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Currently available gestational age scoring systems are complex and inaccurate for wider use in low- and middle-income countries (LMIC), particularly in infants with neonatal encephalopathy. Here, we aimed to develop a scoring system based on physical characteristics for identifying late preterm infants from term infants. This was a prospective observational study conducted in 2 phases- the discovery phase and validation phase. In the first phase, we examined the accuracy of 10 objective physical characteristics in a prospective cohort of 1,006 infants recruited from three hospitals in South India. A weighted scoring system and a photo card were then developed based on the six best performing characteristics which were validated in another prospective cohort of 1,004 infants. The final score had a sensitivity of 66.0% (95% confidence intervals [CIs], 58.4-73.8%), specificity of 80.0% (95% CI, 77.2-82.7%), and a negative predictive value of 93.0% (95% CI, 90.5-94.5%). This scoring system may have wider applications in LMIC, particularly in community settings and in infants with neonatal encephalopathy.· This is an easily administered scoring system using physical characters to identify late preterm infants.. · The scoring is not affected by neurological injury and can be used in encephalopathic infants.. · Overall accuracy is better than previous scores encompassing the physical criteria alone..

Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate (n = 150) or severe NE (n = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion (n = 141) were more hypotensive (49% vs. 25%, p = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days, p = 0.009) than those who did not (n = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group (p > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5; p = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12–0.21] vs. 0.13 [0.11–0.18]; p = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10; p = 0.98), language (89 ± 22 vs. 93 ± 8; p = 0.53), and cognitive scores (95 ± 21 vs. 99 ± 13; p = 0.56) at 22 months. Adverse neurodevelopmental outcome (adjusted for severity of encephalopathy) was seen in 26 (18%) of the morphine group, and none of the nonmorphine group (p = 0.11). Preemptive morphine sedation during TH does not offer any neuroprotective benefits and may be associated with increased hospital stay. Optimal sedation during induced hypothermia requires further evaluation in clinical trials.

J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.

Background Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy. Methods The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks’ gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. Results We included data from seven studies (6 Case-control studies, 1 cluster-randomised trial) of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; p Conclusions Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.

Background Parental consent rates for neonatal interventional trials are significantly higher in Low and middle-income countries (LMIC) than in high-income countries, raising concerns about the credibility of the consent processes (Patterson et al PLOS One 2021). We conducted a mixed-methods study to understand the informed consent process in a neonatal cooling trial [Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial] conducted in India, Sri Lanka and Bangladesh. Methods Term infants with neonatal encephalopathy, aged less than six hours were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed the A-V records of the consent process using a 5-point Likert scale on three parameters – Empathy, Information, Autonomy. Additionally, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 health care professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts. Results In HELIX trial, a total of 475 parents were approached, of which 408 (86%) consented. Of these, 294 A-V records were analysed. Median (Interquartile range) score for empathy, information, autonomy was 5 (0), 5 (1) and 5 (1) respectively. However, thematic analysis suggested that the parental decision to participate was based on a unreserved trust in the treating doctors, therapeutic misconception, and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial, nor the nature of the intervention. Lower levels of parental education and misinformation further convoluted the voluntary informed consent process. Parents were visibly incapacitated, and many told the doctor to do whatever is best for the baby. Clinicians lacked equipoise and were biased towards cooling therapy as it was already a standard of care in high-income countries, and this influenced parental decision making. However, the HELIX trial results subsequently showed cooling was harmful and increased mortality in these settings. Conclusion Despite rigorous research governance and consent process, parental decisions were heavily influenced by situational incapacity and a trust in doctors to make the right decision on their behalf. Further research is required to identify culturally and context appropriate strategies to ensure truly informed trial participation.

Tagin and Gunn suggest that the current criteria from randomised controlled trials of hypothermia for moderate or severe encephalopathy are limiting the application to infants with perinatal hypoxia-ischaemia.1 They propose that current criteria be expanded and simplified based on clinical judgement to maximise potential benefit. Extending hypothermia therapy based on clinical context alone will be difficult to implement without many potential downsides (cooling for the wrong diagnosis, overtreatment, iatrogenic problems from a therapy not needed and so on). The criteria of the trials of hypothermia for moderate or severe encephalopathy used parameters which indicated that an impairment of gas exchange had occurred close to the time of birth and detailed the response to the impaired gas exchange [encephalopathy, abnormal amplitude integrated electroencephalogram (aEEG)].2 Acid base disturbances and elevations of lactate at birth or in the first postnatal hour provide objective measures to support critical events close to birth. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) screening criteria for hypoxia-ischaemia included approaches when no blood gases were available or when there was less fetal acidemia; infants then had to have evidence of an acute perinatal sentinel event and either a 10 min Apgar score

