Goat lung surfactant for treatment of respiratory distress syndrome among preterm neonates: a multi-site randomized non-inferiority trial.

OBJECTIVE: To investigate the safety and efficacy of goat lung surfactant extract (GLSE) compared with bovine surfactant extract (beractant; Survanta®, AbbVie, USA) for the treatment of neonatal respiratory distress syndrome (RDS). STUDY DESIGN: We conducted a double-blind, non-inferiority, randomized trial in seven Indian centers between June 22, 2016 and January 11, 2018. Preterm neonates of 26 to 32 weeks gestation with clinical diagnosis of RDS were randomized to receive either GLSE or beractant. Repeat dose, if required, was open-label beractant in both the groups. The primary outcome was a composite of death or bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age (PMA). Interim analyses were done by an independent data and safety monitoring board (DSMB). RESULT: After the first interim analyses on 5% enrolment, the "need for repeat dose(s) of surfactant" was added as an additional primary outcome and enrolment restricted to intramural births at five of the seven participating centers. Following second interim analysis after 98 (10% of 900 planned) neonates were enroled, DSMB recommended closure of study in view of inferior efficacy of GLSE in comparison to beractant. There was no significant difference in the primary outcome of death or BPD between GLSE group (n = 52) and beractant group (n = 46) (50.0 vs. 39.1%; OR 1.5; 95% CI 0.7-3.5; p = 0.28). The need for repeat dose of surfactant was significantly higher in GLSE group (65.4 vs. 17.4%; OR 9.0; 95% CI 3.5-23.3; p < 0.001). CONCLUSIONS: Goat lung surfactant was less efficacious than beractant (Survanta®) for treatment of RDS in preterm infants. Reasons to ascertain inferior efficacy of goat lung surfactant requires investigation and possible mitigating strategies in order to develop a low-cost and effective surfactant.

Causes of death in preterm neonates (<33 weeks) born in tertiary care hospitals in India: analysis of three large prospective multicentric cohorts.

OBJECTIVE: To estimate the direct causes of mortality among preterm neonates <33 weeks' gestation by examining three large multisite, hospital-based datasets in India. METHOD: Three prospective hospital-based datasets: the National Neonatal Perinatal Database (NNPD) of India, the Delhi Neonatal Infection Study (DeNIS) cohort, and the Goat Lung Surfactant Extract (GLSE)-Plus cohort were analyzed to study the causes of death among preterm neonates of less than 33 weeks' gestation admitted to the participating tertiary care hospitals in India. RESULTS: A total of 8024 preterm neonates were admitted in the three cohorts with 2691 deaths. Prematurity-related complications and sepsis contributed to 53.5% and 19.8% of deaths in the NNPD cohort, 51.0% and 25.0% in the DeNIS cohort, and 39.7% and 40.9% in GLSE-Plus cohort, respectively. CONCLUSIONS: Nearly a quarter (20-40%) of preterm neonates less than 33 weeks' gestation admitted to Indian NICUs died of sepsis. The study results have implications for health policies targeted to reduce the neonatal mortality rate in India.

Alarming rates of antimicrobial resistance and fungal sepsis in outborn neonates in North India.

