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AbstractObjectiveTo test the effect on all cause neonatal mortality (aged ≤28 days) of a dose of BCG Danish vaccine and oral polio vaccine (OPV) administered to newborn babies weighing <2000 g.DesignMulticentre, open label, randomised controlled trialSettingThree tertiary neonatal intensive care units (NICUs) in southeast India.PopulationNewborn babies weighing <2000 g. 7067 were assessed for eligibility and 5420 were randomised (2714 BCG-OPV, 2706 control).InterventionsNewborns were randomised 1:1 to receive 0.1 mL of BCG Danish intradermally plus OPV, either within 48 hours of admission to the NICU (early vaccination group) or delayed until at least the time of discharge (control group). Stratification was by NICU, sex, and birth weight (<1000 g, 1000-1499 g, 1500-1999 g).Main outcome measuresThe primary outcome was all cause neonatal mortality. The main secondary outcome, included a third of the way through the trial, was neonatal mortality due to infection.ResultsOf the 5420 newborn babies randomised at a median age of 0.9 days and with a median birth weight of 1560 g, nine were lost to follow-up. Deaths occurred in 238 (8.8%) of 2714 newborn babies in the early vaccination group and 273 (10.1%) of 2706 in the control group. In intention-to-treat Cox survival analysis stratified by NICU and adjusted for postnatal age, birth weight, sex, and gestational age, neonatal mortality per person year was 1.29 in the early vaccination group and 1.50 in the control group (adjusted hazard ratio 0.83, 95% confidence interval (CI) 0.69 to 0.98; P=0.03). The number needed to treat to prevent one death was 21 (95% CI 10 to 245). Infection related neonatal mortality per person year was 0.40 in the early vaccination group and 0.73 in the control group (adjusted hazard ratio 0.53, 95% CI 0.40 to 0.70). No deaths from tuberculosis occurred, and no serious adverse effects were associated with vaccination.ConclusionsIn newborn babies weighing <2000 g in intensive care, BCG-OPV administered at a median age of 0.9 days reduced all cause neonatal mortality owing to a decrease in deaths due to infections other than tuberculosis (a non-specific or off-target effect). A substantial reduction in neonatal mortality could be achieved if a skilled administrator vaccinated a high proportion of newborn babies in high mortality settings on the day of, or soon after, birth.Trial registrationClinical Trials Registry India CTRI/2017/01/007676.

ObjectiveDefinitive guidance regarding the duration of antibiotics for neonatal sepsis is lacking. We hypothesised that a 7-day antibiotic course is non-inferior to a 14-day course for treating culture-proven sepsis.DesignRandomised, controlled, non-inferiority trial with masked outcome assessment in eight centres in a low and middle-income country.PatientsNeonates with a birth weight (BW) ≥1000 g and blood culture-proven sepsis were randomised on day 7 of sensitive antibiotic therapy provided sepsis had clinically remitted. Exclusions: Staphylococcus aureus or fungal sepsis, and infections requiring prolonged antibiotics. We planned to enrol 350 per group, assuming 10% rate of primary outcome, +7% non-inferiority margin, one-sided 5% alpha, 90% power, 10% loss to follow-up.Intervention7 days (no further treatment); comparison: 14 days (7 days postrandomisation).OutcomesPrimary: relapse (definite or probable) within day 21 postantibiotic completion. Secondary outcomes: composite of mortality or definite/probable/secondary sepsis and duration of hospitalisation. One interim analysis (per protocol (PP)) was planned.Results126 and 135 subjects were recruited in 7-day and 14-day groups, respectively, with mean (SD) birth weight (BW) 2250.9 (741.1) and 2187.8 (718.8) g. The trial was terminated early, based on interim PP analysis. 2/125 and 6/130 subjects had the primary outcome in 7-day and 14-day groups, respectively (risk difference (RD)=−3.0% (99.5% CI −9.2%, +3.1%), below non-inferiority margin). The composite secondary outcome also favoured the 7-day regimen (RD: −3.7% (99.5% CI −12.4% to +5.1%)). Duration of hospitalisation was shorter in 7-day group (median difference: −4 days (95% CI −5 to –3)).ConclusionsA 7-day course of antibiotics may be non-inferior to a 14-day course for uncomplicated bacterial neonatal sepsis.Trial registration number NCT03280147.

