Perinatal Hypoxic-ischemic Encephalopathy Research Articles

Treatment with inhaled Argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect

Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols. Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. Invivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while invitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation. The systematic review detected 60 experimental studies (16 invitro, 7 exvivo, 31 invivo, 6 with both invitro and invivo) investigating the role of Ar. Only one clinical study was found. Data from six invitro and nineteen invivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events). This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design. This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416.

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

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

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

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

Neonatal magnesium sulphate for neuroprotection: A systematic review and meta-analysis.

To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE). This was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability). Twenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision. Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries.

Socioemotional and Psychological Outcomes of Hypoxic-Ischemic Encephalopathy: A Systematic Review.

Therapeutic hypothermia has reduced the risk of death or major disability following perinatal hypoxic-ischemic encephalopathy (HIE); however, many children who experience perinatal HIE still go on to develop personal and behavioral challenges, which can be difficult for caregivers and a public health burden for society. Our objective with this review is to systematically identify and synthesize studies that evaluate associations between perinatal HIE and socioemotionalor psychological outcomes. We screened all search-returned journal articles from Cochrane Library, Embase, Medline, PsycINFO, Scopus, and Web of Science from data inception through February 1, 2023. Keywords related to HIE (eg, neonatal encephalopathy, neonatal brain injury) and outcomes (eg, social*, emotion*, behav* problem, psycholog*, psychiatr*) were searched with a predefined search string. We included all observational human studies reporting socioemotional or psychological sequelae of term HIE. Study data were recorded on standardized sheets, and the Newcastle-Ottawa Scale was adapted to assess study quality. We included 43 studies documenting 3244 HIE participants and 2132 comparison participants. We found statistically significant associations between HIE and social and emotional, behavioral, and psychological and psychiatric deficits throughout infancy, childhood, and adolescence (19 studies). The authors of the included studies also report nonsignificant findings (11 studies) and outcomes without statistical comparison (25 studies). Perinatal HIE may be a risk factor for a range of socioemotional and psychological challenges in the short- and long-term. Routine screening, early intervention, and follow-up support may be particularly beneficial to this population.

Efficacy of combined rehabilitation programs for infants with perinatal hypoxic-ischemic encephalopathy

Efficacy of combined rehabilitation programs for infants with perinatal hypoxic-ischemic encephalopathy

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 μg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Small animal PET with spontaneous inhalation of 15O-labelled oxygen gases: Longitudinal assessment of cerebral oxygen metabolism in a rat model of neonatal hypoxic-ischaemic encephalopathy.

Perinatal hypoxic-ischaemic encephalopathy (HIE) is the leading cause of irreversible brain damage resulting in serious neurological dysfunction among neonates. We evaluated the feasibility of positron emission tomography (PET) methodology with 15O-labelled gases without intravenous or tracheal cannulation for assessing temporal changes in cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in a neonatal HIE rat model. Sequential PET scans with spontaneous inhalation of 15O-gases mixed with isoflurane were performed over 14 days after the hypoxic-ischaemic insult in HIE pups and age-matched controls. CBF and CMRO2 in the injured hemispheres of HIE pups remarkably decreased 2 days after the insult, gradually recovering over 14 days in line with their increase found in healthy controls according to their natural maturation process. The magnitude of hemispheric tissue loss histologically measured after the last PET scan was significantly correlated with the decreases in CBF and CMRO2.This fully non-invasive imaging strategy may be useful for monitoring damage progression in neonatal HIE and for evaluating potential therapeutic outcomes.

Physical rehabilitation of children with perinatal lesion of the central nervous system

The relevance and social significance of the problem of medical rehabilitation of children with perinatal damage to the central nervous system is determined by the high prevalence of this pathology and the possibility of severe disabling diseases in such children. In the complex treatment of such patients, preference is given to non-drug methods. The leading place in the system of rehabilitation measures for children with perinatal central nervous system damage belongs to kinesiotherapy technologies, as the most gentle and pathogenetically justified.&#x0D; To study the results of research conducted by Russian and foreign authors on the issues of physical rehabilitation of children with perinatal damage to the central nervous system and to conduct an analysis of the effectiveness of the proposed technologies. The literature review for this article was conducted from the eLibrary, PubMed, Cochrane Library databases with a search depth of 20 years. The selection of publications was carried out using keywords: medical rehabilitation, non-drug technologies, perinatal damage to the central nervous system; perinatal hypoxic-ischemic encephalopathy, kinesotherapy, neurodevelopmental therapy, massage, thin finger training method, dry immersion, fitball gymnastics, Vojta therapy; Bobat therapy.

