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.

Desarrollo motor, cognitivo y conductual tras encefalopatía hipóxico-isquémica neonatal / Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy

Introducción: El neurodesarrollo actual de pacientes con encefalopatía hipóxico-isquémica (EHI) neonatal en España se desconoce. Recientes estudios europeos destacan el desplazamiento de la patología grave hacia trastornos motores leves y problemas emocionales. El objetivo de este estudio fue analizar el estado neuroevolutivo integral a los 3años de una cohorte de neonatos con EHI. Pacientes y métodos: Estudio observacional multicéntrico de neonatos ≥35 semanas de edad gestacional con EHI moderada-grave nacidos entre 2011 y 2013 en 12 hospitales de una extensa región española (91.217m2) y ampliado hasta 2017 en el hospital coordinador. Se evaluaron los estudios de neuroimagen neonatal y del neurodesarrollo a los 3años mediante Bayley-III, Peabody Picture Vocabulary Test y Child Behaviour Checklist. Se incluyeron 79 controles sin asfixia perinatal. Resultados: Se reclutaron 63 pacientes, de los cuales 5/63 (7,9%) se excluyeron por presentar otra patología, y 14/58 (24%) fallecieron. De los 44 supervivientes, 42/44 (95,5%) fueron evaluados. De ellos, 10/42 (24%) presentaron evolución adversa (alteraciones visuales o auditivas, epilepsia, parálisis cerebral [PC] o retraso del desarrollo). Adicionalmente se detectaron otras alteraciones: trastorno motor mínimo (TMM) en 6/42 (14%) y más problemas de introversión (10,5% vs 1,3%), ansiedad (34,2% vs 11,7%) y depresión (28,9% vs 7,8%) que los controles (p<0,05). La gravedad de las lesiones en neuroimagen fue significativamente mayor en pacientes con trastorno motor (PC o TMM) (p=0,004) y muerte o evolución adversa (p=0,027). Conclusiones: Además de las secuelas clásicas, el seguimiento de los pacientes con EHI neonatal debería incluir el diagnóstico y el manejo de trastornos motores mínimos y problemas emocionales.(AU)

Introduction: The current neurodevelopmental status of patients with neonatal hypoxic-ischaemic encephalopathy (HIE) in Spain is unknown. Recent European studies highlight a shift of severe pathology towards mild motor disorders and emotional problems. The aim of this study was to analyse neurodevelopmental outcomes in a cohort of neonates with HIE at age 3years. Patients and method: Multicentre observational study of neonates born at 35 or more weeks of gestation with moderate to severe HIE in 2011-2013 in 12 hospitals in a large Spanish region (91,217m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3years (Bayley-III, Peabody Picture Vocabulary Test and Child Behavior Checklist). The sample included 79 controls with no history of perinatal asphyxia. Results: Sixty-three patients were recruited, of whom 5 (7.9%) were excluded due to other pathology and 14 (24%) died. Of the 44 survivors, 42 (95.5%) were evaluated. Of these 42, 10 (24%) had adverse outcomes (visual or hearing impairment, epilepsy, cerebral palsy or developmental delay). Other detected problems were minor neurological signs in 6 of the 42 (14%) and a higher incidence of emotional problems compared to controls: introversion (10.5% vs. 1.3%), anxiety (34.2% vs. 11.7%) and depression (28.9% vs. 7.8%) (P<.05). The severity of the lesions on neuroimaging was significantly higher in patients with motor impairment (P=.004) or who died or had an adverse outcome (P=.027). Conclusion: In addition to classical sequelae, the follow-up of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems.(AU)

Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.

Hypoxic Ischemic Encephalopathy with Cervical Spinal Cord Injury: A Diagnostic Dilemma.

