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. Interpretatio...

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 < 0.00001). Conclusions Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.

Objective We examined whether erythropoietin monotherapy improves neurodevelopmental outcomes in near-term and term infants with neonatal encephalopathy (NE) in low-middle income countries (LMICs). Methods We searched Pubmed, Embase, and Web of Science databases to identify studies that used erythropoietin (1500–12,500 units/kg/dose) or a derivative to treat NE. Results Five studies, with a total of 348 infants in LMICs, were retrieved. However, only three of the five studies met the primary outcome of death or neuro-disability at 18 months of age or later. Erythropoietin reduced the risk of death (during the neonatal period and at follow-up) or neuro-disability at 18 months or later (p < 0.05). Death or neuro-disability occurred in 27.6% of the erythropoietin group and 49.7% of the comparison group (risk ratio 0.56 (95% CI: 0.42–0.75)). Conclusion The pooled data suggest that erythropoietin monotherapy may improve outcomes after NE in LMICs where therapeutic hypothermia is not available.

IntroductionTime-critical neonatal trials in low-and-middle-income countries (LMICs) raise several ethical issues. Using a qualitative-dominant mixed-methods design, we explored informed consent process in Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial conducted in India, Sri Lanka and Bangladesh.MethodsTerm infants with neonatal encephalopathy, aged less than 6 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 A-V records of the consent process using a 5-point Likert scale on three parameters—empathy, information and autonomy. In addition, 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 healthcare professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.ResultsA total of 294 A-V records of the HELIX trial were analysed. Median (IQR) score for empathy, information and autonomy was 5 (0), 5 (1) and 5 (1), respectively. However, thematic analysis suggested that the consenting was a ceremonial process; and parental decision to participate was based on 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. Professionals showed a strong bias towards cooling therapy and reported time constraints and explaining to multiple family members as key challenges.ConclusionDespite 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 for informed trial participation.

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 0.18À0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45À7.82)) 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 0.16À1.00); specificity 0.95 (95% CI 0.84À0.99)). Interpretation: Thalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes.