Development and Validation of a Neonatal Physical Maturity Score for Low- and Middle-Income Countries.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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%). CONCLUSION: This scoring system may have wider applications in LMIC, particularly in community settings and in infants with neonatal encephalopathy. KEY POINTS: · 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..

Duration of birth depression and neurodevelopmental outcomes after whole-body hypothermia for hypoxic ischemic encephalopathy in India, Sri Lanka and Bangladesh - an exploratory analysis of the HELIX trial.

Background: Effect of duration of birth depression on neurodevelopmental outcomes in low- and middle-income countries (LMICs) is not known. We examined the association of birth depression with brain injury, neurodevelopmental outcomes, and hypothermia after hypoxic ischemic encephalopathy (HIE) in south Asia. Methods: We compared cerebral magnetic resonance (MR) at 2 weeks, and adverse outcomes (death or moderate or severe disability) at 18 months in 408 babies with moderate or severe HIE who had long birth depression (positive pressure ventilation (PPV) >10 min or Apgar score<6 at 10 min or cord pH < 7.0) and short birth depression (PPV for 5-10 min or Apgar score<6 at 5 min, but ≥6 at 10 min). Findings: Long depression group (n = 201) had more severe HIE (32.8% versus 6.8%), mortality (47.5% versus 26.4%), death or disability at 18 months (62.2% versus 35.4%) (all p < 0.001), MR injury (Odds ratio; 95% CI) to basal ganglia (2.4 (1.3, 4.1); p = 0.003), posterior limb of internal capsule (2.3 (1.3, 4.3); p < 0.001) and white matter (1.7 (1.1, 2.7); p = 0.021), and lower thalamic N-acetylaspartate levels (7.69 ± 1.84 versus 8.29 ± 1.60); p = 0.031) than short depression group (n = 207). Three babies had no heartbeat at 5 min, of which 1 died and 2 survived with severe disability. No significant interaction between the duration of birth depression and whole-body hypothermia was seen for any of the MR biomarker or clinical outcomes. Interpretation: Long birth depression was associated with more brain injury and adverse outcomes than short depression. Effect of hypothermia was not modified by duration of birth depression. Funding: National Institute for Health Research.

Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy.

Importance: Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden. Objective: To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia. Design, Setting, and Participants: This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023. Exposure: Whole-blood RNA that underwent next-generation sequencing. Main Outcome and Measures: The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort. Results: The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14). Conclusions and Relevance: This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India.

Background: Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital. Methods: We recruited neonates born ≥35 weeks and aged <72 h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20 mg/kg x 2 doses, second line) followed by phenytoin (20 mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60 min within 40 min from the start of infusion. Findings: Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%-20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%-66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose. Interpretation: With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials. Funding: National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).

Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial.

OBJECTIVE: To examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE). DESIGN: Double-blind pilot randomised controlled trial. SETTING: Eight neonatal units in South Asia. PATIENTS: Neonates (≥36 weeks) with moderate or severe HIE admitted between 31 December 2022 and 3 May 2023. INTERVENTIONS: Erythropoietin (500 U/kg daily) or to the placebo (sham injections using a screen) within 6 hours of birth and continued for 9 days. MRI at 2 weeks of age. MAIN OUTCOMES AND MEASURES: Feasibility of randomisation, drug administration and assessment of brain injury using MRI. RESULTS: Of the 154 neonates screened, 56 were eligible; 6 declined consent and 50 were recruited; 43 (86%) were inborn. Mean (SD) age at first dose was 4.4 (1.2) hours in erythropoietin and 4.1 (1.0) hours in placebo. Overall mortality at hospital discharge occurred in 5 (19%) vs 11 (46%) (p=0.06), and 3 (13%) vs 9 (40.9%) (p=0.04) among those with moderate encephalopathy in the erythropoietin and placebo groups. Moderate or severe injury to basal ganglia, white matter and cortex occurred in 5 (25%) vs 5 (38.5%); 14 (70%) vs 11 (85%); and 6 (30%) vs 2 (15.4%) in the erythropoietin and placebo group, respectively. Sinus venous thrombosis was seen in two (10%) neonates in the erythropoietin group and none in the control group. CONCLUSIONS: Brain injury and mortality after moderate or severe HIE are high in South Asia. Evaluation of erythropoietin monotherapy using MRI to examine treatment effects is feasible in these settings. TRIAL REGISTRATION NUMBER: NCT05395195.

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial.