In the past decade, therapeutic hypothermia using a variety of low-cost devices has been widely implemented in India and other low-and middle-income countries (LMIC) without adequate evidence of either safety or efficacy. The recently reported data from the world’s largest cooling trial (HELIX - hypothermia for encephalopathy in low- and middle-income countries) in LMIC provides definitive evidence of harm of cooling therapy with increase in mortality (number to harm 9) and lack of neuroprotection. Although the HELIX participating centers were highly selected tertiary neonatal intensive care units in South Asia with facilities for invasive ventilation, cardiovascular support, and 3 Tesla magnetic resonance imaging (MRI), and the trial used state-of-the-art automated servo-controlled cooling devices, a therapy that is harmful under such optimal conditions cannot be safe in low-resource settings that cannot even afford servo-controlled cooling devices.The HELIX trial has set a new benchmark for conducting high quality randomized controlled trials in terms of research governance, consent, ethics, follow-up rates, and involvement of parents. The standard care for neonatal encephalopathy in LMIC should remain normothermia, with close attention to prevention of hyperthermia. There is no role for therapeutic hypothermia in LMIC as the efficacy of hypothermia is dependent on the population, and not merely on the level of neonatal intensive care facilities. Future research should explore timings and origins of brain injury and prevention of brain injury in LMIC, with a strong emphasis on academic research capacity building and patient and public engagement.

Stillbirth is the loss of a fetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing fetus. We observed four heterozygous, nonsynonymous variants in transient receptor potential melastatin 7 (TRPM7), a ubiquitously expressed ion channel known to regulate cardiac development and repolarization in mice. We used site-directed mutagenesis and single-cell patch-clamp to analyze the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. Our results show that two TRPM7 variants, p.G179V and p.T860M, lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents; however, siRNA knockdown did not directly affect action potential morphology. TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.

Summary Background Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia. Methods We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18–22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , NCT02387385 . Findings We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention. Interpretation Therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available. Funding National Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation. Translations For the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section.

Increasing confidence in therapeutic hypothermia and ambiguity of cooling guidelines has led to many clinicians extending its use to untested populations like mild encephalopathy, or even no encephalopathy. Poor quality clinical neurological examination for encephalopathy staging coupled with a fear of litigation if a baby with mild encephalopathy progress to moderate or severe encephalopathy appears to be the primary driver for this therapeutic creep. Recent data suggesting increased apoptosis with cooling uninjured brains, and lack of hypothermic neuroprotection in partial prolonged hypoxia, implies that such therapeutic creeps may cause more harm than benefit. Currently available preclinical and clinical data do not support the clinical use of therapeutic hypothermia for mild encephalopathy, although phase II clinical trials are ongoing. We recommend that until further evidence from adequately powered randomised controlled trials are available, cooling in mild encephalopathy need to be considered experimental and parental consent should be obtained before providing this therapy.

We examined the association of Total Sarnat Score (TSS) with brain injury on neonatal magnetic resonance (MR) and adverse neurodevelopmental outcome (NDO) (death or moderate or severe disability) at 2 years of age in 145 infants undergoing therapeutic hypothermia for neonatal encephalopathy. TSS was associated with basal ganglia/thalamic injury on conventional MR (p=0.03) and thalamic N-acetyl aspartate on MR spectroscopy (R2=0.16, p=0.004) at 2 weeks of age, and Bayley Composite Cognitive (R2=0.18, p=0.01), Motor (R2=0.15, p=0.02) and Language (R2=0.11, p=0.01) Scores at 2 years of age after adjustment for seizures at the time of neurological assessment. The accuracy of TSS (area under the curve (AUC)=0.71) for predicting adverse NDO was similar to the modified Sarnat staging (AUC=0.72). TSS of >12 within 6 hours of birth indicated high risk of adverse NDO, while TSS of

