Therapeutic hypothermia is an effective therapy for moderate-to-severe hypoxic-ischemic encephalopathy (HIE) in infants born at term or near-term in high-resource settings. Yet there remains a substantial proportion of infants who do not benefit or who will have significant disability despite therapeutic hypothermia. Novel investigational therapies that may confer additional neuroprotection by targeting known pathogenic mechanisms of hypoxic-ischemic brain injury are under development. This review focuses on putative neuroprotective agents that have shown promise in animal models of HIE, and that have been translated to clinical studies in neonates with HIE. We include agents that have been studied both with and without concurrent therapeutic hypothermia. Our review therefore addresses not just neonatal HIE in high-resource countries where therapeutic hypothermia is the standard of care, but also neonatal HIE in low- and middle-income countries where therapeutic hypothermia has been shown to be ineffective, and where the greatest burden of HIE-related morbidity and mortality exists.

To assess variability among data elements collected among existing neonatal hypoxic-ischemic encephalopathy (HIE) data registries worldwide and to determine the need for future harmonization of standard common data elements.

This was a cross-sectional study of data elements collected from current or recently employed HIE registry data forms. Registries were identified by literature search and email inquiries to investigators worldwide. Data elements were categorized by group consensus.

A total of 1281 data elements were abstracted from 22 registries based in 14 countries, including 3 middle-income countries. Registries had a median of 106.5 distinct data elements per registry (range 59-458). The most commonly collected data were related to pregnancy, therapeutic hypothermia, and short-term hospital outcomes. The least consistently collected data were laboratory values other than acid/base status values. Only 4 variables were consistently collected in every registry. Five registries included neurodevelopmental follow-up fields and 5 others linked their data to a separate follow-up registry.

Many HIE registries are collecting patient data around the world, but there is considerable variability in the number, type, and format of data collected. Future attempts to develop standard common data elements to harmonize data collection globally will be crucial to facilitate worldwide collaboration and to optimize management and outcome of neonatal HIE.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of perinatal brain injury. Creatine is a dietary supplement that can increase intracellular phosphocreatine to improve the provision of intracellular adenosine triphosphate (ATP) to meet the increase in metabolic demand of oxygen deprivation. Here, we assessed prophylactic fetal creatine supplementation in reducing acute asphyxia-induced seizures, disordered electroencephalography (EEG) activity and cerebral inflammation and cell death histopathology.

Fetal sheep (118 ± 1 days' gestational age [dGA]; 0.8 gestation) were implanted with electrodes to continuously record EEG and nuchal electromyogram activity. At 121 dGA, fetuses were randomly assigned to sham control (i.v. saline infusion without umbilical cord occlusion [UCO]; SalCon), continuous i.v. creatine infusion (6 mg/kg/h; CrUCO) or isovolumetric saline (SalUCO) followed by UCO at 128 ± 2 dGA that lasted until the mean arterial blood pressure reached 19 mmHg. Brain tissue was collected for histopathology after 72 hours of recovery.

Creatine supplementation had no effects on basal systemic or neurological physiology. UCO duration did not differ between CrUCO and SalUCO. After reperfusion, CrUCO fetuses had improved EEG power and frequency recovery and reduced electrographic seizure incidence (SalUCO, 86% vs CrUCO, 29%) and burden. At 72 hours after UCO, cell death in the cerebral cortex and astrogliosis in the periventricular white matter were reduced in CrUCO fetuses compared with SalUCO.

Creatine supplementation reduced post-asphyxial seizures and improved EEG recovery. Improvements in functional recovery with creatine were associated with regional reductions in cell death and astrogliosis. Prophylactic creatine treatment has the potential to mitigate functional indices of HIE in the late gestation fetal brain. ANN NEUROL 2025;97:673-687.

Hypoxic-ischemic (HI) encephalopathy is a cerebrovascular injury caused by oxygen deprivation to the brain and remains a major cause of neonatal mortality and morbidity worldwide. Therapeutic hypothermia is the current standard of care but it does not provide complete neuroprotection. Our aim was to investigate the neuroprotective effect of oleuropein (Ole) in a neonatal (seven-day-old) mouse model of HI. Ole, a secoiridoid found in olive leaves, has previously shown to reduce damage against cerebral and other ischemia/reperfusion injuries. Here, we administered Ole as a pretreatment prior to HI induction at 20 or 100 mg/kg. A week after HI, Ole significantly reduced the infarct area and the histological damage as well as white matter injury, by preserving myelination, microglial activation and the astroglial reactive response. Twenty-four hours after HI, Ole reduced the overexpression of caspase-3 and the proinflammatory cytokines IL-6 and TNF-α. Moreover, using UPLC-MS/MS we found that maternal supplementation with Ole during pregnancy and/or lactation led to the accumulation of its metabolite hydroxytyrosol in the brains of the offspring. Overall, our results indicate that pretreatment with Ole confers neuroprotection and can prevent HI-induced brain damage by modulating apoptosis and neuroinflammation.

United Nations Sustainable Development Goals (SDGs) target reduction of global neonatal and infant mortality. We examined trends in both neonatal/overall infant mortality (NMR/IMR) and those related to neonatal encephalopathy (NE) for India.

NE mortality data (1990-2019), stratified by age (0-6 days, 7-27 days) and location, were sourced from the Global Health Data Exchange. Birth cohort data were obtained from the UN Population Prospects. NE-NMR trends were analyzed using joinpoint regression to estimate annual percent change (APC) and average APC (AAPC). Pearson correlation assessed relationships between NE-NMR and sociodemographic index (SDI) or composite coverage index (CCI).

Of 811 million live births (1990-2019), 4.3 million deaths (uncertainty interval [UI]: 3.6-5.3 million) were NE-related. NE-NMR declined from 6.7 to 3.5 (47.5%, AAPC: -2.2%)], while all-cause NMR and IMR declined from 57.3 to 21.6 (62.6%; AAPC: -3.3%) and from 83.2 to 29.9 (64.1%, AAPC: -3.5%) per 1000 livebirths, respectively. NE-NMR correlated inversely with SDI (R² = 0.57, p < 0.01) but not with CCI (R² = 0.08, p = 0.13). Regional disparities persisted.

NE-related neonatal mortality declines, though significant, lags overall neonatal and infant mortality improvements. Sustained, focused and community-oriented efforts are critical to closing these disparities to meet India's SDG targets.