Perinatal spinal cord injury is a relatively uncommon, but a frequently misdiagnosed disorder. Improvements in obstetric care have certainly led to a decrease in the incidence of birth related spinal cord trauma but unfortunately the incidence of hypoxic-ischemic encephalopathy is still very high. The exact incidence of spinal cord trauma is difficult to determine because the spinal cord is not routinely examined in far and few neonatal autopsies done in India. Here, authors present a neonate who received treatment for birth asphyxia and then had extubation failure which made the clock tick towards cervical cord injury. This baby had a hemorrhagic contusion of cervical spinal cord.

The Association of Therapeutic Hypothermia With Seizure Burden in Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: This was a retrospective cohort study on infants born after 35 weeks' gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE. RESULTS: Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001). CONCLUSIONS: TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy.

The influence of late prematurity on the encephalopathy exam of infants with neonatal encephalopathy.

BACKGROUND: Late preterm (LPT) infants are increasingly treated for hypoxic-ischemic encephalopathy (HIE). However, neurodevelopmental differences of LPT infants may independently influence the neurologic exam and confound care. METHODS: Perinatal and outcome characteristics were extracted along with the worst autonomic and state/neuromuscular/reflex Sarnat components in a cross-section of infants with moderate/severe HIE. Infants were classified as late preterm (LPT, 34-36 weeks) or term (>36 weeks). RESULTS: 250 infants were identified, 55 were late preterm. LPT infants had lower mean gestational age and birthweight and greater length of stay (LOS). LPT infants had higher median scores for the Moro and respiratory autonomic components, but no difference in total score. CONCLUSIONS: LPT infants had increased LOS, worse Moro reflex, and respiratory status, but no clinically or statistically significant differences in total Sarnat scores. Although it is important to note the impact of immaturity on the exam, it is unlikely to independently alter management.

Timely Detection of Infants at Risk of Intrapartum Acidosis and Hypoxic-Ischemic Encephalopathy Using Cardiotocography.

This work aims to improve the intrapartum detection of fetuses with an increased risk of developing fetal acidosis or hypoxic-ischemic encephalopathy (HIE) using fetal heart rate (FHR) and uterine pressure (UP) signals. Our study population comprised 40,831 term births divided into 3 classes based on umbilical cord or early neonatal blood gas assessments: 374 with verified HIE, 3,047 with acidosis but no encephalopathy and 37,410 healthy babies with normal gases. We developed an intervention recommendation system based on a random forest classifier. The classifier was trained using classical and novel features extracted electronically from 20-minute epochs of FHR and UP. Then, using the predictions of the classifier on each epoch, we designed a decision rule to determine when to recommended intervention. Compared to the Caesarean rates in each study group, our system identified an additional 5.68% of babies who developed HIE (54.55% vs 60.23%, p < 0.01) with a specific alert threshold. Importantly, about 75% of these recommendations were made more than 200 minutes before birth. In the acidosis group, the system identified an additional 17.44% (37.15% vs 54.59%, p < 0.01) and about 2/3 of these recommendations were made more than 200 minutes before birth. Compared to the Caesarean rate in the healthy group, the associated false positive rate was increased by 1.07% (38.80% vs 39.87%, p<0.01).Clinical Relevance- This method recommended intervention in more babies affected by acidosis or HIE, than the intervention rate observed in practice and most often did so 200 minutes before delivery. This was early enough to expect that interventions would have clinical benefit and reduce the rate of HIE. Given the high burden associated with HIE, this would justify the marginal increase in the normal Cesarean rate.

Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy.

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.

The Placenta and Neonatal Encephalopathy with a Focus on Hypoxic-Ischemic Encephalopathy.

Background: Placental examination is important for its diagnostic immediacy to correlate with maternal and/or fetal complications and parturitional difficulties. In a broader context, clinicopathologic studies of the placenta have addressed a range of pathogenetic questions that have led to conclusive and inconclusive results and interpretations. Methods: Recent standardized morphologic criteria and terminology of placental lesions have facilitated the ability to compare findings from studies that have focused on complications and outcomes of pregnancy. This review is an evaluation of recent studies on placental lesions associated with hypoxic-ischemic encephalopathy (HIE). Conclusion: No apparent consensus exists on whether it is fetal inflammation with the release of cytokines or chronic maternal and/or fetal vascular malperfusion is responsible for HIE with a lowering of the threshold for hypoxic ischemia. The counter argument is that HIE occurs solely as an intrapartum event. Additional investigation is necessary.

