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BACKGROUND To describe the pattern of gestational weight gain (GWG), derive reference centiles for GWG specific to North Indian population, and to compare the weight gain across different periods of gestation with the INTERGROWTH-21st reference. METHODS A prospective pregnancy (GARBH-Ini) cohort was initiated and followed between May 2015 and June 2019 in a district hospital, Gurguram, North India. GWG centile curves were modelled by Generalized Additive Models for Location, Scale and Shape method (n = 2844) and compared with INTERGROWTH-21st reference. The independent association of GWG with biological and social predictors was assessed using multivariable regression analysis. RESULTS Percentiles (3rd, 10th, 50th, 90th and 97th) for each completed week from 18-40 weeks of gestation were derived from smoothed centile curves. The median GWG across pregnancy during specific antenatal visits was 1.29 at 18, 4.44 at 26, 5.8 at 30 and 9.06 kg at 40 weeks of gestation. Nearly 26% of participants had GWG

The establishment and maintenance of pregnancy in humans proceed through a continuous change of biochemical and biophysical processes. It requires a constant interaction between the fetus and the maternal system. The present prospective study aims to elucidate changes in salivary proteome from the early to middle stages of term pregnancy, and establishing an expressional trajectory for modulated proteins. To date, a comprehensive characterization of the longitudinal salivary proteome in pregnancy has not been performed and it is our immediate interest. In the discovery phase, maternal saliva (N = 20) at 6–13, 18–21, and 26–29 weeks of gestation was analyzed using level-free proteomics (SWATH-MS) approach. The expression levels of 65 proteins were found to change significantly with gestational age and distributed into two distinct clusters with a unique expression trajectory. The results revealed that altered proteins are involved in maternal immune modulation, metabolism, and host defense mechanism. Further, verification of 12 proteins was employed using targeted mass spectrometry (MRM-MS) in a separate subset of saliva (N = 14). The MRM results of 12 selected proteins confirmed a similar expression pattern as in SWATH-MS analysis. Overall, the results not only demonstrate the longitudinal maternal saliva proteome for the first time but also set the groundwork for comparative analysis between term birth and adverse pregnancy outcomes.

Background: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores. Methods: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules. Results: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73). Conclusions: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting. publishedVersion

BackgroundThe prevalence of preterm birth (PTB) is high in lower and middle-income countries (LMIC) such as India. In LMIC, since a large proportion seeks antenatal care for the first time beyond 14-weeks of pregnancy, accurate estimation of gestational age (GA) using measures derived from ultrasonography scans in the second and third trimesters is of paramount importance. Different models have been developed globally to estimate GA, and currently, LMIC uses Hadlock’s formula derived from data based on a North American cohort. This study aimed to develop a population-specific model using data from GARBH-Ini, a multidimensional and ongoing pregnancy cohort established in a district hospital in North India for studying PTB.MethodsData obtained by longitudinal ultrasonography across all trimesters of pregnancy was used to develop and validate GA models for second and third trimesters. The first trimester GA estimated by ultrasonography was considered the Gold Standard. The second and third trimester GA model named, Garbhini-GA2 is a multivariate random forest model using five ultrasonographic parameters routinely measured during this period. Garbhini-GA2 model was compared to Hadlock and INTERGROWTH-21st models in the TEST set by estimating root-mean-squared error, bias and PTB rate.FindingsGarbhini-GA2 reduced the GA estimation error by 23-45% compared to the published models. Furthermore, the PTB rate estimated using Garbhini-GA2 was more accurate when compared to published formulae that overestimated the rate by 1·5-2·0 times.InterpretationThe Garbhini-GA2 model developed is the first of its kind developed solely using Indian population data. The higher accuracy of GA estimation by Garbhini-GA2 emphasises the need to apply population-specific GA formulae to improve antenatal care and better PTB rate estimates.FundingCentre for Integrative Biology and Systems Medicine, IIT Madras; Department of Biotechnology, Government of India; Grand Challenges India, BIRAC.Panel: Research in ContextEvidence before this studyThe appropriate delivery of antenatal care and accurate delivery date estimation is heavily dependent on accurate pregnancy dating. Unlike GA estimation using crown-rump length in the first trimester, dating using foetal biometry during the second and third trimesters is prone to inaccuracies. This is a public health concern, particularly in low and middle-income countries like India, where nearly 40% of pregnant women seek their first antenatal care beyond 14 weeks of gestation. The dating formulae used in LMIC were developed using foetal biometry data from the Caucasian population, and these formulae are prone to be erroneous when used in ethnically different populations.Added value of this studyThis study developed a dating model, the Garbhini-GA2 model for second and third trimesters of pregnancy using multiple candidate biometric predictors measured in a North Indian population. When evaluated internally, this model outperformed the currently used dating models by reducing the errors in the estimation of gestational age by 25-40%. Further, Garbhini-GA2 estimated a PTB rate similar to that estimated by the Gold Standard in our population, while the published formulae overestimated the PTB rates.Implications of all the available evidenceOur Garbhini-GA2 model, after due validations in independent cohorts across the Southeast Asian regions, has the potential to be quickly translated for clinical use across the region. A precise dating will benefit obstetricians and neonatologists to plan antenatal and neonatal care more exactly. From an epidemiologist standpoint, using the Garbhini-GA2 dating formulae will improve the precision of the estimates of pregnancy outcomes that heavily depend on gestational age, such as preterm birth, small for gestational age and stillbirth in our population. Additionally, our dating models will improve phenotyping by reducing the risk of misclassification between outcomes for mechanistic and biomarker research.