Background Neonatal sepsis is a global public health problem. There is no consensus regarding the optimum duration of antibiotics for culture-proven neonatal sepsis. Published randomized controlled trials (RCTs) comparing shorter versus longer courses of antibiotics provide low-quality evidence with serious risk of bias. We hypothesized that among neonates with uncomplicated culture-proven sepsis, antibiotic duration of 7 days is not inferior to 14 days. Methods This is a multi-centric, parallel-group, stratified, block-randomized, active-controlled, non-inferiority trial with outcome assessment blinded. Stratification is by center and birth weight. Neonates weighing ≥1000 g at birth, with blood-culture-proven sepsis (barring Staphylococcus aureus and fungi), without conditions warranting > 14 days antibiotics, and who clinically remit, are enrolled in the RCT on day 7 of administration of sensitive antibiotics. They are randomly allocated to no further antibiotics (intervention arm: total 7 days) or 7 more days of the same antibiotics (control arm: total 14 days). Allocation is concealed by opaque, sealed envelopes. The primary outcome is “definite or probable relapse” within 21 days after antibiotic completion. Secondary outcomes include definite and probable relapses at various timepoints until day 35 post-randomization, secondary infections, and adverse events. The neonatologist adjudicating probable relapses and lab personnel are blinded. Three hundred fifty subjects will be recruited in each arm, assuming a non-inferiority margin of 7%, one-sided alpha error 5%, and power of 90%. Analysis will be per protocol and by intention-to-treat. An independent Data Safety Monitoring Board monitors adverse events and will perform one interim analysis when 50% of expected primary outcomes have occurred or 50% of subjects have completed follow-up, whichever is earlier. O’Brien-Fleming criteria will be used to stop for mid-term benefit and Pocock’s to stop for mid-term harm. A priori subgroup analyses are planned by birth weight categories, gram-stain status of pathogens, and radiological pneumonia. Discussion This trial will provide evidence to guide practice regarding optimum duration of antibiotics for culture-proven neonatal bacterial sepsis. If a 7-day regime is proved to be non-inferior to a 14-day regime, it is likely to reduce hospital stay, costs, adverse effects of drugs, and nosocomial infections. Trial registration Clinical Trials Registry India CTRI/2017/09/009743 . Registered on 13 September 2017.

BackgroundLimited evidence exists on perinatal transmission and outcomes of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in neonates.ObjectiveTo describe clinical outcomes and risk factors for transmission in neonates born to mothers with perinatal SARS-CoV-2 infection.DesignProspective cohort of suspected and confirmed SARS-CoV-2 infected neonates entered in National Neonatology Forum (NNF) of India registry.SubjectsNeonates born to women with SARS-CoV-2 infection within two weeks before or two days after birth and neonates with SARS-CoV-2 infection.OutcomesIncidence and risk factors of perinatal transmission.ResultsAmong 1713 neonates, SARS-CoV-2 infection status was available for 1330 intramural and 104 extramural neonates. SARS-CoV-2 positivity was reported in 144 intramural and 39 extramural neonates. Perinatal transmission occurred in 106 (8%) and horizontal transmission in 21 (1.5%) intramural neonates. Neonates roomed-in with mother had higher transmission risk (RR1.16, 95% CI 1.1 to 2.4; P=0.01). No association was noted with the mode of delivery or type of feeding. The majority of neonates positive for SARS-CoV2 were asymptomatic. Intramural SARS-CoV-2 positive neonates were more likely to be symptomatic (RR 5, 95%CI 3.3 to 7.7; P<0.0001) and need resuscitation (RR 2, 95%CI 1.0 to 3.9; P=0.05) compared to SARS-CoV-2 negative neonates. Amongst symptomatic neonates, most morbidities were related to prematurity and perinatal events.ConclusionData from a large cohort suggests perinatal transmission of SARS-CoV-2 infection and increased morbidity in infected infants.

BackgroundAmong term and late preterm infants, hypoxic ischemic encephalopathy (HIE) is an important cause of mortality, and neurologic morbidity among survivors.ObjectiveThe primary objective was to study the incidence of survival to discharge among late preterm and term infants with moderate or severe HIE. Secondary objectives were to explore variation in the management of HIE across participating sites and to identify the predictors of survival.SettingIndian Neonatal Collaborative (INNC), a network of 28 neonatal units in India.Study designRetrospective cohort.ParticipantsLate preterm (34–36 weeks) and term (37–42 weeks) infants with moderate to severe HIE from 2018–2019.OutcomeThe primary outcome was survival to discharge (including discharged home and transfer to other hospital). A multivariate logistic regression model was constructed to identify the predictors of survival.ResultsOf 352 infants with moderate or severe HIE, 59% received therapeutic hypothermia. Survival to discharge among infants with moderate or severe HIE was 82%. Severe HIE (aOR 0.04; 95% CI 0.02–0.10), persistent pulmonary hypertension (PPHN) (aOR 0.22; 95% CI 0.08–0.61) and requirement of epinephrine during resuscitation (aOR 0.21; 95% CI 0.05–0.84) were independently associated with decreased odds of survival to discharge.ConclusionSurvival to discharge among infants with moderate or severe HIE was 82%. Severe HIE, requirement of epinephrine during resuscitation and PPHN decreased the odds of survival.

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.

Background Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18–22 months after neonatal encephalopathy, in LMICs. Methods We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1–2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. Discussion Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. Trial registration ClinicalTrials.gov, NCT02387385 . Registered on 27 February 2015.

ObjectiveTo compare supplemental intravenous fluids with no supplementation in asymptomatic polycythemic late preterm and term neonates.Methods55 infants with venous haematocrit of 65-75 were randomly allocated to receive either 25 mL/kg IV normal saline over 6-8 hours or routine fluids. They were followed up for 48 hours.ResultsThere was no significant difference between fluid supplementation and control groups regarding need for partial exchange transfusion [6/27 (22.2%) vs 8/28 (28.6%); P=0.59].ConclusionsWe did not find any evidence of clinical benefit with IV fluid supplementation in late preterm and term neonates with asymptomatic polycythemia (PCV 65-75).

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.

Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC.DesignWe recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge.ResultsEighty-two babies were included—61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality.ConclusionsThe low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs.Clinical trial registration number NCT01760629.