India has achieved significant reductions in neonatal encephalopathy (NE) and all-cause neonatal mortality over the past three decades. From 1990 to 2019, infant mortality rate (IMR) declined from 83 to 29 per 1000 livebirths though NE's share of IMR increased from 8% to 11.8%. Significant interstate variations in NE mortality persist, highlighting the need for targeted state-specific healthcare strategies. NE mortality strongly correlates with sociodemographic development, reflecting the critical role of broad social and economic progress. Strategic and sustained investments in healthcare systems are vital to closing data gaps, reducing disparities, and achieving single-digit neonatal mortality rates by 2030.

This study aimed to evaluate the utility of early and late magnetic resonance imaging (MRI) in infants with neonatal encephalopathy (NE) after therapeutic hypothermia (TH), and to determine the concordance between magnetic resonance spectroscopy (MRS) and early MRI findings.We conducted a retrospective, observational study including encephalopathic neonates born between 2017 and 2023 at two regional perinatal centers. All subjects underwent early diffusion-weighted MRI (DWI) with or without MRS (day: 4-5), and late conventional T1/T2-weighted MRI (day: 12-14). Both MRIs were assigned an injury severity score based on the National Institute of Child Health and Human Development (NICHD) neonatal research network (NRN) pattern of injury, reflecting the injury apparent on the MR modality obtained. MRS injury was defined as the presence of a lactate peak.The majority of the cohort (n = 98) was moderately encephalopathic (78%). Early and late MR imaging was performed at an average of 5.7 and 13.6 days, respectively. Fifteen percent of infants had evidence of hypoxic-ischemic (HI) injury on early imaging only, and 6% on late imaging only. Forty percent of infants exhibited a change in NICHD score severity between early and late MRI. Twenty-three infants (24%) were found to have a milder injury and 16 (16%) were found to have more severe injury on late imaging, when scores were compared with early imaging scores. The concordance of injury between early MRS and MRI was 62.5%. Among the cases of discordant MRI/MRS, MRS detected additional injury in 70% of cases, and MRI detected additional injury in 30% of cases.Both early and late imaging are important to fully define injury and provide accurate neurodevelopmental prognoses in cases of encephalopathic infants following TH. Failure to perform imaging at two intervals would have potentially resulted in missed diagnoses in 6 to 15% of cases and misestimation of injury in up to 40% of cases. · Early and late neuroimaging is important for accurate neurodevelopmental prognostication of encephalopathic neonates.. · The NICHD NRN MRI scoring system is a helpful tool for clinical practice.. · MR spectroscopy shows promise for HI injury but requires more validation..

Neonatal Encephalopathy (NE) remains a major cause of death and long-term severe disabilities, including epilepsy and cerebral palsy in term and near-term infants. The single most common cause is hypoxic-ischemic encephalopathy (HIE). However, there are many other potential causes, including infection, intracranial hemorrhage, stroke, brain malformations, metabolic disorders, and genetic causes. The appropriate management depends on both the specific cause and the stage of evolution of injury. Key tools to expand our understanding of the timing and causes of NE include aEEG, or even better, video EEG monitoring, neuro-imaging including cranial ultrasound and MRI, placental investigations, metabolic, biomarker, and genetic studies. This information is critical to better understand the underlying causes of NE. Therapeutic hypothermia improves outcomes after HIE, but there is still considerable potential to do better. Careful clinical and pre-clinical studies are needed to develop novel therapeutics and to help provide the right treatment at the right time for this high-risk population. IMPACT: Neonatal encephalopathy is complex and multifactorial. This review seeks to expand understanding of the causes, timing, and evolution of encephalopathy in newborns. We highlight key unanswered questions about neonatal encephalopathy.

Detecting and responding to deterioration of a baby during labour is likely to benefit from a standardised approach supported by principles of track-and-trigger systems. To inform co-design of a standardised approach and associated implementation strategies, we sought the views of UK-based maternity professionals.

Two successive cross-sectional surveys were hosted on an online collaboration platform (Thiscovery) between July 2021 and April 2022.

UK.

Across both surveys, 765 UK-based maternity professionals.

Count and percentage of participants selecting closed-ended response options, and categorisation and counting of free-text responses.

More than 90% of participants supported the principle of a standardised approach that systematically considers a range of intrapartum risk factors alongside fetal heart rate features. Over 80% of participants agreed on the importance of a proposed set of evidence-based risk factors underpinning such an approach, but many (over 75%) also indicated a need to clarify the clinical definitions of the proposed risk factors. A need for clarity was also suggested by participants' widely varying views on thresholds for actions of the proposed risk factors, particularly for meconium-stained liquor, rise in baseline fetal heart rate and changes in fetal heart rate variability. Most participants (>75%) considered a range of resources to support good practice as very useful when implementing the approach, such as when and how to escalate in different situations (82%), how to create a supportive culture (79%) and effective communication and decision-making with those in labour and their partners (75%).

We found strong professional support for the principle of a standardised approach to detection and response to intrapartum fetal deterioration and high agreement on the clinical importance of a set of evidence-based risk factors. Further work is needed to address: (1) clarity of clinical definitions of some risk factors, (2) building evidence and agreement on thresholds for action and (3) deimplementation strategies for existing local practices.

To translate and investigate the validity and test-retest reliability of the Vietnamese Paediatric Evaluation of Disability Inventory (vPEDI).

The PEDI was translated and adapted following established guidelines, including forward translation, reconciliation and back translation. Content validity was assessed by expert panels, and the Iitem-Content Validity Index (I-CVI), universal Agreement among experts Scale-Content Validity Index (S-CVI/UA) and the Average CVI (S-CVI/Ave) were calculated. The kappa statistics tested the level of agreement among content experts. The face validity was assessed by determining the percentage of each level of the rating of easiness to understand as rated by 32 caregivers. A total of 446 Vietnamese children ages 6-90 months were recruited to assess the normal raw scores by administering the Vietnamese PEDI. From this total, 50 children were evaluated twice within 2 weeks to examine the test-retest reliability of the vPEDI using intraclass correlation coefficients (ICC) and Bland-Altman analysis.

The vPEDI required minor modifications to be responsive to the culture and typical daily activities in Vietnam. The I-CVI for all domains was above 0.8. The S-CVI/UA and S-CVI/Ave for clarity and relevance were from 0.78 to 0.98. Face validity ratings indicated high understandability. The test-retest reliability of all domains was excellent with ICCs above 0.93.