BackgroundDNA methylation (DNAm) may play an important role in birth outcomes.Material and MethodsGenome wide DNAm was analysed in peripheral blood DNA of women at multiple time points during gestation. A novel empirical method was used to identify CpG sites with high temporal variance in methylation associating with preterm birth.ResultsHigh variability at 1296 CpG sites from the promoter regions of 1197 genes significantly associated with PTB. These genes belonged to pathways involved in signalling by platelet derived growth factor, platelet homeostasis, collagen degradation, extracellular matrix and circadian clock.ConclusionsThe findings provide novel information which might help in development of predictive biomarkers of preterm birth outcome.

BackgroundThe incidence of preterm birth (PTB) in India is around 13%. Specific bacterial communities or individual taxon living in the vaginal milieu of pregnant women is a potential risk factor for PTB and may play an important role in its pathophysiology. Besides, bacterial taxa associated with PTB vary across populations.ObjectiveConduct a comparative analysis of vaginal microbiome composition and microbial genomic repertoires of women who enrolled in the Interdisciplinary Group for Advanced Research on Birth Outcomes – A DBT India Initiative (GARBH-Ini) pregnancy cohort to identify bacterial taxa associated with term birth (TB) and PTB in Indian women.MethodsVaginal swabs were collected during all three trimesters from 38 pregnant Indian women who delivered spontaneous term (n=20) and preterm (n=18) neonates. Paired-end sequencing of V3-V4 region of 16S rRNA gene was performed using the metagenomic DNA isolated from vaginal swabs (n=115). Whole genome sequencing of bacterial species associated with birth outcomes was carried out by shotgun method. Lactobacillus species were grown anaerobically in the De Man, Rogosa and Sharpe (MRS) agar culture medium for isolation of genomic DNA and whole genome sequencing.ResultsVaginal microbiome of both term and preterm samples reveals similar alpha diversity indices. However, significantly higher abundance of Lactobacillus iners (p-value All_TrimestersMegasphaera sp (p-value1st_Trimester <0.05), Gardnerella vaginalis (p-value2nd_Trimester= 0.01) and Sneathia sanguinegens (p-value2nd_Trimester <0.0001) were identified in preterm samples whereas higher abundance of L. gasseri (p-value3rd_Trimester =0.010) was observed in term samples by Wilcoxon rank-sum test. The relative abundance of L. iners, and Megasphaera sp. were found to be significantly different over time between term and preterm mothers. Analyses of the representative genomes of L. crispatus and L. gasseri indicate presence of secretory transcriptional regulator and several ribosomally synthesized antimicrobial peptides correlated with anti-inflammatory condition in the vagina. These findings indicate protective role of L. crispatus and L. gasseri in reducing the risk of PTB.ConclusionOur findings indicate that the dominance of specific Lactobacillus species and few other facultative anaerobes are associated with birth outcomes.

