Evidence-based antenatal interventions to reduce the incidence of small vulnerable newborns and their associated poor outcomes.

A package of care for all pregnant women within eight scheduled antenatal care contacts is recommended by WHO. Some interventions for reducing and managing the outcomes for small vulnerable newborns (SVNs) exist within the WHO package and need to be more fully implemented, but additional effective measures are needed. We summarise evidence-based antenatal and intrapartum interventions (up to and including clamping the umbilical cord) to prevent vulnerable births or improve outcomes, informed by systematic reviews. We estimate, using the Lives Saved Tool, that eight proven preventive interventions (multiple micronutrient supplementation, balanced protein and energy supplementation, low-dose aspirin, progesterone provided vaginally, education for smoking cessation, malaria prevention, treatment of asymptomatic bacteriuria, and treatment of syphilis), if fully implemented in 81 low-income and middle-income countries, could prevent 5·202 million SVN births (sensitivity bounds 2·398-7·903) and 0·566 million stillbirths (0·208-0·754) per year. These interventions, along with two that can reduce the complications of preterm (<37 weeks' gestation) births (antenatal corticosteroids and delayed cord clamping), could avert 0·476 million neonatal deaths (0·181-0·676) per year. If further research substantiates the preventive effect of three additional interventions (supplementation with omega-3 fatty acids, calcium, and zinc) on SVN births, about 8·369 million SVN births (2·398-13·857) and 0·652 million neonatal deaths (0·181-0·917) could be avoided per year. Scaling up the eight proven interventions and two intrapartum interventions would cost about US$1·1 billion in 2030 and the potential interventions would cost an additional $3·0 billion. Implementation of antenatal care recommendations is urgent and should include all interventions that have proven effects on SVN babies, within the context of access to family planning services and addressing social determinants of health. Attaining high effective coverage with these interventions will be necessary to achieve global targets for the reduction of low birthweight births and neonatal mortality, and long-term benefits on growth and human capital.

Linear growth beyond 24 months and child neurodevelopment in low- and middle-income countries: a systematic review and meta-analysis.

AIM: To synthesize available evidence on the association between change in linear growth (height for age z score, HAZ) beyond the first two years of life with later child neurodevelopment outcomes in Low- and middle-income countries (LMICs). METHODS: We searched PubMed, Web of Science, and EMBASE for cohort studies on the association between change in HAZ after age two and neurodevelopment outcomes in middle or late childhood. Data extraction was done independently by two reviewers. RESULTS: A total of 21 studies, that included 64,562 children from 13 LMICs were identified. Each unit increase in change in HAZ above two years is associated with a + 0.01 increase (N = 8 studies, 27,393 children) in the cognitive scores at 3.5 to 12 years of age and a + 0.05-standard deviation (SD) increase (95% CI 0.02 to 0.08, N = 3 studies, 17,830 children) in the language score at 5 to 15 years of age. No significant association of change in HAZ with motor (standardized mean difference (SMD) 0.04; 95% CI: -0.10, 0.18, N = 1 study, 966 children) or socio-emotional scores (SMD 0.00; 95% CI: -0.02, 0.01, N = 4 studies, 14,616 participants) was observed. CONCLUSION: Changes in HAZ after the first two years of life appear to have a small or no association with child neurodevelopment outcomes in LMICs.

Child Neurodevelopment After Multidomain Interventions From Preconception Through Early Childhood: The WINGS Randomized Clinical Trial.

Importance: Multidomain interventions in pregnancy and early childhood have improved child neurodevelopment, but little is known about the effects of additional preconception interventions. Objective: To evaluate the effect of a multifaceted approach including health; nutrition; water, sanitation, and hygiene (WASH); and psychosocial support interventions delivered during the preconception period and/or during pregnancy and early childhood on child neurodevelopment. Design, Setting, and Participants: In this randomized trial involving low- and middle-income neighborhoods in Delhi, India, 13 500 participants were assigned to preconception interventions or routine care for the primary outcome of preterm births and childhood growth. Participants who became pregnant were randomized to pregnancy and early childhood interventions or routine care. Neurodevelopmental assessments, the trial's secondary outcome reported herein, were conducted in a subsample of children at age 24 months, including 509 with preconception, pregnancy, and early childhood interventions; 473 with preconception interventions alone; 380 with pregnancy and early childhood interventions alone; and 350 with routine care. This study was conducted from November 1, 2000, through February 25, 2022. Interventions: Health, nutrition, psychosocial care and support, and WASH interventions delivered during preconception, pregnancy, and early childhood periods. Main Outcomes and Measures: Cognitive, motor, language, and socioemotional performance at age 24 months, assessed using the Bayley Scales of Infant and Toddler Development 3 tool. Results: The mean age of participants at enrollment was 23.8 years (SD, 3.0 years). Compared with the controls at age 24 months, children in the preconception intervention groups had higher cognitive scores (mean difference [MD], 1.16; 98.3% CI, 0.18-2.13) but had similar language, motor, and socioemotional scores as controls. Those receiving pregnancy and early childhood interventions had higher cognitive (MD, 1.48; 98.3% CI, 0.49-2.46), language (MD, 2.29; 98.3% CI, 1.07-3.50), motor (MD, 1.53; 98.3% CI, 0.65-2.42), and socioemotional scores (MD, 4.15; 98.3% CI, 2.18-6.13) than did controls. The pregnancy and early childhood group also had lower incidence rate ratios (RRs) of moderate to severe delay in cognitive (incidence RR, 0.62; 98.3% CI, 0.40-0.96), language (incidence RR, 0.73; 98.3% CI, 0.57-0.93), and socioemotional (incidence RR, 0.49; 98.3% CI, 0.24-0.97) development than did those in the control group. Children in the preconception, pregnancy, and early childhood intervention group had higher cognitive (MD, 2.60; 98.3% CI, 1.08-4.12), language (MD, 3.46; 98.3% CI, 1.65-5.27), motor (MD, 2.31; 98.3% CI, 0.93-3.69), and socioemotional (MD, 5.55; 98.3% CI, 2.66-8.43) scores than did those in the control group. Conclusions and Relevance: Multidomain interventions during preconception, pregnancy and early childhood led to modest improvements in child neurodevelopment at 24 months. Such interventions for enhancing children's development warrant further evaluation. Trial Registration: Clinical Trials Registry-India CTRI/2017/06/008908.