Clinical Prediction Models and Predictors for Death or Adverse Neurodevelopmental Outcome in Term Newborns with Hypoxic-Ischemic Encephalopathy: A Systematic Review of the Literature.

BACKGROUND: Although many predictive parameters have been studied, an internationally accepted, validated predictive model to predict the clinical outcome of asphyxiated infants suffering from hypoxic-ischemic encephalopathy is currently lacking. The aim of this study was to identify, appraise and summarize available clinical prediction models, and provide an overview of all investigated predictors for the outcome death or neurodevelopmental impairment in this population. METHODS: A systematic literature search was performed in Medline and Embase. Two reviewers independently included eligible studies and extracted data. The quality was assessed using PROBAST for prediction model studies and QUIPS assessment tools for predictor studies. RESULTS: A total of nine prediction models were included. These models were very heterogeneous in number of predictors assessed, methods of model derivation, and primary outcomes. All studies had a high risk of bias following the PROBAST assessment and low applicability due to complex model presentation. A total of 104 predictor studies were included investigating various predictors, showing tremendous heterogeneity in investigated predictors, timing of predictors, primary outcomes, results, and methodological quality according to QUIPS. Selected high-quality studies with accurate discriminating performance provide clinicians and researchers an evidence map of predictors for prognostication after HIE in newborns. CONCLUSION: Given the low methodological quality of the currently published clinical prediction models, implementation into clinical practice is not yet possible. Therefore, there is an urgent need to develop a prediction model which complies with the PROBAST guideline. An overview of potential predictors to include in a prediction model is presented.

Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

BACKGROUND: Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH. METHODS: This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15). FINDINGS: Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (ß (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl × mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. INTERPRETATION: Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE. FUNDING: This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).

Value of EEG in outcome prediction of hypoxic-ischemic brain injury in the ICU: A narrative review.

Prognostication of comatose patients after cardiac arrest aims to identify patients with a large probability of favourable or unfavouble outcome, usually within the first week after the event. Electroencephalography (EEG) is a technique that is increasingly used for this purpose and has many advantages, such as its non-invasive nature and the possibility to monitor the evolution of brain function over time. At the same time, use of EEG in a critical care environment faces a number of challenges. This narrative review describes the current role and future applications of EEG for outcome prediction of comatose patients with postanoxic encephalopathy.

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

OBJECTIVE: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified. STUDY DESIGN: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test. RESULT: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified. CONCLUSIONS: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care.

Predictive performance of multiple organ dysfunction in asphyxiated newborns treated with therapeutic hypothermia on 24-month outcome: a cohort study.

BACKGROUND: Perinatal asphyxia may be followed by multiple organ dysfunction (MOD) and is often included in prognostication of the individual patient, but evidence of discriminating accuracy is lacking. The aim of this study was to assess whether MOD in asphyxiated neonates during therapeutic hypothermia (TH) predicts mortality or neurodevelopmental impairment (NDI) at 24 months of age and which peripartum variables are associated with the onset of MOD. METHODS: A retrospective analysis of a prospective cohort study of asphyxiated newborns undergoing TH was performed. MOD was defined as dysfunction of the brain (encephalopathy) combined with two or more organ systems. Outcome was routinely assessed by standardised developmental testing at the age of 24 months. The predictive accuracy of MOD on the combined outcome and its components (death and NDI) was expressed as areas under the receiver operating characteristic curves (AUROCs). The associations of peripartum variables and development of MOD were expressed as ORs and their CIs. RESULTS: 189 infants (median gestation 40 (range 36-42 weeks) with moderate to severe hypoxic ischaemic encephalopathy were included. 47% developed MOD. The prediction of the combined 24-month outcome or its components showed AUROCs <0.70. Associated with MOD were pH at birth (OR 0.97, CI 0.95 to 0.99), lactate at birth (OR 1.09, CI 1.04 to 1.15), Base Excess (BE) at birth (OR 0.94, CI 0.90 to 0.99) and epinephrine administration during resuscitation (OR 2.09, CI 1.02 to 4.40). CONCLUSION: MOD has a low discriminating accuracy in predicting mortality or NDI at 24 months age and might not be useful for prognostication. Signs of acid-base disturbance and adrenalin use at birth are associated with the development of MOD.