BackgroundDevelopment of methods to detect risk of preterm birth in pregnant women can result in reduction in occurrence of preterm birth. Our objective was to undertake a longitudinal study to investigate the association of telomere length shortening in peripheral blood DNA of women during pregnancy with preterm birth.MethodsTelomere length reduction in peripheral blood DNA was measured at two time points by Real Time PCR in pregnant women enrolled in a large prospective cohort (GARBH-Ini) in Gurugram, India. Out of 248 women who participated in this study, 60 mothers delivered preterm while 188 mothers delivered at term. ResultsTelomere length was found to be significantly reduced in preterm birth delivering mothers compared to those who delivered at term at less than 20 weeks (p=0.02) and at 26-28 weeks (p=0.84 x 10-15) of pregnancy. Predictive modelling by binary logistic regression analysis revealed that reduction of telomere length (T/S ratio) at 26-28 weeks was found to be significantly (p=7.7181 x 10-06) associated with enhanced risk of preterm birth. A mean odds ratio of 8.4 was found for association of T/S ratio with preterm birth outcome. There was no significant difference in maternal age between the mothers who delivered preterm and those who delivered at term. ConclusionsOur preliminary results indicate that telomere length reduction in maternal peripheral blood DNA might be a potential indicator of risk of preterm delivery.

Pregnancy is characterized by intense physiological and structural alterations in the vagina, cervix, and overlying fetal membranes. High vaginal fluid (HVF) is a proximal fluid that covers the lower part of the female reproductive system and the severity of vaginal pathology often adversely affects pregnancy outcomes. To identify the correlation of vaginal fluid proteome dynamics and physiological changes during the progression of pregnancy, a longitudinal study was performed on 20 pregnant women who delivered a baby in >37 weeks without any complications. SWATH-MS-based label-free quantitative proteomics was performed to profile the HVF proteome at three time points defined as V1 (7-12 weeks), V2 (18-20 weeks), and V3 (26-28 weeks). Linear mixed-effect models were used to estimate protein abundance as a function of the period of gestational age. In this study, we identified 1015 HVF proteins and 61 of them were significantly altered until late second trimester. Our result demonstrates that the HVF proteins reveal gestational age-specific expression patterns and the function of these proteins is associated with tissue remodeling, organ development, and microbial defense. Our study provides an opportunity to monitor the underlying physiology of pregnancy that may be further probed for the biomarker identification in pregnancy-related adverse outcomes. Data are available via ProteomeXchange with identifiers PXD014846 and PXD021811.

Sepsis, an important and preventable cause of death in the newborn, is associated with high out of pocket hospitalization costs for the parents/guardians. The government of Nepal’s Free Newborn Care (FNC) service that covers hospitalization costs has set a maximum limit of Nepalese rupees (NPR) 8000 i.e. USD 73.5, the basis of which is unclear. We aimed to estimate the costs of treatment in neonates and young infants fulfilling clinical criteria for sepsis, defined as clinical severe infection (CSI) to identify determinants of increased cost. This study assessed costs for treatment of 206 infants 3–59 days old, enrolled in a clinical trial, and admitted to the Kanti Children’s Hospital in Nepal through June 2017 to December 2018. Total costs were derived as the sum of direct costs for bed charges, investigations, and medicines and indirect costs calculated by using work time loss of parents. We estimated treatment costs for CSI, the proportion exceeding NPR 8000 and performed multivariable linear regression to identify determinants of high cost. Of the 206 infants, 138 (67%) were neonates (3–28 days). The median (IQR) direct costs for treatment of CSI in neonates and young infants (29–59 days) were USD 111.7 (69.8–155.5) and 65.17 (43.4–98.5) respectively. The direct costs exceeded NPR 8000 (USD 73.5) in 69% of neonates with CSI. Age

