for inclusion. Scalp electrodes were placed in the C3-C4; P3-P4 position on the infant's scalp and connected to the aEEG amplifier. The aEEG amplifier was, in turn, connected to a clinical tablet computer with EEG software to collect and analyze aEEG information. Recordings were reviewed by the chief principal investigator and two independent reviewers (blinded) for background trace and artifact. Predefined criteria for data quality were set to movement artifacts and software impedance notifications. Surveys were completed by healthcare staff and parents for acceptability and ease of use.

Artificial Intelligence Outcome Prediction in Neonates with Encephalopathy (AI-OPiNE).

Purpose To develop a deep learning algorithm to predict 2-year neurodevelopmental outcomes in neonates with hypoxic-ischemic encephalopathy using MRI and basic clinical data. Materials and Methods In this study, MRI data of term neonates with encephalopathy in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial (ClinicalTrials.gov: NCT02811263), who were enrolled from 17 institutions between January 25, 2017, and October 9, 2019, were retrospectively analyzed. The harmonized MRI protocol included T1-weighted, T2-weighted, and diffusion tensor imaging. Deep learning classifiers were trained to predict the primary outcome of the HEAL trial (death or any neurodevelopmental impairment at 2 years) using multisequence MRI and basic clinical variables, including sex and gestational age at birth. Model performance was evaluated on test sets comprising 10% of cases from 15 institutions (in-distribution test set, n = 41) and 10% of cases from two institutions (out-of-distribution test set, n = 41). Model performance in predicting additional secondary outcomes, including death alone, was also assessed. Results For the 414 neonates (mean gestational age, 39 weeks ± 1.4 [SD]; 232 male, 182 female), in the study cohort, 198 (48%) died or had any neurodevelopmental impairment at 2 years. The deep learning model achieved an area under the receiver operating characteristic curve (AUC) of 0.74 (95% CI: 0.60, 0.86) and 63% accuracy in the in-distribution test set and an AUC of 0.77 (95% CI: 0.63, 0.90) and 78% accuracy in the out-of-distribution test set. Performance was similar or better for predicting secondary outcomes. Conclusion Deep learning analysis of neonatal brain MRI yielded high performance for predicting 2-year neurodevelopmental outcomes. Keywords: Convolutional Neural Network (CNN), Prognosis, Pediatrics, Brain, Brain Stem Clinical trial registration no. NCT02811263 Supplemental material is available for this article. © RSNA, 2024 See also commentary by Rafful and Reis Teixeira in this issue.

Evaluation of Myocardial Injury Using Serum Cardiac Troponin-I in Asphyxiated Neonates at Enugu State University Teaching Hospital, Enugu, South-East Nigeria.

BACKGROUND: The burden of perinatal asphyxia remains high in our environment and when asphyxia is severe, vital organs are affected, with resultant multiorgan hypoxic-iscahemic injury to the heart, the brain, adrenals and other organs. STUDY AIM: To evaluate for myocardial injury in asphyxiated term neonates with hypoxic ischaemic encephalopathy using serum cardiac troponin-I (cTnI). METHODS: The study was a hospital-based descriptive cross-sectional study involving sixty term asphyxiated neonates and sixty gestational age-and sex-matched controls. The subjects were term neonates with five-minute Apgar score ≤ 6 and HIE while the controls were healthy term neonates with five-minute Apgar score > 6. Five-minute Apgar score was utilized to classify asphyxia into mild, moderate and severe asphyxia. The degree of encephalopathy was determined by modified Sarnat and Sarnat criteria. The serum cTnI was measured in subjects and controls at 12-24 hours of life using Enzyme-linked immunosorbent assay technique. The serum bilirubin levels were also measured in participants to exclude hyperbilirubinemia. RESULTS: The median serum cTnI levels was significantly higher in the subjects (0.56ng/mL; 0.25-0.94ng/mL) than in the controls (0.50ng/mL; 0.00-0.67ng/mL), respectively; p=0.001. Similarly, the median serum cTnI level in HIE stage II (0.56ng/mL; 0.38-0.72ng/mL) or III (0.56ng/ml; 0.50-0.94ng/mL) was also significantly higher than the median value in HIE stage I (0.38ng/mL;0.25-0.72ng/mL) or in controls (0.50ng/mL; 0.00-0.67ng/mL); p<0.001. There was significant positive correlation between serum cTnI levels and severity of HIE in asphyxiated neonates (rs = 0.505, p < 0.001). CONCLUSION: serum cTnI levels were elevated in severely asphyxiated neonates with HIE. The concentration of serum cTnI demonstrated significant positive correlation with HIE severity. Hence, the presence of HIE in asphyxiated neonates should prompt an evaluation for myocardial injury using serum cTnI. Any derangement noted should warrant instituting cardiovascular support in order to improve outcome and reduce asphyxia-related mortality.

