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Objectives: To ascertain the prevalence of newborn encephalopathy in term live births, and also the underlying diagnoses, timing, and outcome at 2 years of surviving infants. Design: Population based observational study. Setting: North Pas-de-Calais area of France, January to December 2000. Patients: All 90 neonates with moderate or severe newborn encephalopathy. Results: The prevalence of moderate or severe newborn encephalopathy was 1.64 per 1000 term live births (95% confidence interval (CI) 1.30 to 1.98). The prevalence of birth asphyxia was 0.86 per 1000 term live births (95% CI 0.61 to 1.10). The main cause of newborn encephalopathy was birth asphyxia, diagnosed in 47 (52%) infants. It was associated with another diagnosis in 11/47 cases (23%). The timing was intrapartum in 56% of cases, antepartum in 13%, ante-intrapartum in 10%, and postpartum in 2%. In 19% of cases, no underlying cause was identified during the neonatal course. Twenty four infants died in the neonatal period, giving a fatality rate of 27% (95% CI 17% to 36%). Three infants died after the neonatal period. At 2 years of age, 38 infants had a poor outcome, defined by death or severe disability, a prevalence of 0.69 per 1000 term live births (95% CI 0.47 to 0.91). In infants with isolated birth asphyxia, this prevalence was 0.36 per 1000 term live births (95% CI 0.20 to 0.52). Conclusions: The causes of newborn encephalopathy were heterogeneous but the main one was birth asphyxia. The prevalence was low, but the outcome was poor, emphasising the need for prevention programmes and new therapeutic approaches.

Purpose of ReviewTherapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research in to ways to further improve neurologic outcomes.Recent FindingsRecent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed.SummaryIn conclusion, recent studies suggest that current protocols for therapeutic hypothermia are near-optimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.

This review discusses an approach to determining the cause of neonatal encephalopathy, as well as current evidence on resuscitation and subsequent management of hypoxic-ischaemic encephalopathy (HIE). Encephalopathy in neonates can be due to varied aetiologies in addition to hypoxic-ischaemia. A combination of careful history, examination and the judicious use of investigations can help determine the cause. Over the last 7 years, infants with moderate to severe HIE have benefited from the introduction of routine therapeutic hypothermia; the number needed to treat for an additional beneficial outcome is 7 (95% CI 5 to 10). More recent research has focused on optimal resuscitation practices for babies with cardiorespiratory depression, such as delayed cord clamping after establishment of ventilation and resuscitation in air. Around a quarter of infants with asystole at 10 min after birth who are subsequently cooled have normal outcomes, suggesting that individualised decision making on stopping resuscitation is needed, based on access to intensive treatment unit and early cooling. The full benefit of cooling appears to have been exploited in our current treatment protocols of 72 hours at 33.5°C; deeper and longer cooling showed adverse outcome. The challenge over the next 5–10 years will be to assess which adjunct therapies are safe and optimise hypothermic brain protection in phase I and phase II trials. Optimal care may require tailoring treatments according to gender, genetic risk, injury severity and inflammatory status.

Neonatal brain injury and associated inflammation is more common in males. There is a well-recognised difference in incidence and outcome of neonatal encephalopathy according to sex with a pronounced male disadvantage. Neurodevelopmental differences manifest from an early age in infancy with females having a lower incidence of developmental delay and learning difficulties in comparison with males and male sex has consistently been identified as a risk factor for cerebral palsy in epidemiological studies. Important neurobiological differences exist between the sexes with respect to neuronal injury which are especially pronounced in preterm neonates. There are many potential reasons for these sex differences including genetic, immunological and hormonal differences but there are limited studies of neonatal immune response. Animal models with induced neonatal hypoxia have shown various sex differences including an upregulated immune response and increased microglial activation in males. Male sex is recognized to be a risk factor for neonatal hypoxic ischemic encephalopathy (HIE) during the perinatal period and this review discusses in detail the sex differences in brain injury in preterm and term neonates and some of the potential new therapies with possible sex affects.

Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products, and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the \"liquid brain biopsy.\" A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.