The vPEDI is a valid and reliable tool for assessing functional abilities in Vietnamese children. Healthcare providers can use the vPEDI to set individual goals and guide intervention strategies for contexts and environments relevant to Vietnam.

Hypoxic-ischemic encephalopathy (HIE) is a common cause of significant neonatal morbidity and mortality. The stronghold of the treatment for moderate-to-severe HIE is therapeutic hypothermia (TH) which provides a neuroprotective effect. However, it also is associated with pain and stress. Moreover, neonates with HIE are subjected to a significant number of painful procedures. Untreated pain during the early neonatal period may entail future challenges such as impaired brain growth and development as well as impaired pain sensitivity later in life. Hereby, the provision of adequate sedation and alleviation of pain and discomfort is essential. There are currently no universally accepted guidelines for sedation and pain management for this patient population. In this review, we highlight non-pharmacologic and pharmacologic methods currently in use to provide comfort and sedation to patients with HIE undergoing TH.

To explore the relationship between motor activities and executive functions (EF) in children (aged 10-12 years) with a history of neonatal hypothermia-treated hypoxic-ischemic encephalopathy (HIE).

Forty-five children (mean age 11 years) with a history of neonatal hypothermia-treated HIE in Stockholm (2007-2009) were included in this cross-sectional study. The children were assessed with Movement Assessment Battery for Children-2 (MABC-2) and Wechsler Intelligence Scale for Children-V (WISC-V). Their parents completed Behavior Rating Inventory of Executive Function-2 (BRIEF-2), Five to Fifteen-R, and MABC-2 Checklist.

Associations between motor capacity and EF, specifically Processing Speed, Working Memory, Flexibility, and Inhibition, were detected. Children scoring below the 15th percentile on MABC-2 had weaker EF, evident in Cognitive Proficiency Index from WISC-V (t43 = 2.515, p = 0.016) and a higher mean Global Executive Composition Score from BRIEF-2 (t43 = -2.890, p = 0.006). Children with stronger EF exhibited better motor capacity. Parental questionnaires indicated everyday difficulties in 52% of the children.

Weaker EF were associated with difficulties in motor activities in early adolescence following hypothermia-treated HIE. These results highlight the importance of evaluating both motor activities and EF to understand children's everyday challenges.

Birth asphyxia is a significant factor contributing to neonatal mortality, particularly in low- and middle-income countries where most neonatal deaths occur. Encouraging women to deliver in hospitals has become a pivotal strategy. Numerous training programmes, such as Helping Babies Breathe (HBB), have been designed to impart neonatal resuscitation and infant care skills to support breathing at birth. Limited attention has been given to exploring the perspectives and experiences of midwives and their hospital managers in translating the acquired knowledge from these programmes into practice. This study aims to explores the understanding, perspectives, and first-hand experiences related to the factors impacting neonatal resuscitation practices and survival, both pre-HBB and post-HBB training.

Qualitative individual interviews and focus group discussions study. A data-driven inductive content analysis approach was used for the analysis.

The high-risk labour ward and theatre at a National Referral Hospital, Uganda.

45 clinically active midwives were enrolled; all had recently completed the HBB training programme.

Semistructured individual interviews (n=2) and focus group discussions (n=43, distributed across seven groups) were held from 26 April to 4 May 2018. Discussions were audio-recorded and transcribed verbatim.

Three emerging themes illustrated midwives' knowledge, opinion on and experience of neonatal resuscitation and survival. Excessive workload, limited access to clean equipment, and ethical dilemmas hampered performance and neonatal survival. Midwives, facing inadequate support, strived to ensure patient safety. While HBB training addresses malpractices, additional training was needed.

Midwives had few opportunities to change their workload and improve their education. This highlights the need for a closer examination of the challenges faced by healthcare providers in ensuring effective neonatal resuscitation and survival in low-resource settings. To address this, we propose better routines for organising work, cleaning and maintaining equipment, and implementing better training routines.

There are divergent views and limited data regarding therapeutic hypothermia (TH) for neonatal hypoxic ischaemic encephalopathy (HIE) in sub-Saharan Africa (SSA). Our aim was to map and synthesize the published literature describing the use of TH for HIE in SSA, and the associated outcomes.

We searched Pubmed, Scopus, Google Scholar, and Web of Science from 1 January 1996 to 31 December 2023 for research studies, protocols, feasibility studies and surveys on term and near-term babies with HIE (population) treated with TH (concept) in SSA (context).

Thirty records were included: Three surveys, one feasibility study and 26 publications describing 23 studies of 21 cohorts, cooling 1420 babies in South Africa, Uganda, and Ghana. There were five studies recruiting at follow-up, five pilot studies, one randomised controlled trial, one case series, and 10 birth cohorts. The methods and design of the studies were highly variable and often inadequate. Only three studies with adequately described and validated cooling methods, non-selective sequential recruitment, and neurological outcomes were identified. Two studies of babies from birth, both with intensive care facilities, reported survival with normal/mildly abnormal outcome in 71% at discharge in one study, and 71% at 12 months in another, with 16% cerebral palsy (CP) in survivors, and only 16% loss to follow-up. The third study, which only included clinic attenders after TH without intensive care, reported 7% CP in survivors, but 36% loss to follow-up.

Data from the adequately described TH studies in SSA indicate outcomes at discharge and twelve months which are similar to global norms. However, these data are limited to South Africa. Interpretation of other studies was limited by loss to follow-up, variable methodology and exclusion of babies with severe HIE in some studies. There is a need for standardised definitions to facilitate interpretation in TH studies.

The aims of this prospective study were to describe feeding difficulties in term infants with perinatal asphyxia and to determine whether the time it takes to achieve full oral feeding correlates with early neurological outcome in a high-income setting. Recruitment included 52 term infants with perinatal asphyxia: 32 without hypoxic-ischaemic encephalopathy (HIE), 9 with mild HIE, and 11 with moderate HIE. The time in days it takes to achieve full oral independent feeding was used as a marker of feeding difficulty. Early neurological outcome was evaluated using neonatal brain magnetic resonance imaging (MRI) and Hammersmith Infant Neurological Examination (HINE) at 3 months. In this cohort, 85% of infants (44/52) needed short-term assisted feeding after birth. The time it takes to achieve full oral feeding correlated with neonatal brain MRI findings and structured neurological examination results at three months. The time it takes to achieve full oral feeding could be a useful clinical measure to assess neurologic recovery after perinatal asphyxia, especially in low-resource settings.