Neuromonitoring in neonatal intensive care units-an important need towards individualized neuroprotective care.

Neuromonitoring has been widely accepted as an important part in neonatal care. Amplitude-integrated EEG (aEEG) and near-infrared spectroscopy (NIRS) are often mentioned in this context, though being only a part of the fully array of methods and examinations that could be considered neuromonitoring. Within the broad array of medical conditions that could be encountered in a neonatal patient, it is important to be aware of the indications for neuromonitoring and especially which neuromonitoring technique to use best for the individual condition. aEEG is now a widely accepted neuromonitor in neonatology with its value in hypoxic events and seizures only rarely questioned. Other methods like NIRS still have to prove themselves in the future. The SafeBoosC-III trial showed that it still remains difficult for some of these methods to prove their value for the improvement of outcome. Bute future developments such as multimodal neuromonitoring with data integration and artificial intelligence analysis could improve the value of these methods.

Emergent Management of Hypoxic-Ischemic Brain Injury.

OBJECTIVE: This article outlines interventions used to improve outcomes for patients with hypoxic-ischemic brain injury after cardiac arrest. LATEST DEVELOPMENTS: Emergent management of patients after cardiac arrest requires prevention and treatment of primary and secondary brain injury. Primary brain injury is minimized by excellent initial resuscitative efforts. Secondary brain injury prevention requires the detection and correction of many pathophysiologic processes that may develop in the hours to days after the initial arrest. Key physiologic parameters important to secondary brain injury prevention include optimization of mean arterial pressure, cerebral perfusion, oxygenation and ventilation, intracranial pressure, temperature, and cortical hyperexcitability. This article outlines recent data regarding the treatment and prevention of secondary brain injury. Different patients likely benefit from different treatment strategies, so an individualized approach to treatment and prevention of secondary brain injury is advisable. Clinicians must use multimodal sources of data to prognosticate outcomes after cardiac arrest while recognizing that all prognostic tools have shortcomings. ESSENTIAL POINTS: Neurologists should be involved in the postarrest care of patients with hypoxic-ischemic brain injury to improve their outcomes. Postarrest care requires nuanced and patient-centered approaches to the prevention and treatment of primary and secondary brain injury and neuroprognostication.

Neonatal Seizures.

Neonatal seizures are common among patients with acute brain injury or critical illness and can be difficult to diagnose and treat. The most common etiology of neonatal seizures is hypoxic-ischemic encephalopathy, with other common causes including ischemic stroke and intracranial hemorrhage. Neonatal clinicians can use a standardized approach to patients with suspected or confirmed neonatal seizures that entails laboratory testing, neuromonitoring, and brain imaging. The primary goals of management of neonatal seizures are to identify the underlying cause, correct it if possible, and prevent further brain injury. This article reviews recent evidence-based guidelines for the treatment of neonatal seizures and discusses the long-term outcomes of patients with neonatal seizures.

Quality assessment of clinical practice guidelines on hypoxic-ischaemic encephalopathy in newborns using the AGREE II tool: a systematic review.

INTRODUCTION: Hypoxic-ischaemic encephalopathy is a clinical syndrome of neurological dysfunction that occurs immediately after birth following an episode of perinatal asphyxia. We conducted a scoping review to assess the methodological quality of clinical practice guidelines that address this condition. METHODOLOGY: We conducted the evaluation using the AGREE II tool. High methodological quality was defined as a score greater than 70% in every domain. RESULTS: The analysis included three clinical practice guidelines; the highest scores were in the scope and purpose domain (84.26%; SD, 14.25%) and the clarity of presentation domain (84.26%; SD, 17.86%), while the lowest score corresponded to the applicability domain (62.50%; SD, 36.62%). Two guidelines were classified as high quality and one guideline as low-quality. CONCLUSIONS: Two of the assessed guidelines were classified as being of high quality; however, the analysis identified shortcomings in the applicability domain, in addition to methodological variation between guidelines developed in middle- or low-income countries versus high-income countries. Efforts are needed to make high-quality guidelines available to approach the management of hypoxic-ischaemic encephalopathy in newborns.