An Exploratory Analysis of Gastrointestinal Morbidities and Feeding Outcomes Associated with Neonatal Hypoxic-Ischemic Encephalopathy With or Without Hypothermia Therapy.

This study investigates the clinical profile and predictors of gastrointestinal/hepatic morbidities and feeding outcomes among neonates with hypoxic-ischemic encephalopathy (HIE). A single-center retrospective chart review of consecutive neonates >35 weeks of gestation admitted with a diagnosis of HIE between January 1, 2015, and December 31, 2020, and treated with therapeutic hypothermia, if met the institutional eligibility criteria. Outcomes assessed included necrotizing enterocolitis (NEC), conjugated hyperbilirubinemia, hepatic dysfunction, assisted feeding at discharge, and time to reach full enteral and oral feeds. Among 240 eligible neonates (gestational age 38.7 [1.7] weeks, birth weight 3279 [551] g), 148 (62%) received hypothermia therapy, and 7 (3%) and 5 (2%) were diagnosed with stage 1 NEC and stage 2-3 NEC, respectively. Twenty-nine (12%) were discharged home with a gastrostomy/gavage tube, conjugated hyperbilirubinemia (first week 22 [9%], at discharge 19 [8%]), and hepatic dysfunction (74 [31%]). Time to reach full oral feeds was significantly longer in hypothermic neonates compared with neonates who did not receive hypothermia (9 [7-12] days vs. 4.5 [3-9] days, p < 0.0001). Factors significantly associated with NEC were renal failure (odds ratio [OR] 9.24, 95% confidence interval [CI] 2.7-33), hepatic dysfunction (OR 5.69, 95% CI 1.6-26), and thrombocytopenia (OR 3.6, 95% CI 1.1-12), but no significant association with hypothermia, severity of brain injury, or stage of encephalopathy. Transient conjugated hyperbilirubinemia, hepatic dysfunction within first week of life, and need for assistive feeding are more common than NEC in HIE. Risk of NEC was associated with the severity of end-organ dysfunction in the first week of life, rather than severity of brain injury and hypothermia therapy per se.

Use of EEG in neonatal hypoxic-ischemic encephalopathy: A French survey of current practice and perspective for improving health care.

OBJECTIVES: Controlled therapeutic hypothermia (CTH) is a standard of care in the management of neonatal hypoxic-ischemic encephalopathy HIE in newborns after 36 weeks of gestational age (WGA) in France. The electroencephalogram (EEG) plays a major role in HIE diagnosis and follow-up. We conducted a French national survey on the current use of EEG in newborn undergoing CTH. METHODS: Between July and October 2021, an email survey was sent to the heads of the Neonatal intensive care units (NICUs) in metropolitan and overseas French departments and territories. RESULTS: Out of 67, 56 (83%) of NICUs responded. All of them performed CTH in children born after 36 WGA with clinical and biological criteria of moderate to severe HIE. 82% of the NICUs used conventional EEG (cEEG) before 6 h of life (H6), prior to CTH being performed, to inform decisions about its use. However, half of the 56 NICUs had limited access after regular working hours. 51 of the 56 centers (91%) used cEEG, either short-lasting or continuous monitoring during cooling, while 5 centers conducted only amplitude EEG (aEEG). Only 4 of 56 centers (7%) used cEEG systematically both prior to CTH and for continuous monitoring under CTH. DISCUSSION: The use of cEEG in the management of neonatal HIE was widespread in NICUs, but with significant disparities when considering 24-hour access. The introduction of a centralized neurophysiological on-call system grouping several NICUs would be of major interest for most centers which do not have the facility of EEG outside working hours.