BACKGROUND: There is a paucity of data on the epidemiology of sepsis in outborn neonates being referred to level-3 units in low- and middle-income countries (LMIC). The objective of the present study was to evaluate the prevalence of sepsis and outcomes of outborn neonates with sepsis, and to characterize the pathogen profile and antimicrobial resistance (AMR) patterns of common isolates in them. METHODS: In this prospective observational cohort study (2011-2015), a dedicated research team enrolled all neonates admitted to an outborn level-3 neonatal unit and followed them until discharge/death. Sepsis work-up including blood culture(s) was performed upon suspicion of sepsis. All the isolates were identified and tested for antimicrobial susceptibility. Gram-negative pathogens resistant to any three of the five antibiotic classes (extended-spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, and piperacillin-tazobactam) were labeled multi-drug resistant. RESULTS: Of the total of 2588 neonates enrolled, culture positive sepsis and total sepsis-i.e. culture positive and/or culture negative sepsis-was diagnosed in 13.1% (95% CI 11.8% to 14.5%) and 54.7% (95% CI 52.8% to 56.6%), respectively. The case fatality rates were 23.4% and 11.0% in culture-positive and total sepsis, respectively. Sepsis accounted for two-thirds of total neonatal deaths (153/235, 63.0%). Bacterial isolates caused about three-fourths (296/401; 73.8%) of the infections. The two common pathogens-Klebsiella pneumoniae (n = 50, 12.5%) and Acinetobacter baumannii (n = 46, 11.5%)-showed high degree of multi-drug resistance (78.0% and 91.3%, respectively) and carbapenem resistance (84.0% and 91.3%, respectively). About a quarter of infections were caused by Candida spp. (n = 91; 22.7%); almost three-fourths (73.7%) of these infections occurred in neonates born at or after 32 weeks' gestation and about two-thirds (62.1%) in those weighing 1500 g or more at birth. CONCLUSIONS: In this large outborn cohort, we report high burden of sepsis, high prevalence of systemic fungal infections, and alarming rates of antimicrobial resistance among bacterial pathogens.

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India: An Indian Council of Medical Research-INCLEN Initiative.

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

Comparison of Human Neonatal and Adult Blood Leukocyte Subset Composition Phenotypes.

The human peripheral leukocyte subset composition depends on genotype variation and pre-natal and post-natal environmental influence diversity. We quantified this composition in adults and neonates, and compared the median values and dispersal ranges of various subsets in them. We confirmed higher frequencies of monocytes and regulatory T cells (Tregs), similar frequencies of neutrophils, and lower frequencies of CD8 T cells, NKT cells, B1 B cells and gamma-delta T cells in neonatal umbilical cord blood. Unlike previous reports, we found higher frequencies of eosinophils and B cells, higher CD4:CD8 ratios, lower frequencies of T cells and iNKT cells, and similar frequencies of CD4 T cells and NK cells in neonates. We characterized monocyte subsets and dendritic cell (DC) subsets in far greater detail than previously reported, using recently described surface markers and gating strategies and observed that neonates had lower frequencies of patrolling monocytes and lower myeloid dendritic cell (mDC):plasmacytoid DC (pDC) ratios. Our data contribute to South Asian reference values for these parameters. We found that dispersal ranges differ between different leukocyte subsets, suggesting differential determination of variation. Further, some subsets were more dispersed in adults than in neonates suggesting influences of postnatal sources of variation, while some show the opposite pattern suggesting influences of developmental process variation. Together, these data and analyses provide interesting biological possibilities for future exploration.

Newborn screening for G6PD deficiency: A 2-year data from North India.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzymopathy, being present in more than 400 million people worldwide that may lead to neonatal jaundice or hemolytic crisis due to drugs or infections. In our study, we aimed to study the frequency of G6PD deficiency in neonates and the proportion of deficient neonates, who developed neonatal hyperbilirubinemia in the study population. The study was an observational one, conducted at the Division of Genetics of Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, over a 2-year period from January 2011 to December 2012. A total of 6,000 newborns delivered during that period underwent newborn screening on 24-72 h of birth. Neonatal hyperbilirubinemia was presented in 13.3% of the study population. Of female neonates, 16% demonstrated G6PD deficiency. This is worth noting for an X-linked recessive trait. Thus, in view of a high gene frequency for a disorder that is manageable with just elimination of few drugs and foodstuff, we stress the need for a newborn screening program for G6PD deficiency.

Urinary organic acids quantitated in a healthy north Indian pediatric population.