Clinical outcome prediction with an automated EEG trend, Brain State of the Newborn, after perinatal asphyxia.

OBJECTIVE: To evaluate the utility of a fully automated deep learning -based quantitative measure of EEG background, Brain State of the Newborn (BSN), for early prediction of clinical outcome at four years of age. METHODS: The EEG monitoring data from eighty consecutive newborns was analyzed using the automatically computed BSN trend. BSN levels during the first days of life (a of total 5427 hours) were compared to four clinical outcome categories: favorable, cerebral palsy (CP), CP with epilepsy, and death. The time dependent changes in BSN-based prediction for different outcomes were assessed by positive/negative predictive value (PPV/NPV) and by estimating the area under the receiver operating characteristic curve (AUC). RESULTS: The BSN values were closely aligned with four visually determined EEG categories (p < 0·001), as well as with respect to clinical milestones of EEG recovery in perinatal Hypoxic Ischemic Encephalopathy (HIE; p < 0·003). Favorable outcome was related to a rapid recovery of the BSN trend, while worse outcomes related to a slow BSN recovery. Outcome predictions with BSN were accurate from 6 to 48 hours of age: For the favorable outcome, the AUC ranged from 95 to 99% (peak at 12 hours), and for the poor outcome the AUC ranged from 96 to 99% (peak at 12 hours). The optimal BSN levels for each PPV/NPV estimate changed substantially during the first 48 hours, ranging from 20 to 80. CONCLUSIONS: We show that the BSN provides an automated, objective, and continuous measure of brain activity in newborns. SIGNIFICANCE: The BSN trend discloses the dynamic nature that exists in both cerebral recovery and outcome prediction, supports individualized patient care, rapid stratification and early prognosis.

Hypoxic-ischaemic encephalopathy code: A systematic review for resource-limited settings.

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia (TH), continuous electroencephalographic monitoring and magnetic resonance imaging (MRI) in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term "HIE Code", evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: (1) prevention of HIE, (2) resuscitation, (3) first 6h post birth, (4) identification and grading of encephalopathy, (5) seizure management, (6) other therapeutic interventions, (7) multiple organ dysfunction, (8) diagnostic tests and (9) family care.

General movement assessment efficacy for assessment of nervous system integrity in children after hypoxic-ischemic encephalopathy in middle income countries.

BACKGROUND: Many infants who survive hypoxic-ischemic encephalopathy (HIE) face long-term complications like epilepsy, cerebral palsy, and developmental delays. Detecting and forecasting developmental issues in high-risk infants is critical. AIM: This study aims to assess the effectiveness of standardized General Movements Assessment (GMA) and Hammersmith Infant Neurological Examinations (HINE) in identifying nervous system damage and predicting neurological outcomes in infants with HIE. DESIGN: Prospective. SUBJECTS AND MEASURES: We examined full-term newborns with perinatal asphyxia, classifying them as Grade 2 HIE according to Sarnat and Sarnat. The study included 31 infants, with 14 (45.2 %) receiving therapeutic hypothermia (Group 1) and 17 (54.8 %) not (Group 2). We evaluated general movements during writhing and fidgety phases and conducted neurological assessments using the HINE. RESULTS: All infants exhibited cramped-synchronized - like movements, leading to cerebral palsy (CP) diagnosis. Three children in Group 1 and four in Group 2 lacked fidgety movements. During active movements, HINE and GMA showed high sensitivity and specificity, reaching 96 % and 100 % for all children. The ROC curve's area under the curve (AUC) was 0.978. CONCLUSION: Our study affirms HINE and GMA as effective tools for predicting CP in HIE-affected children. GMA exhibits higher sensitivity and specificity during fidgety movements. However, study limitations include a small sample size and data from a single medical institution, necessitating further research.

Umbilical artery eucapnic pH to assess fetal well-being.