Biomarkers of hypoxic-ischemic encephalopathy: a systematic review.

BACKGROUND: Current diagnostic criteria for hypoxic-ischemic encephalopathy in the early hours lack objective measurement tools. Therefore, this systematic review aims to identify putative molecules that can be used in diagnosis in daily clinical practice (PROSPERO ID: CRD42021272610). DATA SOURCES: Searches were performed in PubMed, Web of Science, and Science Direct databases until November 2020. English original papers analyzing samples from newborns > 36 weeks that met at least two American College of Obstetricians and Gynecologists diagnostic criteria and/or imaging evidence of cerebral damage were included. Bias was assessed by the Newcastle-Ottawa Scale. The search and data extraction were verified by two authors separately. RESULTS: From 373 papers, 30 met the inclusion criteria. Data from samples collected in the first 72 hours were extracted, and increased serum levels of neuron-specific enolase and S100-calcium-binding protein-B were associated with a worse prognosis in newborns that suffered an episode of perinatal asphyxia. In addition, the levels of glial fibrillary acidic protein, ubiquitin carboxyl terminal hydrolase isozyme-L1, glutamic pyruvic transaminase-2, lactate, and glucose were elevated in newborns diagnosed with hypoxic-ischemic encephalopathy. Moreover, pathway analysis revealed insulin-like growth factor signaling and alanine, aspartate and glutamate metabolism to be involved in the early molecular response to insult. CONCLUSIONS: Neuron-specific enolase and S100-calcium-binding protein-B are potential biomarkers, since they are correlated with an unfavorable outcome of hypoxic-ischemic encephalopathy newborns. However, more studies are required to determine the sensitivity and specificity of this approach to be validated for clinical practice.

Perinatal antecedents of moderate and severe neonatal hypoxic ischaemic encephalopathy: An Australian birth cohort study.

BACKGROUND: Neonatal hypoxic ischaemic encephalopathy (HIE) is the most common cause of encephalopathy in the neonatal period and carries a high risk of mortality and long-term morbidity. AIM: The aim of this study was to investigate key antecedents of moderate and severe HIE in a large contemporary birth cohort. METHODS: A retrospective cohort study of births meeting criteria was conducted between 2016 and 2020 at the Mater Mothers' Hospital, Brisbane, Australia. This is a quaternary perinatal centre and Australia's largest maternity hospital. Univariate and multivariate Firth logistic regression were used to account for imbalanced frequency classes between non-HIE and HIE groups. Maternal variables and intrapartum factors were investigated for associations with neonatal moderate and severe HIE. RESULTS: Overall, 133 of 46 041 (0.29%) infants were diagnosed with HIE: 77 (0.17%) with mild HIE and 56 (0.12%) with moderate/severe HIE. Nulliparity, type 1 diabetes mellitus and maternal intensive care unit admission were associated with increased odds of moderate/severe HIE. Intrapartum risk factors included emergency caesarean birth, emergency caesarean for non-reassuring fetal status or failure to process, intrapartum haemorrhage and an intrapartum sentinel event (shoulder dystocia, cord prolapse, uterine rupture and placental abruption). Neonatal risk factors included male sex, late preterm gestation (35+0 -36+6  weeks), Apgar score less than four at 5 min, severe respiratory distress requiring ventilatory support and severe acidosis at birth. CONCLUSIONS: This cohort study identified a series of potentially modifiable maternal and obstetric risk factors for HIE. Risk factors for HIE do not appear to have changed significantly with evolution in modern obstetric care.