Fluid management in the first postnatal week among infants with perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE) is an important knowledge gap. We aimed to evaluate the effects of fluid restriction on short- and long-term outcomes in infants with HIE. Term infants with moderate or severe HIE on therapeutic hypothermia were randomized within 6 hours of age to receive either restricted intravenous maintenance fluids (45 ml/kg/day on day 1 to a maximum of 120 ml/kg/day on day 6) vs conventional fluid (60 ml/kg/day on day 1 to a maximum of 150 ml/kg/day on day 6). The primary outcome was a composite of mortality or neurological abnormality at hospital discharge. We studied neurodevelopmental disability at 18-24 months using Bayley Scales of Infant Development, third edition. A total of 210 infants were randomized. Three infants died during the hospital stay. The primary outcome of mortality or neurological abnormality at discharge was not significantly different between the restricted and the conventional fluid group [57% vs 53%, RR: 1.07 (95% CI: 0.83, 1.37), P-value .58]. The incidence of cranial magnetic resonance imaging abnormalities was similar in the groups (65% vs 71%, P-value .30). There were no differences in the rates of severe neurodevelopmental disability at 18-24 months in the two groups [27% vs 28%, RR: 0.96 (95% CI: 0.62, 1.50), P-value .88]. Adverse outcomes were similar in both groups. Fluid restriction in the first postnatal week of life did not improve short- and long-term neurodevelopmental outcomes in term infants with moderate or severe HIE.

Preterm fetuses and newborns have a high risk of neural injury and impaired neural maturation, leading to neurodevelopmental disability. Developing effective treatments is rather challenging, as preterm brain injury may occur at any time during pregnancy and postnatally, and many cases involve multiple pathogenic factors. This review examines research on how the preterm fetus responds to hypoxia-ischemia and how brain injury evolves after hypoxia-ischemia, offering windows of opportunity for treatment and insights into the mechanisms of injury during key phases. We highlight research showing that preterm fetuses can survive hypoxia-ischemia and continue development in utero with evolving brain injury. Early detection of fetal brain injury would provide an opportunity for treatments to reduce adverse neurodevelopmental outcomes, including cerebral palsy. However, this requires that we can detect injury using noninvasive methods. We discuss how circadian changes in fetal heart rate variability may offer utility as a biomarker for detecting injury and phases of injury.

Hypoxic ischemic encephalopathy (HIE) is a brain dysfunction occurring in approximately 1-5/1000 term-born neonates. Accurate segmentation of HIE lesions in brain MRI is crucial for prognosis and diagnosis but presents a unique challenge due to the diffuse and small nature of these abnormalities, which resulted in a substantial gap between the performance of machine learning-based segmentation methods and clinical expert annotations for HIE. To address this challenge, we introduce ParadiseNet, an algorithm specifically designed for HIE lesion segmentation. ParadiseNet incorporates global-local learning, progressive uncertainty learning, and self-evolution learning modules, all inspired by clinical interpretation of neonatal brain MRIs. These modules target issues such as unbalanced data distribution, boundary uncertainty, and imprecise lesion detection, respectively. Extensive experiments demonstrate that ParadiseNet significantly enhances small lesion detection (<1%) accuracy in HIE, achieving an over 4% improvement in Dice, 6% improvement in NSD compared to U-Net and other general medical image segmentation algorithms.

Neonatal encephalopathy (NE) is a leading cause of childhood death and disability, particularly in sub-Saharan Africa. Detection of NE-related seizures is challenging. We explored NE seizure semiology and management in Uganda.

Video-EEG was recorded (days 1-5), seizure semiology reviewed according to ILAE classification and administration of antiseizure medication (ASM) evaluated. Clinicians treated seizures based on the clinical presentation alone.

Among 50 participants, 52% (26) had EEG-confirmed seizures; 70% (18) combined electroclinical/electrographic; 4% (1) exclusively electroclinical; 22% (6) electrographic. Of those with electroclinical seizures (19), 42% displayed >1 semiology. Distribution of seizure semiology was; clonic 34% (11); autonomic 24% (8, of which 6 had prolonged ictal apnea); automatisms 18% (6); behavioral arrest 12% (4); and sequential 12% (4). ASM was administered to 64% (32/50). Of those with EEG-confirmed seizures, only 62% (16/26) received ASM. In the non-seizure group, 38% (9/24) received ASM during monitoring. ASM was administered 42 times, of which 45% (19) were considered appropriate.

In this Ugandan NE population, incidence of seizures was high and clinical manifestations frequent. Clonic, autonomic and automatisms were most common. Clinical management was challenging, with both under and overtreatment evident. Respiratory impairment due to autonomic seizures frequently went unrecognized and is a prominent concern, particularly in settings without neonatal intensive care.

Background/Objectives: Neonatal hypoxic-ischemic encephalopathy (HIE) due to perinatal complications remains an important pathology with a significant burden for neonates, families, and the healthcare system. Resuscitation and simulation team training are key elements in increasing patient safety. In this retrospective cohort study, we evaluated whether regular constant training of all personnel working in delivery rooms in South Tyrol improved the outcome of neonates with HIE. Methods: We retrospectively analyzed three groups of neonates with moderate to severe HIE who required therapeutic hypothermia. The first group included infants born before the systematic introduction of training and was compared to the second group, which included infants born after three years of regular training. A third group, which included infants born after the SARS-CoV-2 pandemic, was compared with the previous two to evaluate retention of skills and the long-term effect of our training program. Results: Over the three study periods, mortality decreased from 41.2% to 0% and 14.3%, respectively. There was also a significant reduction of patients with subclincal seizures detected only through EEG, from 47.1% in the first period to 43.7% and 14.3% in the second and third study periods, respectively. Clinical manifestations of seizures decreased significantly from 47.1% to 37.5% and 10.7%, respectively, as well as severe brain lesions in ultrasound (US) and MRI. Conclusions: In this study, constant and regular simulation training for all birth attendants significantly decreases mortality and improves the outcome in neonates with moderate to severe HIE. This positive effect seems to last even after a one-year period during which training sessions could not be performed due to the COVID-19 pandemic.