BACKGROUND: Umbilical artery gas results help obstetricians assess fetal well-being during labor and guide screening decisions on eligibility for therapeutic hypothermia (ie, whole-body or head cooling). The accuracy of results, especially for the base deficit on arterial cord gas analysis, in predicting brain injury is questioned. A novel biomarker specifically calculated for fetal acid-base physiology and response to asphyxia-neonatal eucapnic pH as a marker of neonatal metabolic acidosis-has the potential to be an accurate predictor of hypoxic-ischemic encephalopathy. OBJECTIVE: We aimed to compare false-negative rates of hypoxic-ischemic encephalopathy for umbilical artery pH, base deficit, and neonatal eucapnic pH in assessing fetal acid-base balance as a marker of fetal well-being and predicting acute brain injury. STUDY DESIGN: This is a retrospective single-center cohort study of newborns ≥ 35 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy. We compared false-negative rates for any grade of hypoxic-ischemic encephalopathy using unilateral paired chi-square statistical analysis based on cutoff values for umbilical artery pH ≤7.00, base deficit ≥16 mmol/L, base deficit ≥12 mmol/L and neonatal eucapnic pH ≤7.14. We performed an analysis of variance between umbilical artery pH, base deficit, and neonatal eucapnic pH for each hypoxic-ischemic encephalopathy grade. RESULTS: We included 113 newborns. False-negative rate for hypoxic-ischemic encephalopathy was significantly higher for base deficit <16 mmol/L (n=78/113; 69.0%) than <12 mmol/L (n=46/113; 40.7%), pH >7.00 (n=41/113; 36.3%), or neonatal eucpanic pH >7.14 (n=35/113; 31.0%) (P<.0001). All true-positive cases were identified using only umbilical artery pH and neonatal eucapnic pH. Base deficit ≥16 or ≥12 mmol/L did not add any value in identifying newborns with hypoxic-ischemic encephalopathy when using umbilical artery pH and neonatal eucapnic pH. No association emerged between any marker and hypoxic-ischemic encephalopathy severity grading. CONCLUSION: Our findings support the accuracy of neonatal eucapnic pH to assess fetal well-being during labor and to improve predictive performance for acute brain injury. Neonatal eucpanic pH, in addition to umbilical artery pH, may be a viable alternative in identifying newborns at risk for hypoxic-ischemic encephalopathy.

Clinical exome sequencing uncovers genetic disorders in neonates with suspected hypoxic-ischemic encephalopathy: A retrospective analysis.

Hypoxic-ischemic encephalopathy (HIE) occurs in up to 7 out of 1000 births and accounts for almost a quarter of neonatal deaths worldwide. Despite the name, many newborns with HIE have little evidence of perinatal hypoxia. We hypothesized that some infants with HIE have genetic disorders that resemble encephalopathy. We reviewed genetic results for newborns with HIE undergoing exome or genome sequencing at a clinical laboratory (2014-2022). Neonates were included if they had a diagnosis of HIE and were delivered ≥35 weeks. Neonates were excluded for cardiopulmonary pathology resulting in hypoxemia or if neuroimaging suggested postnatal hypoxic-ischemic injury. Of 24 patients meeting inclusion criteria, six (25%) were diagnosed with a genetic condition. Four neonates had variants at loci linked to conditions with phenotypic features resembling HIE, including KIF1A, GBE1, ACTA1, and a 15q13.3 deletion. Two additional neonates had variants in genes not previously associated with encephalopathy, including DUOX2 and PTPN11. Of the six neonates with a molecular diagnosis, two had isolated HIE without apparent comorbidities to suggest a genetic disorder. Genetic diagnoses were identified among neonates with and without sentinel labor events, abnormal umbilical cord gasses, and low Apgar scores. These results suggest that genetic evaluation is clinically relevant for patients with perinatal HIE.

Identifying Newborns with Hypoxic-Ischemic Encephalopathy in Hospital Discharge Data: A Validation Study.

Hospital discharge databases (HDDs) are increasingly used for research on health of newborns. Linkage between a French population-based cohort of newborns with hypoxic-ischemic encephalopathy (HIE) and national HDD showed that the HIE ICD-10 code was not accurately reported. Our results suggest that HDD should not be used for research on neonatal HIE without prior validation of HIE ICD-10 codes.

Acute kidney injury in neonates with hypoxic ischemic encephalopathy based on serum creatinine decline compared to KDIGO criteria.