BackgroundDifferent formulae have been developed globally to estimate gestational age (GA) by ultrasonography in the first trimester of pregnancy. In this study, we develop an Indian population-specific dating formula and compare its performance with published formulae. Finally, we evaluate the implications of the choice of dating method on preterm birth (PTB) rate. This study’s data was from GARBH-Ini, an ongoing pregnancy cohort of North Indian women to study PTB.MethodsComparisons between ultrasonography-Hadlock and last menstrual period (LMP) based dating methods were made by studying the distribution of their differences by Bland-Altman analysis. Using data-driven approaches, we removed data outliers more efficiently than by applying clinical parameters. We applied advanced machine learning algorithms to identify relevant features for GA estimation and developed an Indian population-specific formula (Garbhini-GA1) for the first trimester. PTB rates of Garbhini-GA1 and other formulae were compared by estimating sensitivity and accuracy.ResultsPerformance of Garbhini-GA1 formula, a non-linear function of crown-rump length (CRL), was equivalent to published formulae for estimation of first trimester GA (LoA, - 0.46,0.96 weeks). We found that CRL was the most crucial parameter in estimating GA and no other clinical or socioeconomic covariates contributed to GA estimation. The estimated PTB rate across all the formulae including LMP ranged 11.27 – 16.50% with Garbhini-GA1 estimating the least rate with highest sensitivity and accuracy. While the LMP-based method overestimated GA by three days compared to USG-Hadlock formula; at an individual level, these methods had less than 50% agreement in the classification of PTB.ConclusionsAn accurate estimation of GA is crucial for the management of PTB. Garbhini-GA1, the first such formula developed in an Indian setting, estimates PTB rates with higher accuracy, especially when compared to commonly used Hadlock formula. Our results reinforce the need to develop population-specific gestational age formulae.

Objective To evaluate the effect of zinc as an adjuvant therapy in radiologically confirmed pneumonia in children 2-24 months of age. Patients and methods We analyzed data of 212 children with pneumonia for whom chest X-ray films were available at enrollment and at least two radiologists agreed on the diagnosis of pneumonia. We compared the time to recovery in the two groups (n = 121, zinc group and n = 91, placebo group) using a Cox proportional hazards regression model. Results Time to recovery was similar in both groups [median interquartile range: zinc, 84 h (64, 140 h); placebo, 85 h (65, 140 h)]. The absolute risk reduction for treatment failure was 5.2% (95% confidence interval: -4.8, 15.1) with zinc supplementation. Conclusion There was no significant beneficial effect of zinc on the duration of recovery or risk of treatment failure in children with radiologically confirmed pneumonia.

Background An estimated 2.7 of the 5.9 million deaths in children under 5 years of age occur in the neonatal period. Severe infections contribute to almost a quarter of these deaths. Mortality due to severe infections in developing country settings is substantial despite antibiotic therapy. Effective interventions that can be added to standard therapy for severe infections are required to reduce case fatality. Methods/Design This is a double-blind randomized placebo-controlled parallel group superiority trial to investigate the effect of zinc administered orally as an adjunct to standard therapy to infants aged 3 days up to 2 months (59 days) hospitalized with clinical severe infection, that will be undertaken in seven hospitals in Delhi, India and Kathmandu, Nepal. In a 1:1 ratio, we will randomly assign young infants to receive 10 mg of elemental zinc or placebo orally in addition to the standard therapy for a total of 14 days. The primary outcomes hospital case fatality, which is death due to any cause and at any time after enrolment while hospitalized for the illness episode, and extended case fatality, which encompasses the period until 12 weeks after enrolment. Discussion A previous study showed a beneficial effect of zinc in reducing the risk of treatment failure, as well as a non-significant effect on case fatality. This study was not powered to detect an effect on case fatality, which this current study is. If the results are consistent with this earlier trial, we would have provided strong evidence for recommending zinc as an adjunct to standard therapy for clinical severe infection in young infants. Trial registration Universal Trial Number: U1111-1187-6479, Clinical Trials Registry – India: CTRI/2017/02/007966 : Registered on February 27, 2017.

