OBJECTIVE: Neonatal encephalopathy (NE) is a neurological syndrome that presents with severe neurological impairments and complications. Hypoxic-ischemic encephalopathy is a major contributor to poor outcomes, being responsible for 50%-80% of admissions to neonatal intensive care units. However, some cases of NE accompanied by hypoxic brain damage cannot be solely attributed to hypoxia-ischemia. We aimed to identify diverse pathogenic genetic variations that may be associated with cases of NE accompanied by hypoxic brain damage rather than hypoxia-ischemia.
METHODS: We collected data from 34 patients diagnosed with NE accompanied by hypoxic brain damage over a 10-year period. Patients with the following specific conditions were excluded: 1) premature birth (<32 weeks), 2) no history of hypoxic events, 3) related anomalies, 4) neonatal infections, 5) antenatal or perinatal obstetrical complications, 6) severe hypoxia due to other medical conditions, and 7) early death (within 1 week). A comprehensive review of clinical and radiological features was conducted.
RESULTS: A genetic diagnosis was made in 11 (32.4%) patients, with pathogenic variants being identified in the following 9 genes: CACNA1A (n=2), KCNQ2 (n=2), SCN2A (n=1), SCN8A (n=1), STXBP1 (n=1), NSD1 (n=1), PURA (n=1), ZBTB20 (n=1), and ENG (n=1). No specific treatment outcomes or clinical features other than preterm birth were associated with the results of the genetic analyses. Personalized treatments based on the results of genetic tests were attempted, such as the administration of sodium-channel blockers in patients with KCNQ2 or SCN8A variants and the implementation of a ketogenic diet in patients with STXBP1 or SCN2A mutations, which demonstrated some degree of effectiveness in these patients.
CONCLUSIONS: Genetic analyses may help in diagnosing the underlying etiology of NE and concurrent hypoxic brain damage, irrespective of the initial clinical features.

BACKGROUND: Serial neonatal encephalopathy (NE) examinations are difficult to perform in rural community hospitals as on-site experts are not readily available. We implemented a synchronous, acute care model of teleconsultation-the Maine Neonatal Encephalopathy Teleconsultation program (Maine NET)-to provide remote, joint assessment of NE by pediatric neurology and neonatology at nine community hospitals and one tertiary care center. We performed a qualitative study to interview clinicians about their experience of this program.
METHODS: From April 2018 to October 2022, we employed a semistructured interview format with 16 clinicians representing all participating hospitals. We utilized deductive analysis to assign a set of predefined codes to the transcribed interviews.
RESULTS: Thematic analysis supported the anticipated benefits of Maine NET, demonstrating that clinicians felt resource utilization, collaborative decision making, communication, and continuity of care were improved. Clinicians overwhelmingly supported the program: \"This program has truly saved babies\' lives and future function. I have not met any parents through this journey, who aren\'t incredibly grateful for the care that is provided\" and emphasized the benefit of collaboration between all care team members. Teleconsultation was felt to be \"more than adequate to [assess] NE.\" Connectivity issues were cited as a limitation.
CONCLUSIONS: Maine NET has positively impacted care delivery for newborns with clinical concerns for NE. Additionally, the program has improved resource allocation, collaborative decision making, communication, and equity of care. Addressing technological challenges will be vital to the success and sustainability of the planned Maine NET expansion.

Parents of newborns with hypoxic ischemic encephalopathy (HIE) can face communication challenges in the neonatal intensive care unit. Both specialty palliative care and primary palliative care trained clinicians can assist parents as they navigate traumatic experiences and uncertain prognoses. Using evidence-based frameworks, the authors provide samples of how to communicate with parents and promote parent well-being across the care trajectory. The authors demonstrate how to involve parents in a shared decision-making process and give special consideration to the complexities of hospital discharge and the transition home. Sustained investment to guide the development of effective communication skills is crucial to support families of infants with HIE.

Hypoxic-ischemic encephalopathy in low resource settings is associated with low occurrence of perinatal sentinel events, growth restriction, short birth depression, early seizure onset, white matter injury, and non-acute hypoxia on whole genome expression profile suggesting that intra-partum hypoxia might be occurring from a normal or augmented labor process in an already compromised fetus. Induced hypothermia increases mortality and does not reduce brain injury. Strict adherence to the updated National Neonatology forum guidelines is essential to prevent harm from induced hypothermia in low resource settings.

Reproductive, pregnancy, and placental exposomes influence the fetal neural exposome through toxic stressor interplay, impairing the maternal-placental-fetal (MPF) triad. Neonatal encephalopathy represents different clinical presentations based on complex time-dependent etiopathogenetic mechanisms including hypoxia-ischemia that challenge diagnosis and prognosis. Reproductive, pregnancy, and placental exposomes impair the fetal neural exposome through toxic stressor interplay within the MPF triad. Long intervals often separate disease onset from phenotype. Interdisciplinary fetal-neonatal neurology training, practice, and research closes this knowledge gap. Maintaining reproductive health preserves MPF triad health with life-course benefits.

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.