A predictive model for perinatal hypoxic ischemic encephalopathy using linked maternal and neonatal hospital data

PurposeTo build an evidence-based model to estimate case-specific risk of perinatal hypoxic ischemic encephalopathy. MethodsA retrospective, cross-sectional study of all births in Hawaii, Michigan, and New Jersey between 2010 and 2015, using linked maternal labor/delivery and neonatal birth records. Stepwise logistic regression and competitive Akaike information criterion were used to identify the most parsimonious model. Predictive ability of the model was measured with bootstrapped optimism-adjusted area under the ROC curve. ResultsAmong 836,216 births there were 376 (0.45 per 1000) cases of hypoxic ischemic encephalopathy. The final model included 28 variables, 24 associated with increased risk, and 4 that were protective. The optimism-adjusted area under the ROC curve was 0.84. Estimated risk in the study population ranged from 1 in ∼323,000 to 1 in 2.5. The final model confirmed known risk factors (e.g., sentinel events and shoulder dystocia) and identified novel risk factors, such as maternal race and insurance status. ConclusionOur study shows that risk of perinatal hypoxic ischemic encephalopathy injury can be estimated with high confidence. Our model fills a notable gap in the study of hypoxic ischemic encephalopathy prevention: the estimation of risk, particularly in the United States population which is unique with respect to racial and socioeconomic disparities.

Ginkgolide B promotes spontaneous recovery and enhances endogenous netrin-1 after neonatal hypoxic-ischemic brain damage.

Perinatal hypoxic-ischemic encephalopathy (HIE) is a condition that can lead to long-term cognitive, motor, and behavioral impairments in newborns. Although brain hypothermia therapy is currently the standard treatment for HIE, it does not provide complete neuroprotection. As a result, there is a need to explore additional therapies to enhance treatment outcomes. This study aims to investigate the potential role of Ginkgolide B (GB) in promoting neuroplasticity and facilitating spontaneous recovery after HIE. In this study, we employed a neonatal rat model of HIE to investigate the effects of GB on spontaneous recovery. GB treatment was initiated 24 h after hypoxia and administered continuously for a duration of 14 days. We evaluated several outcome measures after the treatment period, including spontaneous behavioral recovery and brain repair. Additionally, we quantified the levels of netrin-1 in both plasma and the peri-ischemic zone after the occurrence of HIE. We found that GB treatment significantly facilitated spontaneous behavioral recovery in the HIE pups. Furthermore, cognitive function was restored, and brain tissue repair had a noticeable acceleration. We observed increased cell proliferation in the subventricular, stratum, and subgranular zones. Of particular interest, we observed elevated levels of netrin-1 in both plasma and the ischemic penumbra following GB treatment. Our findings suggest that GB promotes neuroplasticity and enhances spontaneous recovery in newborns affected by HIE. The observed upregulation of netrin-1 may be crucial in mediating these effects. These results highlight the promising potential of GB as a post-HIE therapy, particularly in enhancing spontaneous recovery and improving long-term outcomes.

Childhood-onset epilepsy in patients with dyskinetic cerebral palsy caused by basal ganglia and thalamic lesions

ObjectiveTo elucidate the incidence and outcomes of childhood-onset epilepsy and associated factors in term-born patients with basal ganglia and thalamic lesion (BGTL)-induced dyskinetic cerebral palsy (DCP) caused by perinatal hypoxic-ischemic encephalopathy (HIE). MethodsWe studied 104 term-born patients with BGTL-induced DCP (63 males and 41 females, aged 2–22 years) to investigate the incidence of epilepsy and the factors related to its development. We used multivariate analysis to assess perinatal factors, gross motor function, and the extent of brain lesions. We also investigated the seizure onset, clinical course, and electroencephalography (EEG) characteristics. ResultsThe cumulative epilepsy incidence was 36%. Multiple logistic regression analysis revealed that deep white matter lesions were the only independent risk factor for epilepsy. The confirmed seizure types included epileptic spasms (ES, n = 13), myoclonic seizures (MS, n = 6), and focal-onset seizures (FS, n = 24). Only patients with deep white matter lesions exhibited ES or MS. The symptoms of FS resembled those of self-limited epilepsy with centrotemporal spikes; however, only half of the patients reached remission by the time of investigation, and four patients had more than one seizure per month despite appropriate drug therapy. Focal spikes in the peri-rolandic area were detected not only in patients with FS but also in half of the patients without epilepsy. ConclusionsOne-third of term-born patients with BGTL-induced DCP caused by perinatal HIE develop epilepsy, and deep white matter lesions increase the likelihood of epilepsy. Preparation for early-onset ES, MS, and subsequent FS is beneficial.