This study aimed to evaluate the hemodynamic and ventricular performance of neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia using conventional and advanced echocardiographic techniques. This observational, prospective study included 22 neonates with HIE matched with 22 healthy neonates. Echocardiographic studies were performed 24 h after achieving target temperature during hypothermia and 24 h after rewarming. Evaluated echocardiographic parameters included ejection fraction (EF), shortening fraction (SF), right ventricular fractional area change, biventricular Tei index, right ventricular s' wave velocity, tricuspid annular plane systolic excursion, biventricular stroke volume and cardiac output, left ventricular (LV) and right ventricular (RV) global longitudinal strain (GLS), LV circumferential and radial strain, LV twist, and LV torsion. LV EF and SF did not change significantly between the hypothermia and rewarming periods (EF:73 ± 7% vs. 74 ± 5%, p = 0.21; SF:39 ± 6% vs. 41 ± 5%, p = 0.26); however, both were higher after rewarming compared to the control group (EF:70 ± 5%, p = 0.003; SF:36 ± 4%, p = 0.002). There were no significant differences in LV GLS, circumferential and radial strain, twist, and torsion between the HIE and control groups. Pulmonary artery systolic pressure (PASP) and RV GLS were worse in the study group compared to the control group (PASP: hypothermia 45 ± 24 mmHg, p = 0.01; rewarming 53 ± 34 mmHg, p = 0.01; control group 29 ± 11 mmHg; RV GLS: hypothermia 18 ± 5%, p = 0.02; rewarming: 18 ± 4%, p = 0.01; control group 21 ± 2%). Therapeutic hypothermia appears to have no detrimental impact on LV systolic function. RV GLS was the only parameter that demonstrated impaired RV systolic function during therapeutic hypothermia, likely due to elevated PASP.

7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury.

Left-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples.

Our PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p < 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain.

The plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.

Hypoxic ischemic encephalopathy (HIE) is a brain injury that occurs in 1 ~ 5/1000 term neonates. Accurate identification and segmentation of HIE-related lesions in neonatal brain magnetic resonance images (MRIs) is the first step toward identifying high-risk patients, understanding neurological symptoms, evaluating treatment effects, and predicting outcomes. We release the first public dataset containing neonatal brain diffusion MRI and expert annotation of lesions from 133 patients diagnosed with HIE. HIE-related lesions in brain MRI are often diffuse (i.e., multi-focal), and small (over half the patients in our data having lesions occupying <1% of the brain volume (including ventricles)). Segmentation for HIE MRI data is remarkably different from, and arguably more challenging than, other segmentation tasks such as brain tumors with focal and relatively large lesions. We hope that this dataset can help fuel the development of MRI lesion segmentation methods for HIE and small diffuse lesions in general.

Therapeutic hypothermia (TH) is the standard treatment for moderate to severe hypoxic-ischemic encephalopathy (HIE) in developed countries, but data on its safety and efficacy in low-middle-income countries are limited and often conflicting. The impact of enteral feeding during TH remains inadequately explored. We aimed to examine TH's effects on mortality and brain injury and evaluate the safety and effectiveness of minimal enteral feeding during TH. Here, we report our single-center experience with TH over a 10-year period".

A total of 187 neonates with moderate to severe HIE who underwent cooling were included in this retrospective study. Post-rewarming MRI scans were scored using a validated MRI scoring system. The primary outcomes were mortality and composite outcomes of mortality and brain injury.

The mortality rate was 3% in moderate and 25% in severe cases (p < 0.001). Overall, 85% (160/187) of neonates received minimal enteral nutrition. Multivariate regression analysis revealed that the severity of HIE at admission (OR 3.4 (1.03-11.6); p < 0.04) and gestational age (OR: 0.624 (0.442-0.882); p < 0.008) were independent predictors of composite outcomes of death and brain injuries. MRI score was a strong predictor of mortality (AUC: 0.89; p < 0.001) and of ability to orally feed at discharge (AUC: 0.73; p < 0.001).

Mortality rates associated with TH in infants with moderate-severe HIE align with those in high-income countries, and minimal enteral feeding during TH is safe. The severity of HIE, MRI scores, and feeding status are important predictors of outcomes.

Hypoxic ischemic encephalopathy (HIE) is the leading cause of neonatal mortality and disability, but its treatment options are very limited and there is an urgent need to further improve treatment outcomes. The present study aims to reveal the therapeutic effects, action pattern, and potential mechanisms of Cerebroprotein hydrolysate-I (CH-I), a mixture of hydrolyzed peptides and amino acids, for the management of HIE. To simulate the complex pathogenesis of HIE more accurately, we innovatively constructed a "triple hit" neonatal HIE rat model. The efficacy of CH-1 was examined in this model, and it was found that CH-I treatment not only significantly improved the behavior and small molecule metabolism disorders of neonatal HIE rats, but also reduced intracerebral neuronal apoptosis, neuroinflammation, and oxidative stress levels. In addition, the neuroprotective effect of CH-I was also confirmed in the hypoxic oligodendrocyte precursor cell model. We innovatively found that CH-I could reverse myelin damage induced by HIE modeling via activating the Wnt/β-catenin signaling pathway. More importantly, a robust quantitative analysis assay for the main peptides in CH-I was developed based on LC-MS/MS system combining Skyline software. Then the pharmacokinetics of the main peptides was studied based on 'relative exposure approach' combining 'mixed calibration curves' strategy. The transient exposure of peptides in vivo indicated that CH-I should exert neuroprotective effects through the "hit and run" pattern.

Annually, 30 million children are affected by newborn conditions, most in low-income countries, with long-term implications for survivors. We aimed to evaluate neonatal intracranial pathologies identifiable on cranial ultrasound (CUS) in sub-Saharan Africa (SSA). This systematic review and meta-analysis explored the spectrum of neonatal intracranial pathology, in nine databases, using the Joanna Briggs Institute Systematic Review Tools. The review was registered with PROSPERO (CRD42022309249). In total, 92 studies from 14 countries were identified, with South Africa (34%) and Nigeria (28%) most represented. Of these, 38 (42%) focused on intraventricular haemorrhage (IVH), 13 (14%) on congenital brain anomalies, 11 (12%) on intracranial infection, 9 (10%) on ventriculomegaly/hydrocephalus, and 7 (8%) on neonatal encephalopathy. IVH pooled prevalence was 29% (CI 23-35%), with a quarter high-grade (24%, CI 20-29%). Higher prevalence was seen at lower gestation (<32 weeks, 38% (CI 26-50%)) and birthweight (<1500 g, 32% (CI 24-40%)). Periventricular leukomalacia was less common than IVH (9% (CI 6-13%)). A spectrum of intracranial pathology has been reported on neonatal CUS from SSA. IVH affected close to one third of at-risk neonates, and PVL one in eleven, with potentially important implications for longer term outcomes for affected children. IMPACT: Newborn conditions, like prematurity and neonatal encephalopathy, are leading causes of under-5 child mortality, with the greatest burden in sub-Saharan Africa. Intracranial pathologies relating to newborn conditions, may have important long-term consequences, yet frequently go undetected in settings with limited access to imaging. We examined the spectrum and prevalence of different neonatal intracranial pathologies detectable on cranial ultrasound imaging from the sub-Saharan Africa region. A wide spectrum of intracranial pathology was reported, including a high prevalence of intraventricular haemorrhage and periventricular leukomalacia among small and preterm neonates, with potential important implications for childhood outcomes.