Objective Legal, ethical, and regulatory requirements of medical research uniformly call for informed consent. We aimed to characterize and compare consent rates for neonatal randomized controlled trials in low- and lower middle-income countries versus high-income countries, and to evaluate the influence of study characteristics on consent rates. Methods In this systematic review, we searched MEDLINE, EMBASE and Cochrane for randomized controlled trials of neonatal interventions in low- and lower middle-income countries or high-income countries published 01/01/2013 to 01/04/2018. Our primary outcome was consent rate, the proportion of eligible participants who consented amongst those approached, extracted from the article or email with the author. Using a generalised linear model for fractional dependent variables, we analysed the odds of consenting in low- and lower middle-income countries versus high-income countries across control types and interventions. Findings We screened 3523 articles, yielding 300 eligible randomized controlled trials with consent rates available for 135 low- and lower middle-income country trials and 65 high-income country trials. Median consent rates were higher for low- and lower middle-income countries (95.6%; interquartile range (IQR) 88.2–98.9) than high-income countries (82.7%; IQR 68.6–93.0; p Conclusion Neonatal randomized controlled trials in low- and lower middle-income countries report consistently higher consent rates compared to high-income country trials. Our study is limited by the overrepresentation of India among randomized controlled trials in low- and lower middle-income countries. This study raises serious concerns about the adequacy of protections for highly vulnerable populations recruited to clinical trials in low- and lower middle-income countries.

Background: Erythropoietin is a promising neuroprotective agent in both pre-clinical models and clinical trials involving infants with neonatal encephalopathy (NE).We examined whether erythropoietin monotherapy improves neurodevelopmental outcomes in near-term and term infants with NE in low-middle income countries (LMICs).Methods: We searched Pubmed, Embase, and Web of Science databases to identify studies published between January 1, 1999 and January 1, 2020that used erythropoietin (1,500 to 12,500 units/kg/dose)or one of its derivatives to treat NE in near-term and term infants. Our primary outcome was death or neuro-disability at 18 months of age or later. The following MeSH terms were used:[hypoxic ischemic encephalopathy], [erythropoietin], [newborn], [clinical trials]. A random effects model was used for the meta-analyses and statistical heterogeneity was assessed using a chi-square test and I2 index. Results: Five studies, which enrolled a total of 348 infants in LMICs, were retrieved. All studies included outcome data related to the use of erythropoietin monotherapy. However, only three of the five studies met the primary outcome of death or neuro-disability at 18 months of age or later. Erythropoietin dosages varied from 300 to 2500units/kg/dose. Erythropoietin significantly reduced the risk of death (during neonatal period and at follow-up) or neuro-disability at 18 months or later (p

ObjectivesTo examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).Data sourceMEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using ‘hypoxic ischaemic encephalopathy’, ‘newborn’ and ‘hypothermia’, and ‘clinical trials’ as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.Study selectionRandomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.Data extractionSafety and efficacy data extracted independently by two reviewers and analysed.ResultsWe included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).ConclusionsCurrent evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.

Little progress has been made over the past decade in improving the outcomes of infants with neonatal encephalopathy in low- and middle-income countries (LMICs), and millions of infants still die or sustain permanent neurodisability every year. One of the key reasons for this lack of progress is a disconnect between encephalopathy research in high-income countries and LMICs. The majority of the neonatal encephalopathy research has been conducted in high-income countries with a low disease burden, without the involvement of LMICs. Here we discuss how a collaborative approach—particularly between middle-income countries and high-income countries—enables the use of state-of-the-art magnetic resonance biomarkers and host gene expression profiling for effective disease stratification. Using the example of the Hypothermia for Encephalopathy in Low- and middle-Income countries (HELIX) trial, we describe how this approach may result in a paradigm shift in global perinatal brain research over the next decade.

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth, predicts adverse neurodevelopmental outcome eighteen months after neonatal encephalopathy. We performed next generation sequencing on whole blood ribonucleic acid obtained within six hours of birth from the first 47 encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX) trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855 genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1 and SMC4 were the most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatonin and polo-like kinase in babies with adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanisms and identify novel therapeutic targets for neuroprotection.

Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82 – 5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n=106 for morphine; n=106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n=1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 μg/kg followed by a continuous infusion of 5 μg/kg/h was predicted across birthweight.

In the past decade a large number of studies of cooling for the treatment of hypoxic-ischaemic encephalopathy have been reported from middleincome countries (MIC), yet credible evidence of its safety and efficacy is still lacking. Although cooling therapy should not be considered in settings which lack basic neonatal care, many neonatal units in India and other MIC have excellent tertiary neonatal intensive care facilities. Most of these centres now routinely offer cooling therapy in clinical practice using a wide range of devices including ice and phase-change material (PCM). A large trial (HELIX: Hypothermia for Encephalopathy in Low- and Middle-Income Countries) involving 408 infants with moderate and severe encephalopathy in seven tertiary academic neonatal units in India, Sri Lanka and Bangladesh recently completed recruitment, and assessment of the neurodevelopmental outcome is ongoing. Considering the differences in population co-morbidities and the strong association between increased neonatal mortality and hypothermia, it would be prudent for clinicians in tertiary neonatal units in MIC to await the results of the HELIX trial before offering cooling therapy as standard care.