Perinatal Hypoxic-Ischemic Encephalopathy: Incidence Over Time Within a Modern US Birth Cohort

BackgroundRecent studies suggest that the incidence of perinatal hypoxic-ischemic encephalopathy (HIE) may be increasing in developed countries. However, this observed increase may be due to increased ascertainment and increased treatment with therapeutic hypothermia rather than an increase in disease burden. In a US population-based cross-sectional study, we determined the incidence of perinatal HIE over time. MethodsThe study population included all 289,793 live-born infants ≥35 weeks gestational age born at 15 Kaiser Permanente Northern California hospitals between 2012 and 2019. Perinatal HIE was defined as the presence of both neonatal acidosis (i.e., cord blood pH < 7 or base deficit ≥10, or base deficit ≥10 on first infant gas) and neonatal encephalopathy confirmed by medical record review. Hospital discharge diagnoses of HIE were determined by extracting International Classification of Disease diagnostic codes for HIE assigned upon hospital discharge. ResultsThe population incidence of perinatal HIE was 1.7 per 1000. Although the incidence of perinatal HIE did not change significantly, both hospital discharge diagnoses of HIE and treatment with therapeutic hypothermia increased significantly during the study period. The sensitivity and positive predictive value of a hospital discharge diagnosis of HIE for identifying perinatal HIE confirmed by chart review were 72% and 79%, respectively. ConclusionsDuring the study years, the incidence of perinatal HIE remained stable despite increases in hospital discharge diagnoses of HIE and in the use of therapeutic hypothermia. Our findings underscore the importance of applying stringent diagnostic criteria when diagnosing this complex condition.

Perinatal asphyxia of full-term newborns: from pathophysiology to long-term outcomes

The fetal environment and circulatory patterns are very different from that of extrauterine life. The fetus evolved to thrive and grow in a relative hypoxemic environment adapted several mechanisms in response to changes in oxygen concentration in the blood to ensure optimal oxygen delivery to the brain and heart. However according to estimates of the World Health Organization in the world from 4 to 9 million newborns are born annually in a state of perinatal asphyxia. In economically underdeveloped countries, this indicator is higher than in developed countries, but in general, the frequency of perinatal asphyxia remains at a rather high level in the modern world. Perinatal asphyxia or hypoxic-ischemic encephalopathy, in newborns can cause multiple organ dysfunction in the neonatal period, severe diseases in the future, lead to disability and infant mortality. Perinatal asphyxia is characterized by a violation of gas exchange, which can lead to varying degrees of hypoxia, hypercapnia and acidosis, depending on the duration and degree of interruption of air flow, however, obstructed perinatal gas exchange does not have precise biochemical criteria. In addition, the exact mechanisms of pathophysiology of perinatal asphyxia have not been fully studied, as a result of which the “gold standard” of treatment remains an active area of research. The publication reflects modern views on the main stages of the pathogenesis of perinatal asphyxia, shows changes in blood circulation during delivery and the neonatal period, presents current data on emerging disorders in the newborn’s body against the background of hypoxic ischemic encephalopathy.

Fetal growth restriction and small for gestational age as predictors of neonatal morbidity: which growth nomogram to use?