Human urine gives evidence of the metabolism in the body and contains numerous organic acids and other compounds at a variety of concentration. The concentration of organic acids in urine varies from population to population due to genotype, food habits and other epigenetic and environmental influences. Knowledge of the reference values for urinary organic acids in a healthy pediatric population is very important for critical evaluation. This study was designed to quantify 16 organic acids in a healthy north Indian pediatric population. Early morning urine samples from healthy pediatric subjects of age 1 day to 16 years who did not have symptoms of any disease were analyzed for organic acid content. The children were not on any supplemental vitamins or drugs and were on a free and unrestricted diet. The creatinine concentration of each sample was determined before organic acid analysis. Organic acids were extracted from urine with ethyl acetate, extracted residue was air dried, converted into trimethylsilyl derivatives and analysed by gas chromatography mass spectrometry. Here we reported the age wise mean values and standard deviations for each compound, adjusted for creatinine content (mmol/mol of creatinine). We found the concentration of most of the metabolites are higher in our population in comparison to other populations. Such data may help to provide a basis for diagnosing metabolic abnormalities in patients in a specific ethnicity.

Association between anthropometry, cardiometabolic risk factors, & early life factors & adult measures of endothelial function: Results from the New Delhi Birth Cohort.

BACKGROUND & OBJECTIVES: Abnormal endothelial function represents a preclinical marker of atherosclerosis. This study was conducted to evaluate associations between anthropometry, cardiometabolic risk factors, and early life factors and adult measures of endothelial function in a young urban Indian cohort free of clinical cardiovascular disease. METHODS: Absolute changes in brachial artery diameter following cuff inflation and sublingual nitroglycerin (400 µg) were recorded to evaluate endothelium-dependent and -independent measures of endothelial function in 600 participants (362 men; 238 women) from the New Delhi Birth Cohort (2006-2009). Data on anthropometry, cardiometabolic risk factors, medical history, socio-economic position, and lifestyle habits were collected. Height and weight were recorded at birth, two and 11 yr of age. Age- and sex-adjusted linear regression models were developed to evaluate these associations. RESULTS: The mean age of participants was 36±1 yr. Twenty two per cent men and 29 per cent women were obese (BMI th > 30 kg/m [2] ). Mean systolic blood pressure (SBP) was 131±14 and 119±13 mmHg, and diabetes prevalence was 12 and 8 per cent for men and women, respectively. Brachial artery diameter was higher for men compared with women both before (3.48±0.37 and 2.95±0.35 cm) and after hyperaemia (3.87±0.37 vs. 3.37±0.35 cm). A similar difference was seen before and after nitroglycerin. Markers of increased adiposity, smoking, SBP, and metabolic syndrome, but not early life anthropometry, were inversely associated with endothelial function after adjustment for age and sex. INTERPRETATION & CONCLUSIONS: The analysis of the current prospective data from a young urban Indian cohort showed that cardiometabolic risk factors, but not early life anthropometry, were associated with worse endothelial function.

Prognostic factors determining mortality in surgical neonates.

BACKGROUND: To assess the prognosis of surgical neonates at admission and the factors responsible for mortality in neonates. MATERIAL AND METHODS: A prospective study was conducted in a tertiary level hospital over 15 months and various clinical and biochemical parameters were collected and analyzed using STATA(®) and SPSS(®). RESULTS: On multivariate analysis of 165 neonates, early gestational age, respiratory distress and shock at presentation were the factors of poor prognosis in neonates. The factors could be related to poor antenatal care and sepsis acquired before transfer of the baby to the nursery. CONCLUSION: The improvement in antenatal care and asepsis during transfer and handling the babies is of utmost importance to improve the prognosis of surgical neonates.

Childhood body mass index and adult pro-inflammatory and pro-thrombotic risk factors: data from the New Delhi birth cohort.