Background: Although thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes. Methods: We performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome. Findings: Of the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18–0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45–7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16–1.00); specificity 0.95 (95% CI 0.84–0.99)). Interpretation: Thalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes. Funding: The National Institute for Health Research (NIHR). Keywords: Therapeutic hypothermia, Magnetic resonance spectroscopy, Magnetic resonance imaging, Biomarkers, Neonatal encephalopathy

Background: Heart rate variability analysis offers real-time quantification of autonomic disturbance after perinatal asphyxia, and may therefore aid in disease stratification and prognostication after neonatal encephalopathy (NE). Objective: To systematically review the existing literature on the accuracy of early heart rate variability (HRV) to predict brain injury and adverse neurodevelopmental outcomes after NE. Design/Methods: We systematically searched the literature published between May 1947 and May 2018. We included all prospective and retrospective studies reporting HRV metrics, within the first 7 days of life in babies with NE, and its association with adverse outcomes (defined as evidence of brain injury on magnetic resonance imaging and/or abnormal neurodevelopment at ≥1 year of age). We extracted raw data wherever possible to calculate the prognostic indices with confidence intervals. Results: We retrieved 379 citations, 5 of which met the criteria. One further study was excluded as it analysed an already-included cohort. The 4 studies provided data on 205 babies, 80 (39%) of whom had adverse outcomes. Prognostic accuracy was reported for 12 different HRV metrics and the area under the curve (AUC) varied between 0.79 and 0.94. The best performing metric reported in the included studies was the relative power of high-frequency band, with an AUC of 0.94. Conclusions: HRV metrics are a promising bedside tool for early prediction of brain injury and neurodevelopmental outcome in babies with NE. Due to the small number of studies available, their heterogeneity and methodological limitations, further research is needed to refine this tool so that it can be used in clinical practice.

Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE). Design Non-randomised cohort study. Setting Eight tertiary neonatal units in the UK and the USA. Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth. Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for

BACKGROUND: Variable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies; hence better disease stratification may facilitate the development of individualized neuroprotective therapies. OBJECTIVES: We examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. MATERIAL AND METHODS: We performed next-generation sequencing on whole blood RNA from 12 babies with neonatal encephalopathy and 6 time-matched healthy term babies. Genes significantly differentially expressed between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. RESULTS: We identified 950 statistically significant genes discriminating perfectly between healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p = 0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 signaling and production in macrophages (p = 0.003), and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. CONCLUSION: Babies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profiles may be useful for disease stratification and for developing personalized neuroprotective therapies.

Post-mortem (PM) magnetic resonance imaging (MRI) is increasingly used as an alternative to conventional autopsy in babies dying from neonatal encephalopathy. However, the confounding effect of post-mortem changes on the detection of ante-mortem ischemic injury is unclear. We examined whether quantitative MR measurements can accurately distinguish ante-mortem ischemic brain injury from artifacts using post-mortem MRI. Methods We compared PM brain MRI (1.5 T Siemens, Avanto) in 7 infants who died with neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin with 7 newborn infants who had sudden unexplained neonatal death (SUND controls) without evidence of hypoxic-ischemic brain injury at autopsy. We measured apparent diffusion coefficients (ADCs), T1-weighted signal intensity ratios (SIRs) compared to vitreous humor and T2 relaxation times from 19 predefined brain areas typically involved in neonatal encephalopathy. Results There were no differences in mean ADC values, SIRs on T1-weighted images or T2 relaxation times in any of the 19 predefined brain areas between NE and SUND infants. All MRI images showed loss of cortical gray/white matter differentiation, loss of the normal high signal intensity (SI) in the posterior limb of the internal capsule on T1-weighted images, and high white matter SI on T2-weighted images. Conclusion Normal post-mortem changes may be easily mistaken for ante-mortem ischemic injury, and current PM MRI quantitative assessment cannot reliably distinguish these. These findings may have important implications for appropriate interpretation of PM imaging findings, especially in medico-legal practice.