Fetal growth nomograms were developed to screen for fetal growth restriction and guide clinical care to improve perinatal outcomes; however, existing literature remains inconclusive regarding which nomogram is the gold standard. This study aimed to compare the ability of 4 commonly used nomograms (Hadlock, International Fetal and Newborn Growth Consortium for the 21st Century, Eunice Kennedy Shriver National Institute of Child Health and Human Development-unified standard, and World Health Organization fetal growth charts) and 1 institution-specific reference to predict small for gestational age and poor neonatal outcomes. This was a retrospective cohort study of all nonanomalous singleton pregnancies undergoing ultrasound at ≥20 weeks of gestation between 2013 and 2020 and delivering at a single academic center. Using random selection methods, the study sample was restricted to 1 pregnancy per patient and 1 ultrasound per pregnancy completed at ≥22 weeks of gestation. Fetal biometry data were used to calculate estimated fetal weight and percentiles according to the aforementioned 5 nomograms. Maternal and neonatal data were extracted from electronic medical records. Logistic regression was used to estimate the association between estimated fetal weight of <10th and <3rd percentiles compared with estimated fetal weight of 10th to 90th percentile as the reference group for small for gestational age and the neonatal composite outcomes (perinatal mortality, hypoxic-ischemic encephalopathy or seizures, respiratory morbidity, intraventricular hemorrhage, necrotizing enterocolitis, hyperbilirubinemia or hypoglycemia requiring neonatal intensive care unit admission, and retinopathy of prematurity). Receiver operating characteristic curve contrast estimation (primary analysis) and test characteristics were calculated for all nomograms and the prediction of small for gestational age and the neonatal composite outcomes. We restricted the sample to ultrasounds performed within 28 days of delivery; moreover, similar analyses were completed to assess the prediction of small for gestational age and neonatal composite outcomes. Among 10,045 participants, the proportion of fetuses classified as <10th percentile varied across nomograms from 4.9% to 9.7%. Fetuses with an estimated fetal weight of <10th percentile had an increased risk of small for gestational age (odds ratio, 9.9 [95% confidence interval, 8.5-11.5] to 12.8 [95% confidence interval, 10.9-15.0]). In addition, the estimated fetal weight of <10th and <3rd percentile was associated with increased risk of the neonatal composite outcome (odds ratio, 2.4 [95% confidence interval, 2.0-2.8] to 3.5 [95% confidence interval, 2.9-4.3] and 5.7 [95% confidence interval, 4.5-7.2] to 8.8 [95% confidence interval, 6.6-11.8], respectively). The prediction of small for gestational age with an estimated fetal weight of <10th percentile had a positive likelihood ratio of 6.3 to 8.5 and an area under the curve of 0.62 to 0.67. Similarly, the prediction of the neonatal composite outcome with an estimated fetal weight of <10th percentile had a positive likelihood ratio of 2.1 to 3.1 and an area under the curve of 0.55 to 0.57. When analyses were restricted to ultrasound within 4 weeks of delivery, among fetuses with an estimated fetal weight of <10th percentile, the risk of small for gestational age increased across all nomograms (odds ratio, 16.7 [95% confidence interval, 12.6-22.3] to 25.1 [95% confidence interval, 17.0-37.0]), and prediction improved (positive likelihood ratio, 8.3-15.0; area under the curve, 0.69-0.75). Similarly, the risk of neonatal composite outcome increased (odds ratio, 3.2 [95% confidence interval, 2.4-4.2] to 5.2 [95% confidence interval, 3.8-7.2]), and prediction marginally improved (positive likelihood ratio, 2.4-4.1; area under the curve, 0.60-0.62). Importantly, the risk of both being small for gestational age and having the neonatal composite outcome further increased (odds ratio, 21.4 [95% confidence interval, 13.6-33.6] to 28.7 (95% confidence interval, 18.6-44.3]), and the prediction of concurrent small for gestational age and neonatal composite outcome greatly improved (positive likelihood ratio, 6.0-10.0; area under the curve, 0.80-0.83). In this large cohort, Hadlock, recent fetal growth nomograms, and a local population-derived fetal growth reference performed comparably in the prediction of small for gestational age and neonatal composite outcomes.

Neurosteroid pathway derangement in asphyctic infants treated with hypothermia: an untargeted metabolomic approach.

