Predictive value of serum interleukin-6 for neonatal encephalopathy outcomes.

BACKGROUND: Serum interleukin-6 (IL-6) may predict adverse outcomes of neonatal encephalopathy (NE); however, limited data regarding the predictive utility of IL-6 during neurodevelopmental follow-up are available. We aimed to determine the utility of IL-6 for predicting adverse outcomes at 18 to 22 months of age. METHODS: Eighty-seven patients with NE who received therapeutic hypothermia were enrolled in this study. Serial serum IL-6 levels during the first 3 postnatal days were collected. Patients were classified into three groups: 1) death, 2) survival with moderate to severe neurodevelopmental disability (NDD) at 18-22 months of age, and 3) survival without NDD (favorable outcome). The predictive ability of IL-6 was determined by the area under the receiver-operating characteristic curve (AUC). RESULTS: Serial IL-6 data of 80 patients with NE were available and showed peak levels on postnatal day 1; these levels gradually decreased toward day 3. By 18-22 months of age, 13 and 17 patients died and experienced moderate to severe NDD without death, respectively. Fifty patients experienced favorable outcomes. Higher IL-6 levels on day 1 predicted the composite adverse outcome (including death and survival with NDD; n = 30; AUC, 0.648). Higher IL-6 levels on day 1 predicted death (n = 13; AUC, 0.799), whereas higher IL-6 levels on day 1 predicted survival with NDD (n = 17; AUC, 0.536). CONCLUSIONS: The AUC of IL-6 that predicted survival with NDD was lower than the AUC of IL-6 that predicted death; therefore, IL-6 may have insufficient utility for predicting NDD without death.

Genetic Diagnosis in Neonatal Encephalopathy With Hypoxic Brain Damage Using Targeted Gene Panel Sequencing.

BACKGROUND AND PURPOSE: 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.

A survey on the diagnosis and management of neonatal hypoxic ischaemic encephalopathy in sub-saharan Africa.

Sub-Saharan Africa (SSA) has the highest burden of neonatal hypoxic ischemic encephalopathy (HIE) in the world. However, there are few descriptions of HIE management in SSA and therapeutic hypothermia (TH) is considered controversial. A web-based survey was distributed to doctors across SSA in 2023. Adequate responses were received from 136 doctors across 43 of 48 countries. Therapeutic hypothermia was available in 13 countries, most frequently in private institutions compared to other settings (69% vs. 28%; P = 0.004). Over 90% of respondents who provided TH, appropriately cooled neonates to rectal temperatures of 33.5 °C before age 6 h, for 72 h, and 79% used automated cooling methods. Intubated ventilation and electroencephalograms were more available where TH was used (81% vs. 55%; p = 0.004 and 65% vs. 8%; p < 0.001 respectively). Indicators of intrapartum hypoxia were more frequently defined with TH provision, including early pH (79% vs. 21%; p < 0.001), base deficit (76% vs. 20%; p < 0.001), and ventilation at age 10 min (87% vs. 53%; p = 0.001). Despite the variation in resources and management of HIE, most respondents had standardised protocols (76%). Most respondents who provided TH, followed evidence-based methods, and had stricter criteria and more resources than institutions who did not cool.

Clinician Stakeholder Experience With Telemedicine Consults to Assess Neonatal Encephalopathy in a Rural State.

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.

Neonatal Encephalopathy is a Complex Phenotype Representing Reproductive and Pregnancy Exposome Effects on the Maternal-Placental-Fetal Triad.

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.

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.

Communicating with Parents About Therapeutic Hypothermia and Hypoxic Ischemic Encephalopathy: Integrating a Palliative Care Approach into Practice.

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.

Moving the Needle in Low-Resource Settings: Is Hypothermia a Friend or a Foe?

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.

Servo-controlled therapeutic hypothermia during neonatal transport: a before-and-after quality improvement project.