Neonatal encephalopathy (NE) is a significant cause of neonatal mortality in low- and middle-income (LAMI) countries, with far-reaching impacts on families and national human capital. Quantifying the disease burden in monetary terms is crucial for resource allocation and public health prioritization, yet data on the economic impact of NE-related neonatal mortality and prevention is limited. This study estimates the country-specific disease burden and economic impacts of NE for the ten countries with the highest death tolls in 2019. Using data from the Global Burden of Disease (GBD) Collaborative Network, we analyzed NE-specific mortality trends and calculated years of life lost (YLLs) based on life expectancy, with and without age weighting and discounting. Economic losses were evaluated using the value per statistical life (VSL) and value per statistical life year (VSLY) methodologies, with sensitivity analyses incorporating variable discount rates. In 2019, the ten countries with the highest NE burden was estimated at 138,763 neonatal deaths. YLLs ranged from 4.5 million with discounting to 9.8 million without. While nine of these countries reduced overall neonatal mortality from 2010 to 2019, six saw rising NE-specific mortality. Economic losses were estimated at $80 billion using the VSL method and between $72 billion and $163 billion using VSLY. Despite overall progress in reducing neonatal mortality, targeted funded strategies are needed to address NE in LAMI countries. Burden of NE could be reduced with improved strategic access to quality antenatal care and effective peripartum practices through efficient and enhanced resource allocation.

There are limited data on the impact of perinatal inflammation on child neurodevelopment in low-middle income countries and among growth-restricted infants.

Population-based, prospective birth cohort study of 288 infants from July 2016-March 2017 in Sylhet, Bangladesh. Umbilical cord blood was analyzed for interleukin(IL)-1α, IL-1β, IL-6, IL-8, and C-reactive protein(CRP). Child neurodevelopment was assessed at 24 months with Bayley-III Scales of Infant Development. We determined associations between cord blood inflammation and neurodevelopmental outcomes, controlling for potential confounders.

248/288 (86%) live born infants were followed until 24 months, among whom 8.9% were preterm and 45.0% small-for-gestational-age(SGA) at birth. Among all infants, elevated concentrations (>75%) of CRP and IL-6 at birth were associated with increased odds of fine motor delay at 24 months; elevated CRP was also associated with lower receptive communication z-scores. Among SGA infants, elevated IL-1α was associated with cognitive delay, IL-8 with language delay, CRP with lower receptive communication z-scores, and IL-1β with lower expressive communication and motor z-scores.

In rural Bangladesh, perinatal inflammation was associated with impaired neurodevelopment at 24 months. The associations were strongest among SGA infants and noted across several biomarkers and domains, supporting the neurobiological role of inflammation in adverse fetal development, particularly in the setting of fetal growth restriction.

Cord blood inflammation was associated with fine motor and language delays at 24 months of age in a community-based cohort in rural Bangladesh. 23.4 million infants are born small-for-gestational-age (SGA) globally each year. Among SGA infants, the associations between cord blood inflammation and adverse outcomes were strong and consistent across several biomarkers and neurodevelopmental domains (cognitive, motor, language), supporting the neurobiological impact of inflammation prominent in growth-restricted infants. Prenatal interventions to prevent intrauterine growth restriction are needed in low- and middle-income countries and may also result in long-term benefits on child development.

Intrapartum-related neonatal encephalopathy (NE) is a leading cause of childhood mortality and morbidity. Continuous electroencephalography (EEG) is gold standard for neonatal brain monitoring; however, low-income country data is lacking. We examined EEG in a Ugandan cohort with NE to describe feasibility, background activity, seizure prevalence and burden, and associations with clinical presentation and outcome.

Neonates with NE were recruited from a single hospital referral centre in Kampala, Uganda (Oct 2019-Oct 2020) and underwent EEG monitoring. Feasibility was assessed as to whether EEG monitoring of diagnostic quality could be achieved from days 1-5. Evolution of clinical presentation was assessed by Sarnat classification and daily Thompson score was performed. EEG background severity was graded at 12, 24, 48 and 72 h after birth, and at time of Thompson score. Seizures were annotated remotely by experts and assessed for frequency, duration, burden, and status epilepticus. Early childhood outcome was assessed at follow up, and adverse outcome defined as death or neurodevelopmental impairment (NDI) at 18-24 months of age.

In this prospective feasibility cohort study, diagnostic quality EEGs were recorded for 50 of 51 recruited neonates (median duration 71.4 h, IQR 52.4-72.2), indicating feasibility. Of 39 participants followed to 18-24 months, 13 died and 7 had NDI. Daily Thompson score and EEG background grade were strongly correlated across all timepoints (days 1-5). Thompson score of ≥7 was most predictive of moderate-severe EEG background abnormality (AUC 0.83). Prognostic accuracy of moderate-severe EEG background grade to predict NDI was high (AUC 0.74). Electrographic seizures were seen in 52% (26); median seizure burden was high at 264 min (IQR 27.8-523.7, range 1.3-1374.1); half (13) had status epilepticus.

EEG monitoring was feasible as a research tool in this sub-Saharan Africa setting. EEG background activity correlated strongly with scored neurological assessment and predicted adverse early childhood outcome. Seizure prevalence and burden, including status epilepticus, were high in this uncooled cohort with important potential longer-term implications for survivors.

Bill & Melinda Gates Foundation grant number OPP1210890; Wellcome Trust Innovator award (209325/Z/17/Z).