The pathobiological mechanisms associated with perinatal asphyxia and hypoxic-ischemic encephalopathy are complex and poorly understood. The metabolic effects of therapeutic hypothermia have been partially explored. We conducted a single-center longitudinal study to investigate the metabolic effects of perinatal asphyxia and hypoxic-ischemic encephalopathy on the urinary metabolome of a group of 12 asphyctic infants over time compared to 22 matched healthy newborns, using untargeted metabolomics based on mass spectrometry. Over-representation pathway analysis identified the steroidogenesis pathway as being significantly disrupted, with reduced steroid levels in the first three days of life despite treatment with hypothermia. Comparison with matched healthy newborns showed that the urinary steroid content was lower in asphyctic infants before hypothermia. The lysine degradation and carnitine synthesis pathways were also significantly affected. Steroidogenesis is significantly disrupted in asphyctic infants compared to healthy newborns. Given how neurosteroids are involved in neuromodulation and neuroprotection, translational research is warranted on the potential role of neurosteroid-based intervention in asphyctic infants. None.

Exposure to maternal diabetes during pregnancy is associated with aggravated short-term neonatal and neurological outcomes following perinatal hypoxic-ischemic encephalopathy.

Infants of diabetic mothers are at higher risk of perinatal morbidities and glycemic instability, but the impact of maternal diabetes on neonatal and neurological short-term outcomes of neonates with hypoxic-ischemic encephalopathy (HIE) remains poorly described. To determine the impact of maternal diabetes on neonatal and neurological short-term outcomes following neonatal HIE. A retrospective single-center study including 102 term neonates with HIE who received therapeutic hypothermia (TH) treatment between 2013 and 2020. Multiple regression analysis was used to assess the relationship between the presence of maternal diabetes and short-term outcomes. Neonates with HIE and maternal diabetes exposure had a significantly lower gestational age at birth (38.6 vs 39.7 weeks of gestation, **P=0.005) and a significantly higher mean birth weight (3588752 vs 3214514 g, *P=0.012). Infants of diabetic mother (IDM) with HIE were ventilated longer (8 days vs. 4 days, **P=0.0047) and had a longer neonatal intensive care unit (NICU) stay (18 days vs. 11 days, *P=0.0483) as well as longer time to reach full oral feed (15 days vs. 7 days, *P=0.0432) compared to neonates of non-diabetic mother. Maternal diabetes was also associated with increased risk of death or abnormal neurological examination at discharge in neonates with HIE (OR 6,41 [1.54-26,32]). In neonates with HIE, maternal diabetes is associated with an increased risk of death or short-term neonatal morbidities, such as longer duration of ventilation, prolonged neonatal stay, greater need for tube feeding and being discharged with an abnormal neurological examination. Strategies to prevent, reduce or better control maternal diabetes during pregnancy should be prioritized to minimize complications after perinatal asphyxia.

A Scoping Review of Cerebral Doppler Arterial Waveforms in Infants.

Cerebral Doppler ultrasound has been an important tool in pediatric diagnostics and prognostics for decades. Although the Doppler spectrum can provide detailed information on cerebral perfusion, the measured spectrum is often reduced to simple numerical parameters. To help pediatric clinicians recognize the visual characteristics of disease-associated Doppler spectra and identify possible areas for future research, a scoping review of primary studies on cerebral Doppler arterial waveforms in infants was performed. A systematic search in three online bibliographic databases yielded 4898 unique records. Among these, 179 studies included cerebral Doppler spectra for at least five infants below 1 y of age. The studies describe variations in the cerebral waveforms related to physiological changes (43%), pathology (62%) and medical interventions (40%). Characteristics were typically reported as resistance index (64%), peak systolic velocity (43%) or end-diastolic velocity (39%). Most studies focused on the anterior (59%) and middle (42%) cerebral arteries. Our review highlights the need for a more standardized terminology to describe cerebral velocity waveforms and for precise definitions of Doppler parameters. We provide a list of reporting variables that may facilitate unambiguous reports. Future studies may gain from combining multiple Doppler parameters to use more of the information encoded in the Doppler spectrum, investigating the full spectrum itself and using the possibilities for long-term monitoring with Doppler ultrasound.

EBNEO Commentary: Safety and efficacy of erythropoietin in neonates with hypoxic-ischaemic encephalopathy.