Neonatal encephalopathy (NE) due to birth asphyxia and trauma has become the second leading cause of global neonatal and under-5 deaths. However, comprehensive data on the global NE burden is scarce. This study aimed to determine the global, regional, and national trends in NE burden from 1990 to 2019, utilizing the 2019 Global Burden of Disease (GBD) study data. Annual incident cases, deaths, disability-adjusted life years (DALYs), and age-standardized rates (incidence [ASIR], mortality [ASMR], DALYs) of NE were collected from the 2019 GBD study. The percentage of relative changes and estimated annual percentage changes (EAPCs) were calculated to assess temporal trends. NE global incident cases increased from 1.33 million in 1990 to 1.38 million in 2019, with a 4.87% rise in ASIR. Global NE deaths remained at 0.57 million in 2019, despite a 29.88% reduction from 1990. Significant annual reductions in ASMR and DALYs were observed post-2005. South Asia and sub-Saharan Africa accounted for 80.00% of global NE cases, with South Asia, Eastern and Western sub-Saharan Africa contributing to 81.42% of global deaths and 79.50% of DALYs. NE-related deaths comprised 22.76% and 11.24% of neonatal and under-5 mortality. There were 3.91 million epilepsy, 4.23 million developmental intellectual disability, and 0.57 million blindness cases caused by NE globally in 2019. Despite a significant reduction in NE mortality from 1990 to 2019, the ongoing rise in incidence, particularly in South Asia and sub-Saharan Africa, is alarming. Targeted initiatives to prevent NE are needed, especially tailored to high-burden regions.

Maca (Lepidium meyenii) has emerged as a popular functional plant food because of its medicinal properties and nutritional value. Macamides, as the exclusively active ingredients found in maca, are a unique series of non-polar, long-chain fatty acid N-benzylamides with multiple bioactivities such as antifatigue characteristics and improving reproductive health. In this study, a new kind of macamide, N-benzyl eicosapentaenamide (NB-EPA), was identified from maca. We further explore its potential neuroprotective role in hypoxic–ischemic brain injury. Our findings indicated that treatment with biosynthesized NB-EPA significantly alleviates the size of cerebral infarction and improves neurobehavioral disorders after hypoxic–ischemic brain damage in neonatal mice. NB-EPA inhibited the apoptosis of neuronal cells after ischemic challenge. NB-EPA improved neuronal cell survival and proliferation through the activation of phosphorylated AKT signaling. Of note, the protective property of NB-EPA against ischemic neuronal damage was dependent on suppression of the p53–PUMA pathway. Taken together, these findings suggest that NB-EPA may represent a new neuroprotectant for newborns with hypoxic–ischemic encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurological sequelae in (near-)term newborns. Despite the use of therapeutic hypothermia, a significant number of newborns still experience impaired neurodevelopment. Neuroimaging is the standard of care in infants with HIE to determine the timing and nature of the injury, guide further treatment decisions, and predict neurodevelopmental outcomes. Cranial ultrasonography is a helpful noninvasive tool to assess the brain before initiation of hypothermia to look for abnormalities suggestive of HIE mimics or antenatal onset of injury. Magnetic resonance imaging (MRI) which includes diffusion-weighted imaging has, however, become the gold standard to assess brain injury in infants with HIE, and has an excellent prognostic utility. Magnetic resonance spectroscopy provides complementary metabolic information and has also been shown to be a reliable prognostic biomarker. Advanced imaging modalities, including diffusion tensor imaging and arterial spin labeling, are increasingly being used to gain further information about the etiology and prognosis of brain injury. Over the past decades, tremendous progress has been made in the field of neonatal neuroimaging. In this review, the main brain injury patterns of infants with HIE, the application of conventional and advanced MRI techniques in these newborns, and HIE mimics, will be described.

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

BackgroundAcute kidney injury (AKI) is common in neonatal encephalopathy (NE) and is associated with worse outcomes. Our objectives were to determine the incidence, risk factors, and outcomes of AKI in infants with NE.MethodsWe performed a retrospective analysis of infants ≥ 34 weeks’ gestational age with a diagnosis of NE from the Analysis of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN) database. AKI was defined using the modified Kidney Disease Improving Global Outcomes criteria. Perinatal and postnatal factors were evaluated. Multivariate logistic and linear regressions were performed.ResultsOne hundred and thirteen patients with NE were included. 41.6% (47) developed AKI. Being born outside the admitting institution (OR 4.3; 95% CI 1.2–14.8; p = 0.02), intrauterine growth restriction (OR 10.3, 95% CI 1.1–100.5; p = 0.04), and meconium at delivery (OR 2.8, 95% CI 1.04–7.7; p = 0.04) conferred increased odds of AKI. After controlling for confounders, infants with AKI stayed in the hospital an average of 8.5 days longer than infants without AKI (95% CI 0.79–16.2 days; p = 0.03).ConclusionsIn this multi-national analysis, several important perinatal factors were associated with AKI and infants with both NE and AKI had longer length of stay than NE alone. Future research aimed at early AKI detection, renoprotective management strategies, and understanding the long-term renal consequences is warranted in this high-risk group of patients.