The purpose of this paper is to compare the achievement of target temperature and the short-term neurological outcome according to the use of servo-controlled hypothermia in transport. This is a monocentric retrospective observational before-and-after uncontrolled study of newborns transported for neonatal encephalopathy. The first group was transported from 01/01/2019 to 12/31/2019 in passive hypothermia and the second group from 01/01/2021 to 12/31/2021 in controlled hypothermia. We included patients who had a total of 72 h of servo-controlled therapeutic hypothermia (CTH). We excluded those who had no or less than 72 h of CTH. There were 33 children transported in passive hypothermia in 2019 and 23 children transported in CTH in 2021. There were 9/28 (32%) patients in 2019 who reached the target temperature on arrival at the NICU compared with 20/20 (100%) in 2021 (p value < 0.01). There was a trend towards earlier age of therapeutic hypothermia if started in transport: 3.1 h ± 1.0 vs 4.0 h ± 2.4 for passive hypothermia (p value 0.07). There was no difference in age of arrival in NICU (4.0 h ± 1.2 with CTH vs 3.8 h ± 2.2 without CTH). We found no difference in short-term outcome (survival, abnormal MRI, seizures on EEG) between the two groups.
CONCLUSIONS: The use of servo-controlled therapeutic hypothermia makes it possible to reach the temperature target, without increasing the age of arrival in the NICU.
BACKGROUND: • CTH is rarely used during transport in France even if passive hypothermia rarely reaches temperature target, inducing overcooling and hyperthermia.
BACKGROUND: • This study shows better temperature control on arrival in the NICU with CTH compared to passive hypothermia, with no increase in arrival time.

Therapeutic hypothermia is now standard of care for neonates with hypoxic-ischemic encephalopathy (HIE) in high income countries (HIC). Conversely, compelling trial evidence suggests that hypothermia is ineffective, and may be deleterious, in low- and middle-income countries (LMIC), likely reflecting the lower proportion of infants who had sentinel events at birth, suggesting that injury had advanced to a stage when hypothermia is no longer effective. Although hypothermia significantly reduced the risk of death and disability in HICs, many infants survived with disability and in principle may benefit from targeted add-on neuroprotective or neurorestorative therapies. The present review will assess biomarkers that could be used to personalize treatment for babies with HIE - to determine first whether an individual infant is likely to respond to hypothermia, and second, whether additional treatments may be beneficial.

Hypoxic ischemic encephalopathy (HIE) remains a leading cause of neonatal mortality and lifelong disability across the world. While therapeutic hypothermia (HT) is beneficial, it is only partially protective and adjuvant treatments that further improve outcomes are urgently needed. In high-income countries where HT is standard care, novel treatments are tested in conjunction with HT. Mesenchymal stromal cells (MSC) represent a paradigm shift in brain protection, uniquely adapting to the host cellular microenvironment. MSC have low immunogenicity and potent paracrine effects stimulating the host tissue repair and regeneration and reducing inflammation and apoptosis. Preclinical studies in perinatal brain injury suggest that MSC are beneficial after hypoxia-ischemia (HI) and most preclinical studies of MSC with HT show protection. Preclinical and early phase clinical trials have shown that allogenic administration of MSC to neonates with perinatal stroke and HIE is safe and feasible but further safety and efficacy studies of HT with MSC in these populations are needed. Combination therapies that target all stages of the evolution of injury after HI (eg HT, melatonin and MSC) show promise for improving outcomes in HIE.

BACKGROUND: To compare the amplitude-integrated electroencephalography (aEEG) monitoring (short-term versus prolonged-period) for neonatal seizure detection and outcome.
METHODS: The aEEG monitoring in a historical cohort (n = 88, preterm:42, and term:46) with neonatal encephalopathy between 2010-2022 was re-evaluated for neonatal seizures (electrographic, electro-clinical, and clinical seizures) and EEG background scoring. The cohort was dichotomized: group I (short-period with 6-12 h, n = 36) and group II (prolonged-period with 24-48 h, n = 52). Both monitoring types were evaluated for the diagnostic accuracy of the \"patients with seizures\" and for outcome characteristics (early death as well as adverse outcomes at 12 months of age).
RESULTS: A total of 67 (76 %) neonates of the cohort were diagnosed as \"patients with seizures\": electrographic-only seizures in 10 (15 %), electro-clinical seizures in 22 (33 %), and clinical-only seizures in 35 (52 %). The aEEG provides the \"patients with seizures\" in neonates with a 36.5 % rate with both types of monitoring: 17/36 (47.2 %) with short-term and 15/52 (28.8 %) with prolonged-period monitoring. The prolonged period aEEG had higher diagnostic values for seizure detection (sensitivity = 0.73 and negative predictivity value = 0.81). However, the aEEG background scores were similar for both types of aEEG monitoring, respectively (the mean ± SD: 4.73 ± 2.9 versus 4.4 ± 4. p = 0.837). The aEEG scoring was correlated with the magnitude of brain injury documented with MRI, the early death, and the adverse outcome at 12 months of age.
CONCLUSIONS: Both aEEG types are valuable for monitoring the \"patients with seizures\" and outcome characteristics.