Importance: The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown. Objective: To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn). Design, Setting, and Participants: This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks' gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020. Exposure: 3T MR imaging, MR spectroscopy, and diffusion tensor imaging. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months. Results: Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], -0.28; 95% CI, -1.62 to 1.07; P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, -0.62 to 0.71; P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08; P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09; P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41). Conclusions and Relevance: In this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs. Trial Registration: ClinicalTrials.gov Identifier: NCT02387385.

Neonatal Seizures-Perspective in Low-and Middle-Income Countries.

Neonatal seizures are the commonest neurological emergency and are associated with poor neurodevelopmental outcome. While they are generally difficult to diagnose and treat, they pose a significant clinical challenge for physicians in low- and middle-income countries (LMIC). They are mostly provoked seizures caused by an acute brain insult such as hypoxic-ischemic encephalopathy (HIE), ischemic stroke, intracranial hemorrhage, infections of the central nervous system, or acute metabolic disturbances. Early onset epilepsy syndromes are less common. Clinical diagnosis of seizures in the neonatal period are frequently inaccurate, as clinical manifestations are difficult to distinguish from nonseizure behavior. Additionally, a high proportion of seizures are electrographic-only without any clinical manifestations, making diagnosis with EEG or aEEG a necessity. Only focal clonic and focal tonic seizures can be diagnosed clinically with adequate diagnostic certainty. Prompt diagnosis and timely treatment are important, with evidence suggesting that early treatment improves the response to antiseizure medication. The vast majority of published studies are from high-income countries, making extrapolation to LMIC impossible, thus highlighting the urgent need for a better understanding of the etiologies, comorbidities, and drug trials evaluating safety and efficacy in LMIC. In this review paper, the authors present the latest data on etiology, diagnosis, classification, and guidelines for the management of neonates with the emphasis on low-resource settings.

Rise and Fall of Therapeutic Hypothermia in Low-Resource Settings: Lessons from the HELIX Trial.

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.

Early Social Experience and Digital-Media Exposure in Children with Autism Spectrum Disorder.

OBJECTIVE: To study the early social experience and digital media exposure in children with autism spectrum disorder (ASD) in comparison with typically developed children. METHODS: Details of digital-media exposure and early social experience in 65 children with ASD were compared with those in a control group of equal number of typically developed children, matched for age and gender. Prenatal and perinatal factors were also studied. The diagnosis of ASD was based on the International Clinical Epidemiology Network (INCLEN) diagnostic tool and Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnostic criteria. Variables which were biologically relevant and has a P value of < 0.05 in the univariate analysis were analyzed by logistic regression to obtain the adjusted effect measures. RESULTS: Children with ASD were exposed to digital media at an earlier age and spent significantly more time with digital media and less time with their mothers, compared to typically developed children. Exposure to digital media before 21 mo was associated with risk of ASD and the risk increased when mothers spent less than 6.5 h per day with the baby. Family history of epilepsy and developmental delay, maternal stress during the antenatal period, and absence of exclusive breastfeeding during the first 6 mo were significantly more in children with ASD. CONCLUSION: There are significant differences in the early life social experience and digital-media exposure in children with ASD compared to typically developed counterparts. Given the reported rise in prevalence of ASD, these findings stress the need for further prospective studies to explore these potentially modifiable risk factors.

Need for more evidence in the prevention and management of perinatal asphyxia and neonatal encephalopathy in low and middle-income countries: A call for action.

Although low- and middle-income countries (LMICs) shoulder 90 % of the neonatal encephalopathy (NE) burden, there is very little evidence base for prevention or management of this condition in these settings. A variety of antenatal factors including socio-economic deprivation, undernutrition and sub optimal antenatal and intrapartum care increase the risk of NE, although little is known about the underlying mechanisms. Implementing interventions based on the evidence from high-income countries to LMICs, may cause more harm than benefit as shown by the increased mortality and lack of neuroprotection with cooling therapy in the hypothermia for moderate or severe NE in low and middle-income countries (HELIX) trial. Pooled data from pilot trials suggest that erythropoietin monotherapy reduces death and disability in LMICs, but this needs further evaluation in clinical trials. Careful attention to supportive care, including avoiding hyperoxia, hypocarbia, hypoglycemia, and hyperthermia, are likely to improve outcomes until specific neuroprotective or neurorestorative therapies available.

Association of Total Sarnat Score with brain injury and neurodevelopmental outcomes after neonatal encephalopathy.

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 <4 indicated intact survival and was reassuring of a good outcome among cooled infants.