Acta PaediatricaEarly View COMMENTARYFree Access EBNEO Commentary: Safety and efficacy of erythropoietin in neonates with hypoxic–ischaemic encephalopathy Lorraine Marie Chung, Corresponding Author Lorraine Marie Chung lorraine.chung2@health.qld.gov.au orcid.org/0000-0003-0207-0435 Department of Child and Adolescent Health Unit, Mackay Base Hospital, Mackay, Queensland, Australia Correspondence Lorraine Marie Chung, Mackay Base Hospital, Mackay, Qld, Australia. Email: lorraine.chung2@health.qld.gov.auSearch for more papers by this authorGopakumar Hariharan, Gopakumar Hariharan orcid.org/0000-0002-6298-5066 Department of Child and Adolescent Health Unit, Mackay Base Hospital, Mackay, Queensland, Australia James Cook University, Mackay, Queensland, AustraliaSearch for more papers by this author Lorraine Marie Chung, Corresponding Author Lorraine Marie Chung lorraine.chung2@health.qld.gov.au orcid.org/0000-0003-0207-0435 Department of Child and Adolescent Health Unit, Mackay Base Hospital, Mackay, Queensland, Australia Correspondence Lorraine Marie Chung, Mackay Base Hospital, Mackay, Qld, Australia. Email: lorraine.chung2@health.qld.gov.auSearch for more papers by this authorGopakumar Hariharan, Gopakumar Hariharan orcid.org/0000-0002-6298-5066 Department of Child and Adolescent Health Unit, Mackay Base Hospital, Mackay, Queensland, Australia James Cook University, Mackay, Queensland, AustraliaSearch for more papers by this author First published: 07 February 2023 https://doi.org/10.1111/apa.16683 Wu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, et al. Trial of erythropoietin for hypoxic–ischemic encephalopathy in newborns. N Engl J Med. 2022;387:148-159. PMID: 35830641. EBNEO commentaries on manuscripts relevant to evidence-based neonatal practice are welcomed and published after a formal peer-review process. To learn more visit https://ebneo.org/author-instructions and contact Dr. Amy Keir amy.keir@adelaide.edu.au or Dr. Clyde J. Wright clyde.wright@cuanschutz.edu with questions. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abbreviations HIE hypoxic-ischaemic encephalopathy MRI magnetic resonance imaging Therapeutic hypothermia remains the only proven treatment to improve mortality and morbidity in neonates with hypoxic–ischaemic encephalopathy (HIE).1 Preclinical models have demonstrated erythropoietin as a potential adjuvant therapy in neonatal HIE due to its neuroprotective and neuro-regenerative effects.1 The anti-inflammatory and anti-oxidant effects of erythropoietin promotes neurogenesis through remodelling of brain tissue after HIE.2 The neuroprotective effects of erythropoietin result from its binding to erythropoietin receptors on mature neurons and neuronal progenitors causing induction of antiapoptotic genes.2 The data from small clinical trials suggest that erythropoietin monotherapy for neonates with moderate-to-severe HIE reduces the risk of cerebral palsy and moderate-to-severe cognitive impairment.2, 3 Furthermore, erythropoietin with or without hypothermia demonstrated reduced risk of brain injury on MRI in two randomised control trials.2 Previous randomised control trials investigating erythropoietin in combination with therapeutic hypothermia have shown promising results of neuroprotective benefit although were limited by small sample size.2 A small randomised controlled trial by Saad et al.,4 which included 33 neonates with HIE demonstrated lower occurrence of clinically detectable seizures in the first week of life. Conversely, preclinical data in studies by Fan et al. and Fang et al. did not demonstrate positive effects of erythropoietin in HIE.1 Furthermore, the study conducted by Wassink et al.5 in near-term fetal sheep concluded that high-dose erythropoietin may not be an effective adjuvant therapy in HIE.5 This phase III study by Wu et al. concluded no improvement in neurodevelopmental outcome in neonates with HIE following combined erythropoietin intervention and therapeutic hypothermia compared with placebo. Behavioural abnormalities were found to be four times greater in the erythropoietin group compared with placebo; however, this will need further investigation by a follow-up study beyond 36 months of age. The study concluded a higher risk of serious adverse events in the erythropoietin group compared to the placebo group. The conclusions regarding adverse effects from the study by Wu et al. are in contrast with prior systematic reviews conducted by Razak and Hussain2 and Ivain et al.6 which demonstrated erythropoietin monotherapy not to be associated with significant adverse outcomes or complications. Furthermore, Oorschot et al.1 and Garg et al.7 showed no adverse effects in studies of combined erythropoietin