Objective Some of the conventional serological tests for coeliac disease (CD) are expensive, time-consuming and not readily available in developing countries, leading to a delay in diagnosis. Recently, point-of-care tests (POCT) have been manufactured and tested in Europe but have not been validated in our setting. We therefore aimed to study the diagnostic accuracy of the POCT ‘Biocard’ test in diagnosing CD in Indian children. Design Cross-sectional study. Setting Tertiary care centre in north India. Patients Children, aged 2–18 years, with chronic diarrhoea, short stature or refractory anaemia underwent serological testing for CD with antiendomysial antibodies (AEA), antitissue transglutaminase (tTG) antibodies and Biocard test followed by duodenal biopsy irrespective of serological results. CD was diagnosed with positive AEA and duodenal biopsy showing >grade 2 changes using modified Marsh criteria. Those who were both AEA negative and had normal histology were considered CD negative. Results Of 319 children who underwent the serological testing, 170 agreed for biopsy. Of these, 110 were diagnosed with CD and 30 were found to be CD negative. Remaining 30 had discordant AEA and histology results and were not included in analysis. Biocard test agreed with 92/110 positive and 27/30 negative diagnoses based on reference tests (83.6% sensitivity and 90% specificity). tTG was found to be 93.8% sensitive and 96.4% specific. Conclusions We successfully validated the POCT for CD in our setting. It could be used to increase case detection rates in developing countries with a large undiagnosed CD burden.

Background: Pneumonia is a leading cause of death; in India, an estimated 370,000 children die of pneumonia each year. Zinc has multiple influences on the immune response to infections. Zinc supplementation has been shown to prevent diarrhea and pneumonia in children. However, zinc’s therapeutic effect on respiratory infections is less clear. Objective: We evaluated the role of zinc as an adjunct to antibiotics in the treatment of children hospitalized for severe or very severe pneumonia. Design: In this randomized, double-blind, placebo-controlled trial, we enrolled 550 children aged 2‐24 mo with severe or very severe pneumonia. Within each hospital and pneumonia-severity stratum, children were randomly assigned to receive zinc (20 mg elemental zinc/d) or a placebo in addition to antibiotics and supportive care. Results: The time to recovery from severe or very severe pneumonia was similar in both groups (HR: 0.98; 95% CI: 0.82, 1.17). In the stratified analysis, zinc was shown to be efficacious in reducing the time to recovery in children with very severe pneumonia (HR: 1.52; 95% CI: 1.03, 2.23); however, the effect was no longer statistically significant after adjustment for differences in severely underweight children in the 2 groups. Conclusions: This study showed no overall benefit of the addition of zinc to antibiotics in reducing the time to recovery from pneumonia but showed a possible benefit of zinc supplementation in a subgroup of children with very severe pneumonia. Additional research is needed in specific subgroups such as children with very severe pneumonia. This trial was registered at http://www.controlled-trials. com as ISRCTN48954234. Am J Clin Nutr 2013;97:1387‐ 94.

To describe the clinico-bacteriological profile, and early outcomes of infants diagnosed with Group B streptococcus (GBS) meningitis. This was a retrospective review of infants (aged 1 mo to 2 y) diagnosed with GBS meningitis in a tertiary care hospital in New Delhi from October 2010 through January 2012. The clinico-bacteriological data and early outcomes of infants with suspected bacterial meningitis and a positive CSF latex agglutination test for GBS were studied. The CSF samples were subjected to PCR for broad spectrum 16s ribosomal DNA and the GBS species specific gene, the scpB. Twenty seven patients (13 boys, and 14 girls) were diagnosed with GBS meningitis during the study period. Broad spectrum 16s ribosomal DNA PCR was performed on 18 of the 27 CSF samples. Sixteen were positive. All these 16 were also positive for the species specific scpB gene. The median duration of hospital stay was 7 d (range 1–72 d). Nine patients died. One patient each developed ventriculitis, optic atrophy and hydrocephalus. Overall, 12 patients had a complete recovery at discharge. GBS must be considered in the etiology of bacterial meningitis in Indian infants.