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. CONCLUSION: The use of servo-controlled therapeutic hypothermia makes it possible to reach the temperature target, without increasing the age of arrival in the NICU. WHAT IS KNOWN: • CTH is rarely used during transport in France even if passive hypothermia rarely reaches temperature target, inducing overcooling and hyperthermia. WHAT IS NEW: • This study shows better temperature control on arrival in the NICU with CTH compared to passive hypothermia, with no increase in arrival time.

The clinical value of amplitude-integrated electroencephalography in a historical cohort with neonatal encephalopathy: A comparison of short-term versus prolonged-period monitoring.

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.

Mesenchymal Stromal Cell therapy for Hypoxic Ischemic Encephalopathy: Future directions for combination therapy with hypothermia and/or melatonin.

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.

How do we reach the goal of personalized medicine for neuroprotection in neonatal hypoxic-ischemic encephalopathy?

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.

Cooling Under a Blanketrol System Versus Cooling With an Arctic Sun Thermoregulation System (CATS) for Neonates Undergoing Therapeutic Hypothermia.

Background Despite evidence suggesting improved outcomes in neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), data on the impact of temperature variability during cooling and its association with clinical outcomes remain limited. Objective To compare the efficacy and ease of use of two different cooling systems, the Arctic Sun (Medivance, Inc., Louisville, CO) vs. the Blanketrol III (Gentherm Medical, Cincinnati, OH) on achieving TH, temperature variability, and clinical outcomes in neonates with HIE undergoing TH. Methods This study was conducted at the Baylor Scott and White Medical Center's Level IV NICU. The study employed a retrospective cohort design, comparing infants treated with the Arctic Sun device (from December 2020 to August 2021) to a historical cohort treated with the Blanketrol system (from January 2017 to November 2020). Both groups were evaluated for clinical characteristics, patients' outcomes, and ease of use of the cooling devices. Ease of use was assessed through a self-developed survey administered to NICU nurses. Core body temperatures throughout the cooling course were documented at four-hour intervals, including induction, maintenance, and rewarming phases. Results Twenty-two infants were cooled using the Arctic Sun system, and 44 infants were cooled with the Blanketrol device. Median birth weight and gestational age were comparable. There were no significant differences in one-minute and five-minute appearance, pulse, grimace, activity, and respiration (APGAR) scores. The Arctic Sun group had a significantly higher rate of maternal morbidities, including diabetes and placental abruption. Although the median temperature achieved with both devices was 33.5°C, temperature variability was significantly greater with the Blanketrol device (p = 0.03). Thrombocytopenia rates were statistically different between the groups (9% in Arctic Sun vs. 38% in Blanketrol, p = 0.001). Although the Blanketrol group had higher rates of disseminated intravascular coagulation (48% vs. 37%), hypercalcemia (23% vs. 5%), and subcutaneous fat necrosis (7% vs. 5%), these differences were not statistically significant. A nurses' survey on ease of use revealed a strong preference for the Arctic Sun cooling system. Over 85% of nurses found it easier to learn and set up and required less manual intervention than the Blanketrol device. Conclusions Gel adhesive pad-based TH is a potentially superior modality to traditional water-circulating cooling devices. These pads offer advantages in user-friendliness, improved temperature control precision, and potentially reduced adverse event profiles.

Brain MRI Injury Patterns across Gestational Age among Preterm Infants with Perinatal Asphyxia.