and therapeutic hypothermia in the treatment of babies with HIE. A wide range of adverse effects were monitored during different clinical trials.1, 2, 6, 7 Wu et al. combined various adverse events which included ‘death, systemic hypertension, polycythaemia, disseminated intravascular coagulation, major venous or arterial thrombosis, pulmonary hypertension, intracranial haemorrhage, cardiopulmonary arrest or other unexpected life-threatening event’ into the composite outcome of ‘serious adverse events’. The results of this single randomised control trial showing contrasting results compared with prior meta-analysis studies in terms of adverse events could be due to variation in parameters and classifications used in different trials. The results of the ongoing trial ‘Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns’ (PAEAN) is likely to provide more information on erythropoietin's adverse effects and neuroprotective effects.8 Further larger-scale studies on the use of erythropoietin without hypothermia would be important, particularly in resource-limited countries where the option of therapeutic hypothermia is limited and most injury related to HIE is sub-acute.9 URL LINK: https://ebneo.org/ebneo-commentary-epo-for-hie CONFLICT OF INTEREST STATEMENT None. REFERENCES 1Oorschot DE, Sizemore RJ, Amer AR. Treatment of neonatal hypoxic-ischemic encephalopathy with erythropoietin alone, and erythropoietin combined with hypothermia: history, current status, and future research. Int J Mol Sci. 2020; 21(4):1487. 2Razak A, Hussain A. Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinat Med. 2019; 47(4): 478- 489. 3Perrone S, Lembo C, Gironi F, et al. Erythropoietin as a neuroprotective drug for newborn infants: ten years after the first use. Antioxidants (Basel). 2022; 11(4): 652. 4Saad K, Badr-El Din M, Abougabal ASH, Abdel-Salam H. Effect of erythropoietin as adjunctive therapy with whole-body cooling for treatment of hypoxic-ischemic encephalopathy in newborns. Alex J Pediatr. 2017; 30(2): 45- 52. 5Wassink G, Davidson JO, Crisostomo A, et al. Recombinant erythropoietin does not augment hypothermic white matter protection after global cerebral ischaemia in near-term fetal sheep. Brain Commun. 2021; 3(3):fcab172. 6Ivain P, Montaldo P, Khan A, et al. Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low-to-middle income countries: a systematic review and meta-analysis. J Perinatol. 2021; 41(9): 2134- 2140. 7Garg B, Sharma D, Bansal A. Systematic review seeking erythropoietin role for neuroprotection in neonates with hypoxic ischemic encephalopathy: presently where do we stand. J Matern Fetal Neonatal Med. 2018; 31(23): 3214- 3224. 8Liley H, Hunt R, Jacobs S, et al. Preventing adverse outcomes of neonatal hypoxic ischaemic encephalopathy with erythropoietin: a phase III randomised placebo controlled multi-centre clinical trial. ClinicalTrials.gov Identifier: NCT03079167. Updated September 22, 2022. Accessed November 29, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03079167 9Thayyil S, Pant S, Montaldo P, et al. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. Lancet Glob Health. 2021; 9(9): e1273- e1285. Early ViewOnline Version of Record before inclusion in an issue This article also appears in:EBNEO Commentaries in Acta Paediatrica ReferencesRelatedInformation

Brief research report: Chest radiographic thoracic area in term ventilated infants without respiratory disease.

To report values of the chest radiographic thoracic area (CRTA) in ventilated, term-born infants without respiratory disease and to evaluate whether CRTA is related to demographic data at birth. Retrospective, observational cohort study in a tertiary neonatal unit at King's College Hospital NHS Foundation Trust, London, UK.Newborn infants born after 36 completed weeks of gestation, ventilated for poor perinatal adaptation or hypoxic ischaemic encephalopathy without respiratory disease and admitted in a recent eight-year period (2014-2022).The CRTA was assessed by free-hand tracing of the perimeter of the thoracic area as outlined by the diaphragm and the rib cage excluding the mediastinal structures and was calculated using the Sectra PACS software. One hundred and twenty-one infants (75 male) were included with a median (IQR) gestation of 40 (38-41) weeks and birth weight of 3.41 (3.04-3.75) kg. The median (IQR) CRTA was 2,589 (2,167-2,943) mm2 and was significantly related to birth weight (r = 0.316, p = 0.003), gestation at birth (r = 0.193, p = 0.032) and birth weight z-score (r = 0.187, p = 0.038). We report values of the chest radiographic thoracic area in ventilated term-born infants which could be used as reference for determining respiratory disease severity.