OBJECTIVE: Weight gain and growth in early life may influence adult pro-inflammatory and pro-thrombotic cardiovascular risk factors. METHODS: Follow-up of a birth cohort in New Delhi, India, whose weight and height were measured every 6 months until age 21 years. Body mass index (BMI) at birth, during infancy (2 years), childhood (11 years) and adulthood (26-32 years) and BMI gain between these ages were analysed in 886 men and 640 women with respect to adult fibrinogen, high-sensitivity C-reactive protein (hsCRP) and plasminogen activator inhibitor-1 (PAI-1) concentrations. RESULTS: All the pro-inflammatory/pro-thrombotic risk factors were higher in participants with higher adiposity. In women, BMI at birth and age 2 years was inversely related to fibrinogen (P = 0.002 and 0.05) and, after adjusting for adult adiposity, to hsCRP (P = 0.02 and 0.009). After adjusting for adult adiposity, BMI at 2 years was inversely related to hsCRP and PAI-1 concentrations (P < 0.001 and 0.02) in men. BMI gain between 2 and 11 years and/or 11 years to adulthood was positively associated with fibrinogen and hsCRP in women and with hsCRP and PAI-1 in men. CONCLUSIONS: Thinness at birth or during infancy, and accelerated BMI gain during childhood/adolescence are associated with a pro-inflammatory/pro-thrombotic state in adult life. An altered inflammatory state could be one link between small newborn/infant size and adult cardiovascular disease. Associations between pro-inflammatory markers and childhood/adolescent BMI gain are probably mediated through adult adiposity.

Adult metabolic syndrome and impaired glucose tolerance are associated with different patterns of BMI gain during infancy: Data from the New Delhi Birth Cohort.

OBJECTIVE: The purpose of this study was to describe patterns of infant, childhood, and adolescent BMI and weight associated with adult metabolic risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We measured waist circumference, blood pressure, glucose, insulin and lipid concentrations, and the prevalence of metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III definition) in 1,492 men and women aged 26-32 years in Delhi, India, whose weight and height were recorded every 6 months throughout infancy (0-2 years), childhood (2-11 years), and adolescence (11 years-adult). RESULTS: Men and women with metabolic syndrome (29% overall), any of its component features, or higher (greater than upper quartile) insulin resistance (homeostasis model assessment) had more rapid BMI or weight gain than the rest of the cohort throughout infancy, childhood, and adolescence. Glucose intolerance (impaired glucose tolerance or diabetes) was, like metabolic syndrome, associated with rapid BMI gain in childhood and adolescence but with lower BMI in infancy. CONCLUSIONS: In this Indian population, patterns of infant BMI and weight gain differed for individuals who developed metabolic syndrome (rapid gain) compared with those who developed glucose intolerance (low infant BMI). Rapid BMI gain during childhood and adolescence was a risk factor for both disorders.

Effect of oil massage on growth and neurobehavior in very low birth weight preterm neonates.

OBJECTIVE: To study the effect of oil massage on growth and neurobehavior in preterm babies less than 1500 g. DESIGN: Randomized Controlled Trial. SETTING: Tertiary level neonatal unit of a teaching hospital. SUBJECTS: Neonates with birth weight <1500 grams, gestation >37 weeks, receiving enteral feeds of at least 100 mL/kg/day and less than 10 days of age. OUTCOME VARIABLES: Primary-Weight gain 28 days after enrolment. Secondary-Neonatal neurobehavior, change in other anthropometry and serum triglycerides. METHODS: Eligible neonates were randomized to one of the three groups (a) massage with oil (b) massage without oil and (c) no massage. Weight, length, head circumference and triceps skin fold thickness were measured in the three groups at regular intervals. Serum triglyceride levels were measured at enrolment and at completion. Neurobehavior using Brazeltons Neonatal Behavior Assessment Scale (NBAS) was assessed at enrolment and after 10 days of intervention. RESULTS: Weight gain in the oil massage group (365.8 +/- 165.2g) was higher compared to the only massage group (290.0 +/- 150.2g) and no massage group (285.0 +/- 170.4g). This difference and the difference in other anthropometric parameters was not statistically significant. Serum triglycerides and neonatal neurobehavior were comparable in the three groups. CONCLUSION: Oil application may have a potential to improve weight gain among preterm very low birth weight neonates.