Injury to the developing central nervous system resulting from perinatal hypoxia-ischemia (HI) is still a clinical challenge. The only approach currently available in clinical practice for severe cases of HI is therapeutic hypothermia, initiated shortly after birth and supported by medications to regulate blood pressure, control epileptic seizures, and dialysis to support kidney function. However, these treatments are not effective enough to significantly improve infant survival or prevent brain damage. The need to create a new effective therapy has focused attention on metabotropic glutamate receptors (mGluR), which control signaling pathways involved in HI-induced neurodegeneration. The complexity of mGluR actions, considering their localization and developmental changes, and the functions of each subtype in HI-evoked brain damage, combined with difficulties in the availability of safe and effective modulators, raises the question whether modulation of mGluRs with subtype-selective ligands can become a new treatment in neonatal HI. Addressing this question, this review presents the available information concerning the role of each of the eight receptor subtypes of the three mGluR groups (group I, II, and III). Data obtained from experiments performed on in vitro and in vivo neonatal HI models show the neuroprotective potential of group I mGluR antagonists, as well as group II and III agonists. The information collected in this work indicates that the neuroprotective effects of manipulating mGluR in experimental HI models, despite the need to create more safe and selective ligands for particular receptors, provide a chance to create new therapies for the sensitive brains of infants at risk.

We systematically reviewed the evidence from animal studies assessing the effects of pentoxifylline on neonatal hypoxic-ischemic encephalopathy (HIE). The PubMed, EMBASE, EMCARE, MEDLINE, Cochrane Library, and Google Scholar databases were searched for randomized and quasi randomized controlled trials (RCTs) in December 2023 to determine the effects of pentoxifylline in animal models of HIE. The quality of the included studies was assessed via the SYRCLE risk of bias (ROB) tool. The certainty of evidence was assessed via the GRADE methodology. All seven included studies (n = 248) involved a rat HIE model in which pentoxifylline (25-150 mg/kg) was administered intraperitoneally. The majority had unclear ROB. All the studies reported a protective effect of pentoxifylline on HIE-induced organ injury. Mortality was comparable at pentoxifylline doses between 25 and 75 mg/kg but higher at 150 mg/kg than in the control group. Three studies reported macroscopic changes in HIE-affected organs. There was a significant reduction in cerebral infarction (40 and 75 mg/kg), hippocampal atrophy, and visible gut injury (60 mg/kg). A significantly lower number of Caspase 3 immunoreactive cells and necrotic cells were observed at the 60 mg/kg dose, whereas the 100 mg/kg dose had a deleterious effect. Three other studies reported significantly reduced levels of proinflammatory markers including IL-6 and TNF-alpha. Current evidence (with low uncertainty) from a rat model suggests that pentoxifylline has the potential to improve mortality and attenuate organ injury following HIE. Adequately powered, well-designed human RCTs are needed to confirm our findings.

Background: Perinatal asphyxia is a major cause of neonatal morbidity and mortality, often resulting in hypoxic-ischemic encephalopathy (HIE) with long-term neurodevelopmental impairments. While therapeutic hypothermia has emerged as a promising intervention to reduce brain damage, its specific impact on key brain structures and long-term neurodevelopmental outcomes remains underexplored. This study aims to evaluate the effects of therapeutic hypothermia on brain volumetry, cortical thickness, and neurodevelopment in term neonates with perinatal asphyxia. Methods: This prospective cohort study enrolled 34 term neonates with perinatal asphyxia, with 12 receiving therapeutic hypothermia and 22 serving as controls without hypothermia. Brain MRI data were analyzed using Infant FreeSurfer to quantify the basal ganglia volumes, gray matter, white matter, cerebellum, cortical gyri, and cortical thickness. Neurodevelopmental outcomes were assessed at 18 and 24 months, using the Bayley Scale III, evaluating the motor, cognitive, and language domains. Genetic analyses, including next-generation sequencing (NGS) and microarray testing, were performed to investigate potential neurodevelopmental markers and confounding factors. Results: Neonates treated with hypothermia demonstrated significantly larger gray and white matter volumes, with a 3.7-fold increase in gray matter (p = 0.025) and a 2.2-fold increase in white matter (p = 0.025). Hippocampal volume increased 3.4-fold (p = 0.032) in the hypothermia group. However, no significant volumetric differences were observed in the cerebellum, thalamus, or other subcortical regions. Moderate correlations were found between white matter volume and cognitive outcomes, but these associations were not statistically significant. Conclusions: Therapeutic hypothermia appears to have region-specific neuroprotective effects, particularly in gray and white matter and the hippocampus, which may contribute to improved neurodevelopmental outcomes. However, the impact was not uniform across all brain structures. Further research is needed, to investigate the long-term benefits and to optimize therapeutic strategies by integrating advanced neuroimaging techniques and genetic insights.

Hypoxic ischaemic encephalopathy (HIE), a condition where the brain does not receive enough oxygen and/or blood flow around the time of birth, is associated with significant morbidity and mortality. Systemic circulation may be affected due to poor myocardial function. The cochlear hair cells are vulnerable to changes in microcirculation, which may occur in HIE predisposing to hearing loss. Therefore, all infants with HIE undergo neurodevelopmental surveillance after discharge to monitor for adverse neurodevelopment including speech and hearing problems. This study will examine the incidence of confirmed hearing loss in newborn infants with any stage of HIE (cases) and compare them with controls.

All infants diagnosed with any stage of HIE (cases) over a 12-year period (January 2010 to December 2021) will be examined. Controls were newborn infants without HIE who were admitted to the neonatal unit and received intensive care including antibiotics (control group 1) and stable infants in the postnatal ward who received antibiotics (eg, gentamicin) (control group 2). Controls matched for gestation, gender and birth weight will be selected from a similar time period. Infant details and hearing screening data will be gathered from prospectively entered BadgerNet and S4H system databases, respectively. Categorical data will be analysed using the χ2 test. Predictors for hearing loss will be performed using binary logistic regression analysis.

The study is approved by the Health and Care Research Wales (HCRW) Research Ethics Committee and the Health Research Authority (HRA) (reference 21/HRA/4506). The study findings will be presented at national/international conferences and published in peer-reviewed scientific journals.

Effective post-resuscitation care is crucial for improving outcomes in neonates post-asphyxia. This review aimed to provide a comprehensive overview of post-asphyxial aftercare strategies and forms part of a supplement describing an extensive synthesis of effective newborn interventions in low- and middle-income countries (LMICs).

Evidence was generated by performing de novo reviews, updates to reviews via systematic searches, and reanalyses of studies conducted in LMICs from existing reviews.