BACKGROUND: Neonates with hypoxic ischemic encephalopathy receiving therapeutic hypothermia (HIE + TH) are at risk for acute kidney injury (AKI). The standardized Kidney Disease Improving Global Outcomes (KDIGO) criteria identifies AKI based on a rise in serum creatinine (SCr) or reduced urine output. This definition is challenging to apply in neonates given the physiologic decline in SCr during the first week of life. Gupta et al. proposed alternative neonatal criteria centered on rate of SCr decline. This study aimed to compare the rate of AKI based on KDIGO and Gupta in neonates with HIE and to examine associations with mortality and morbidity. METHODS: A retrospective review was performed of neonates with moderate to severe HIE + TH from 2008 to 2020 at a single center. AKI was assessed in the first 7 days after birth by KDIGO and Gupta criteria. Mortality, brain MRI severity of injury, length of stay, and duration of respiratory support were compared between AKI groups. RESULTS: Among 225 neonates, 64 (28%) met KDIGO, 69 (31%) neonates met Gupta but not KDIGO, and 92 (41%) did not meet either definition. Both KDIGO-AKI and GuptaOnly-AKI groups had an increased risk of the composite mortality and/or moderate/severe brain MRI injury along with longer length of stay and prolonged duration of respiratory support compared to those without AKI. CONCLUSIONS: AKI in neonates with HIE + TH was common and varied by definition. The Gupta definition based on rate of SCr decline identified additional neonates not captured by KDIGO criteria who are at increased risk for adverse outcomes. Incorporating the rate of SCr decline into the neonatal AKI definition may increase identification of clinically relevant kidney injury in neonates with HIE + TH.

Standardizing neonatal hypoxic ischemic encephalopathy evaluation and documentation practices.

BACKGROUND: Infants at risk for hypoxic ischemic encephalopathy (HIE) require a time sensitive evaluation and decision-making regarding treatment with therapeutic hypothermia (TH). Prior to this project, there was no standardized approach to evaluating these infants locally. METHODS: Included infants were "at risk for HIE," defined as meeting the "patient characteristics" and "biochemical criteria" per the institutional HIE pathway. Our primary outcome was documentation of an HIE therapeutic hypothermia evaluation (HIETHE) within the first six hours of life which included: (1) recognition of at-risk status, (2) an encephalopathy exam, and (3) a decision regarding TH. Plan-Do-Study-Act cycles included novel clinical decision support. RESULTS: From October 2020 to May 2023, among infants at-risk for HIE, the average percentage with an HIETHE documented improved from 47% to 82%. CONCLUSIONS: We standardized the approach to infants at risk for HIE and improved the presence of a complete and timely evaluation regarding TH eligibility.

Epilepsy Incidence and Developmental Outcomes After Early Discontinuation of Antiseizure Medication in Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Neonatal seizures caused by hypoxic-ischemic encephalopathy (HIE) have significant morbidity and mortality. There is variability in clinical practice regarding treatment duration with antiseizure medication (ASM) after resolution of provoked neonatal seizures. We examined epilepsy incidence and developmental outcomes in post-HIE neonates discharged or not on ASM. METHODS: We conducted a retrospective chart review of all HIE-admitted neonates to the University of Iowa Hospitals & Clinics neonatal intensive care unit between January 2008 and February 2021 who presented with encephalopathy, underwent therapeutic hypothermia, and developed seizures. Neonates were divided into two groups depending on whether ASM was continued or discontinued on discharge. We evaluated the incidence of epilepsy and developmental outcomes on follow-up in these two cohorts up to 12 months. RESULTS: Sixty-nine neonates met the study criteria. ASM was continued on discharge in 41 neonates (59%) and discontinued before discharge in 28 (41%). At the 12-month follow-up, nine neonates (13%) had a diagnosis of epilepsy, out of which seven neonates had ASM continued on discharge (odds ratio [OR]: 2.84; 95% confidence interval [CI]: 0.48, 29.9)]. There was no statistical difference between the development of postneonatal epilepsy between the two groups (P value 0.29). There was no significant difference in developmental outcome between the two groups after adjusting for covariates like magnetic resonance imaging (MRI) brain abnormality and number of seizure days (OR: 0.68; 95% CI: 0.21, 2.22; P = 0.52). CONCLUSION: We found no significant risk of seizure recurrence by age 12 months in infants who had discontinued ASM before discharge compared with those who had continued ASM. There was no difference in developmental outcomes at the 12-month follow-up between groups after adjusting for brain MRI abnormality and the number of seizure days during admission. Our results support early discontinuation of ASM after resolution of acute provoked seizures in neonates with HIE.