INTRODUCTION: Brain injury patterns of preterm infants with perinatal asphyxia (PA) are underreported. We aimed to explore brain magnetic resonance imaging (MRI) findings and associated neurodevelopmental outcomes in these newborns. METHODS: Retrospective multicenter study included infants with gestational age (GA) 24.0-36.0 weeks and PA, defined as ≥2 of the following: (1) umbilical cord pH ≤7.0, (2) 5-min Apgar score ≤5, and (3) fetal distress or systemic effects of PA. Findings were compared between GA <28.0 (group 1), 28.0-31.9 (group 2), and 32.0-36.0 weeks (group 3). Early MRI (<36 weeks postmenstrual age or <10 postnatal days) was categorized according to predominant injury pattern, and MRI around term-equivalent age (TEA, 36.0-44.0 weeks and ≥10 postnatal days) using the Kidokoro score. Adverse outcomes included death, cerebral palsy, epilepsy, severe hearing/visual impairment, or neurodevelopment <-1 SD at 18-24 months corrected age. RESULTS: One hundred nineteen infants with early MRI (n = 94) and/or MRI around TEA (n = 66) were included. Early MRI showed predominantly hemorrhagic injury in groups 1 (56%) and 2 (45%), and white matter (WM)/watershed injury in group 3 (43%). Around TEA, WM scores were highest in groups 2 and 3. Deep gray matter (DGM) (aOR 15.0, 95% CI: 3.8-58.9) and hemorrhagic injury on early MRI (aOR 2.5, 95% CI: 1.3-4.6) and Kidokoro WM (aOR 1.3, 95% CI: 1.0-1.6) and DGM sub-scores (aOR 4.8, 95% CI: 1.1-21.7) around TEA were associated with adverse neurodevelopmental outcomes. CONCLUSION: The brain injury patterns following PA in preterm infants differ across GA. Particularly DGM abnormalities are associated with adverse neurodevelopmental outcomes.

Melatonin reduces brain injury following inflammation-amplified hypoxia-ischemia in a translational newborn piglet study of neonatal encephalopathy.

There is a need to develop therapies for neonatal encephalopathy (NE) in low- and middle-income countries (LMICs) where the burden of disease is greatest and therapeutic hypothermia (HT) is not effective. We aimed to assess the efficacy of melatonin following inflammation-amplified hypoxia-ischaemia (IA-HI) in the newborn piglet. The IA-HI model accounts for the contribution of infection/inflammation in this setting and HT is not cytoprotective. We hypothesised that intravenous melatonin (5% ethanol, at 20 mg/kg over 2 h at 1 h after HI + 10 mg/kg/12 h between 24 and 60 h) is safe and associated with: (i) reduction in magnetic resonance spectroscopy lactate/N-acetylaspartate (MRS Lac/sNAA); (ii) preservation of phosphorus MRS phosphocreatine/phosphate exchange pool (PCr/Epp); (iii) improved aEEG/EEG recovery and (iv) cytoprotection on immunohistochemistry. Male and female piglets underwent IA-HI by carotid artery occlusion and reduction in FiO2 to 6% at 4 h into Escherichia coli lipopolysaccharide sensitisation (2 µg/kg bolus + 1 µg/kg/h over 12 h). At 1 h after IA-HI, piglets were randomised to HI-saline (n = 12) or melatonin (n = 11). There were no differences in insult severity between groups. Target melatonin levels (15-30 mg/L) were achieved within 3 h and blood ethanol levels were <0.25 g/L. At 60 h, compared to HI-saline, melatonin was associated with a reduction of 0.197 log10 units (95% CrI [-0.366, -0.028], Pr(sup) 98.8%) in basal-ganglia and thalamic Lac/NAA, and 0.257 (95% CrI [-0.676, 0.164], Pr(sup) 89.3%) in white matter Lac/NAA. PCr/Epp was higher in melatonin versus HI-saline (Pr(sup) 97.6%). Melatonin was associated with earlier aEEG/EEG recovery from 19 to 24 h (Pr(sup) 95.4%). Compared to HI-saline, melatonin was associated with increased NeuN+ cell density (Pr(sup) 99.3%) across five of eight regions and reduction in TUNEL-positive cell death (Pr(sup) 89.7%). This study supports the translation of melatonin to early-phase clinical trials. Melatonin is protective following IA-HI where HT is not effective. These data guide the design of future dose-escalation studies in the next phase of the translational pipeline.

Ultrasound Diagnosis and Near-Infrared Spectroscopy in the Study of Encephalopathy in Neonates Born under Asphyxia: Narrative Review.