Anterior lens capsule vascularity in evaluating gestation in small for gestation neonates.

This study evaluated the role of anterior lens capsule vascularity in assessing gestation in small for gestational age (SGA) neonates in a prospective manner. Neonates with birth weight less than 2000 g were recruited. Those with gross congenital malformations, including corneal opacity or cataract and evidence of TORCH infection were excluded from the study. A total of 139 subjects were enrolled into the study (60-appropriate for gestational age (AGA) and 79 small for gestational age (SGA) neonates). Clinical gestational age assessment and ophthalmoscopic examination for anterior lens capsule vascularity grading were done within 24 hours of birth by independent blinded observers. The correlation of lens capsule grading with clinical gestation in AGA neonates (r2 = 0.75) was stronger compared to SGA neonates (r2 = 0.50). Gestational age assessment by lens capsule grading had a better agreement with clinical gestation in AGA subjects (Kappa Index - 0.56 in AGA vs. 0.26 in SGA). The lens capsule grading under-estimated the gestation of SGA subjects by an average of three weeks compared to AGA neonates.

Effect of partial exchange transfusion in asymptomatic polycythemic LBW babies.

This randomized controlled trial was conducted to determine the effect of partial exchange transfusion in polycythemic babies. Forty five asymptomatic polycythemic babies with birth weight < or = 2000 g were included and randomly assigned to undergo either partial exchange transfusion using isotonic saline within 4 hours of screening or routine medical management. Outcome measures were neonatal morbidity (especially hypoglycemia and neurological alterations) and mortality; developmental delays using DDST-II, neurological deficits, tone and DTR abnormalities over 18 months follow up period. The overall neonatal morbidity in this study was low and comparable in the two groups. Some of the polycythemic babies in the non-exchanged group found initially at 3 months age with "suspected development" grew out of their developmental delay at 18 months of age or later while those who underwent exchange transfusion and with retarded development at 3 months of age remained so even at 18 months of age.

Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood.

BACKGROUND: The risk of type 2 diabetes mellitus is increased in people who have low birth weights and who subsequently become obese as adults. Whether their obesity originates in childhood and, if so, at what age are unknown. Understanding the origin of obesity may be especially important in developing countries, where type 2 diabetes is rapidly increasing yet public health messages still focus on reducing childhood "undernutrition." METHODS: We evaluated glucose tolerance and plasma insulin concentrations in 1492 men and women 26 to 32 years of age who had been measured at birth and at intervals of three to six months throughout infancy, childhood, and adolescence in a prospective, population-based study. RESULTS: The prevalence of impaired glucose tolerance was 10.8 percent, and that of diabetes was 4.4 percent. Subjects with impaired glucose tolerance or diabetes typically had a low body-mass index up to the age of two years, followed by an early adiposity rebound (the age after infancy when body mass starts to rise) and an accelerated increase in body-mass index until adulthood. However, despite an increase in body-mass index between the ages of 2 and 12 years, none of these subjects were obese at the age of 12 years. The odds ratio for disease associated with an increase in the body-mass index of 1 SD from 2 to 12 years of age was 1.36 (95 percent confidence interval, 1.18 to 1.57; P<0.001). CONCLUSIONS: There is an association between thinness in infancy and the presence of impaired glucose tolerance or diabetes in young adulthood. Crossing into higher categories of body-mass index after the age of two years is also associated with these disorders.

Cutaneous Involvement in Acute Meningococcemia (Study of an Epidemic in Delhi).

Thirty (88.2%) out of 34 children with skin lesions were observed during the recent epidemic of meningococcus group A infection in Delhi. Purpuric lesions were the commonest (60%), maculo-papular in 26-67% and faint pink macules'm 13.33% Conjunctivae were affected m 3. These eruptions appeared within 6 hours: ulcers and gangrene appeared after 7 days in one child. Severe vascular damage was seen on histoplthology of the ulcers as compared to the early lesions. Gangrene of the extremities developed during the recovery phase when all other signs of the disease had subsided.