Sixty-one trials recruiting 5,046 term infants post-asphyxia were included across all intervention domains. Limited studies were available from LMICs related to fluid restriction, antiseizure medications, and early interventions to improve developmental outcomes. Our reanalysis of whole-body cooling trials in LMICs found effects on neonatal mortality and mortality or neurological disability in infancy differed significantly based on the care center and type of cooling device used. Pharmacological therapies for neuroprotection evaluated in 27 trials in middle-income countries had varied effects in neonates with encephalopathy. Majority of the trials (60%) focused on magnesium sulfate therapy and showed significant improvements in short-term mortality and morbidities.

The sample sizes of included trials were relatively small, and the certainty of evidence ranged from very low to moderate. Evidence on long-term survival and neurodevelopmental outcomes was limited. Further research on promising neuroprotective therapies and factors affecting their implementation in low-resource contexts is required. To reduce the high burden related to asphyxia in LMICs, this review underscores the need for a paradigm shift toward prevention, and strategies that emphasize improving antenatal and obstetric care.

Effective post-resuscitation care is crucial for improving outcomes in neonates post-asphyxia. This review aimed to provide a comprehensive overview of post-asphyxial aftercare strategies and forms part of a supplement describing an extensive synthesis of effective newborn interventions in low- and middle-income countries (LMICs).

Evidence was generated by performing de novo reviews, updates to reviews via systematic searches, and reanalyses of studies conducted in LMICs from existing reviews.

Sixty-one trials recruiting 5,046 term infants post-asphyxia were included across all intervention domains. Limited studies were available from LMICs related to fluid restriction, antiseizure medications, and early interventions to improve developmental outcomes. Our reanalysis of whole-body cooling trials in LMICs found effects on neonatal mortality and mortality or neurological disability in infancy differed significantly based on the care center and type of cooling device used. Pharmacological therapies for neuroprotection evaluated in 27 trials in middle-income countries had varied effects in neonates with encephalopathy. Majority of the trials (60%) focused on magnesium sulfate therapy and showed significant improvements in short-term mortality and morbidities.

The sample sizes of included trials were relatively small, and the certainty of evidence ranged from very low to moderate. Evidence on long-term survival and neurodevelopmental outcomes was limited. Further research on promising neuroprotective therapies and factors affecting their implementation in low-resource contexts is required. To reduce the high burden related to asphyxia in LMICs, this review underscores the need for a paradigm shift toward prevention, and strategies that emphasize improving antenatal and obstetric care.

Despite advances in medical technologies, Hypoxic-Ischemic Encephalopathy (HIE) continues to be a problem for neonatal intensive care units. Analysis of crying sounds may be a valuable tool for predicting neonatal disease. However, the characteristics of crying in newborns with HIE are still unclear. One of the factors limiting the ability to focus on that subject is the lack of commercially available infant cry database for research. Also, another reason that complicates the classification is the varying characteristics of infant cry. Accordingly, crying sounds were recorded from 35 infants and demographic characteristics of the study groups are presented as well as the numerical representation of spectral features. Experiments reveal that the existence of HIE causes distinctive variation in energy, energy entropy and spectral centroid features of the utterances; which leads us to conclude that the presented combination of spectral features would function well with any supervised or unsupervised machine learning algorithm.

Fetal hypoxemia is ubiquitous during labor and, when severe, is associated with perinatal death and long-term neurodevelopmental disability. Adverse outcomes are highly associated with barriers to care, such that developing countries have a disproportionate burden of perinatal injury. The prevalence of hypoxemia and its link to injury can be obscure, simply because the healthy fetus has robust coordinated defense mechanisms, spearheaded by the peripheral chemoreflex, such that hypoxemia only becomes apparent in the minority of cases associated with stillbirth, severe metabolic acidemia or adverse neurodevelopmental outcomes. This represents only the extreme end of the spectrum, when defense mechanisms have failed due to severe/prolonged hypoxemia, or the fetal defenses are compromised by additional risk factors. Understanding the fetal defenses to hypoxemia and when the fetus begins to decompensate is crucial to understanding perinatal health and disease, by linking antenatal health, intrapartum events, the neonatal trajectory and ultimately life-long neurodevelopmental health.

This research presents a comprehensive review of studies on neonatal encephalopathy conducted between 2005 and 2024, utilizing knowledge graph analysis through CiteSpace and VOSviewer software. A search of the Web of Science core database identified 893 articles, with the United States emerging as a prominent contributor in terms of publication volume. Key co-occurrence keywords identified include "Hypoxic-ischemic encephalopathy", "Neonatal encephalopathy", and "Therapeutic hypothermia". Notable contributors, such as Seetha Shankaran and Floris Groenendaal, have significantly advanced research in this area. Leading institutions in this field include the University of Washington, while the journal Pediatrics is recognized as a leading publication in the domain of neonatal encephalopathy. These findings provide a solid foundation for guiding future research endeavors.

Neonatal encephalopathy remains a major contributor to death and disability around the world. Acute hypoxia-ischaemia before, during or after birth creates a series of events that can lead to neonatal brain injury. Understanding the evolution of injury underpinned the development of therapeutic hypothermia. This review discusses the determinants of injury, including maturity, the pattern of exposure to HI, impaired placental function, often associated with fetal growth restriction and in the long-term, socio-economic deprivation. Chorioamnionitis has been associated with the presence of NE, but it is important to note that experimentally, inflammation can either sensitize to greater neural injury after HI or alleviate injury, depending on its precise timing. As fetal surveillance tools improve it is likely that improved detection of specific pathways will offer future opportunities for preventive and reparative interventions in utero and after birth.

Social determinants of health are social, economic and environmental factors known to influence health and development of infants, children and adults. Advancing equity in brain health relies upon interdisciplinary collaboration and recognition of the impact of social determinants on brain health through the lifespan and across generations. Critical periods of fetal, infant and early childhood development encompass intrinsic genetic and extrinsic environmental influences with complex gene-environment interactions. This review discusses the influence of social determinants on the continuum of brain health from preconception and pregnancy health, through fetal, infant and childhood neurodevelopment into adulthood. Opportunities for intervention to address the social determinants of brain health across the life cycle are highlighted.

To examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE).

Double-blind pilot randomised controlled trial.

Eight neonatal units in South Asia.

Neonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023.

Erythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age.

Feasibility of randomisation, drug administration and assessment of brain injury using MRI.

Of the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group.

Brain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings.

NCT05395195.