Brain injury resulting from adverse events during pregnancy and delivery is the leading cause of neonatal morbidity and disability. Surviving neonates often suffer long-term motor, sensory, and cognitive impairments. Birth asphyxia is among the most common causes of neonatal encephalopathy. The integration of ultrasound, including Doppler ultrasound, and near-infrared spectroscopy (NIRS) offers a promising approach to understanding the pathology and diagnosis of encephalopathy in this special patient population. Ultrasound diagnosis can be very helpful for the assessment of structural abnormalities associated with neonatal encephalopathy such as alterations in brain structures (intraventricular hemorrhage, infarcts, hydrocephalus, white matter injury) and evaluation of morphologic changes. Doppler sonography is the most valuable method as it provides information about blood flow patterns and outcome prediction. NIRS provides valuable insight into the functional aspects of brain activity by measuring tissue oxygenation and blood flow. The combination of ultrasonography and NIRS may produce complementary information on structural and functional aspects of the brain. This review summarizes the current state of research, discusses advantages and limitations, and explores future directions to improve applicability and efficacy.

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.

OBJECTIVE: To 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 DESIGN: Prospective 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 24-36 hours and brain magnetic resonance imaging (MRI) at a median of 10 days. Development was followed through 2.5-5 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. RESULTS: Increased 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 2.5-5 years (P < .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/second (Area under the curve of 0.824) correctly classified 80% of infants with severe MRI scores. CONCLUSIONS: Early 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.

Código encefalopatía hipóxico-isquémica: revisión sistematizada para entornos con recursos limitados / Hypoxic-ischaemic encephalopathy code: a systematic review for resource-limited settings

Se estima que el 96% de los recién nacidos (RN) con encefalopatía hipóxico-isquémica (EHI) nacen en entornos con recursos limitados (ERL) sin capacidad para ofrecer el estándar asistencial vigente desde hace cerca de 15 años en los países con altos recursos y que incluye hipotermia terapéutica, neuromonitorización continua electroencefalográfica y resonancia magnética, además de un control intensivo de las constantes vitales y del equilibrio homeostático. Esta situación no parece estar cambiando; sin embargo y aún con estas limitaciones, el conocimiento actualmente disponible permite mejorar la asistencia de los pacientes con EHI atendidos en ERL. El propósito de esta revisión sistematizada es ofrecer, bajo el término «código EHI», recomendaciones de prácticas asistenciales basadas en evidencia científica y factibles en ERL, que permitan optimizar la atención del RN con EHI y ayuden potencialmente a reducir los riesgos asociados a la comorbilidad y a mejorar los resultados neuroevolutivos. El contenido del código EHI se agrupó en nueve epígrafes: 1) prevención de la EHI, 2) reanimación, 3) primeras seis horas de vida, 4) identificación y graduación de la EHI, 5) manejo de las convulsiones, 6) otras intervenciones terapéuticas, 7) disfunción multiorgánica, 8) estudios complementarios, y 9) atención a la familia. (AU)

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, continuous electroencephalographic monitoring and magnetic resonance imaging 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 6hours 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. (AU)

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.

Clinical decisions in fetal-neonatal neurology II: Gene-environment expression over the first 1000 days presenting as "four great neurological syndromes".

Interdisciplinary fetal-neonatal neurology (FNN) training considers a woman's reproductive and pregnancy health histories when assessing the "four great neonatal neurological syndromes". This maternal-child dyad exemplifies the symptomatic neonatal minority, compared with the silent majority of healthy children who experience preclinical diseases with variable expressions over the first 1000 days. Healthy maternal reports with reassuring fetal surveillance testing preceded signs of fetal distress during parturition. An encephalopathic neonate with seizures later exhibited childhood autistic spectrum behaviors and intractable epilepsy correlated with identified genetic biomarkers. A systems biology approach to etiopathogenesis guides the diagnostic process to interpret phenotypic form and function. Evolving gene-environment interactions expressed by changing phenotypes reflect a dynamic neural exposome influenced by reproductive and pregnancy health. This strategy considers critical/sensitive periods of neuroplasticity beyond two years of life to encompass childhood and adolescence. Career-long FNN experiences reenforce earlier training to strengthen the cognitive process and minimize cognitive biases when assessing children or adults. Prioritizing social determinants of healthcare for persons with neurologic disorders will help mitigate the global burden of brain diseases for all women and children.