Prevalence of Wasting and its Associated Factors among Children Under 5 Years of Age in India: Findings from the Comprehensive National Nutrition Survey.

BACKGROUND: The burden of wasting among under five children in India, has not reduced in the last decade. OBJECTIVES: We used child-level data from the latest nationally representative Comprehensive National Nutritional Survey (CNNS) to estimate the prevalence of wasting at the national and state level in India. METHODS: We explored the association of wasting with maternal, child and household factors using multivariable logistic regression for the age group of 0-5, 6-23 and 24-59 months. RESULTS: The overall prevalence of wasting was 17.3%, ranging from 5.8% to 29.1% across states, 23.3% in children 0-5 months, 19.6 % in children 6-23 months and 15.4 % in children 24-59 months of age. Higher birthweight i.e., every 100g increase (0-5 months aOR = 0.96, 6-23 months aOR = 0.94, 24-59 months aOR = 0.96), higher maternal BMI (0-5 months aOR = 0.51, 6-23 months aOR = 0.62, 24-59 months aOR = 0.67), increasing child age in months (0-5 months aOR = 0.84) and female sex of the child (24-59 months aOR = 0.82) was found to have significantly lower odds of wasting. The odds of wasting were significantly higher for poorest wealth quintile (0-5 months aOR = 1.99, 6-23 months aOR = 2.13), maternal unemployment (0-5 months aOR = 2.25), and lower levels of maternal education (6-23 months aOR = 1.74). CONCLUSIONS: Our analyses showed that burden of wasting continues to remain high in India. Preventive interventions must target reduction of low birthweight. Early identification and management of wasting should be done, especially during the first six months of life who are not part of current therapeutic feeding programme.

Effects of kangaroo mother care on maternal and paternal health: systematic review and meta-analysis.

Objective: To investigate the effect of kangaroo mother care for low-birth-weight and preterm infants on parents' mental and physical health. Methods: The Cochrane Central Register of Controlled Trials, Cochrane Register of Studies Online, PubMed®, Web of Science, Scopus and EMBASE® databases were searched on 16 January 2023 for randomized and quasi-randomized trials on kangaroo mother care. Records identified were screened independently by two reviewers. Pooled relative risks (RRs) are reported for categorical variables, and standardized mean differences (SMDs) or mean differences are reported for continuous variables. Evidence quality was assessed using the GRADE approach. Findings: The search identified 30 studies involving 7719 preterm or low-birth-weight infants. There was high-certainty evidence that kangaroo mother care substantially reduced the risk of moderate-to-severe postpartum maternal depressive symptoms compared with no kangaroo mother care (RR: 0.76; 95% confidence interval, CI: 0.59 to 0.96). In addition, there was low-certainty evidence that kangaroo mother care reduced scores for maternal stress (SMD: -0.82; 95% CI: -1.32 to -0.32) and anxiety (SMD: -0.62; 95% CI: -1.01 to -0.23) and increased mother-infant attachment and bonding scores (SMD: 1.19; 95% CI: 0.27 to 2.10). Limited evidence indicated father-infant interactions may be improved, though no marked effect on paternal depression or stress was observed. No trial reported parental physical health outcomes. Conclusion: Kangaroo mother care for preterm and low-birth-weight infants was associated with less postpartum maternal depression, stress and anxiety and better mother-infant attachment and bonding. More research is required to evaluate effects on paternal health.

Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6-7 Years: A Follow-Up of a Randomized Controlled Trial.

BACKGROUND: Deficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. OBJECTIVES: We investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6-7 y. METHODS: This is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6-30-mo-old children. The supplement contained 1.8 µg of vitamin B12, 150 µg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016-November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). RESULTS: At baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 µmol/L (95% CI: 0.09; 2.30 µmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin-adiponectin ratio in subgroups based on their nutritional status. CONCLUSIONS: Supplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations. The original trial was registered at www. CLINICALTRIALS: gov as NCT00717730, and the follow-up study at www.ctri.nic.in as CTRI/2016/11/007494.

Milk-cereal mix supplementation during infancy and impact on neurodevelopmental outcomes at 12 and 24 months of age: a randomised controlled trial in India.

Inadequate protein intake and lack of micronutrients may affect neurodevelopment in infants. This randomised controlled trial was conducted to measure the effect of two milk-cereal mixes with modest and high amounts of protein and enriched with multiple micronutrients, given between 6 and 12 months, on cognitive, language, motor and behavioural scores at 12 and 24 months of age, compared with no-supplementation. The two supplements were also compared with each other. The study was conducted in urban Delhi, India, and the infants were randomised in a 1:1:1 ratio to the three study groups. At 12 and 24 months of age, 1134 and 1214 children were available, respectively. At 12 months of age, compared with no-supplement group, an increase in the motor scores (mean difference, MD 1·52, 95 % CI: 0·28, 2·75) and a decrease in the infant temperament scores (MD - 2·76, 95 % CI: -4·23, -1·29) in the modest-protein group was observed. Those in the high-protein group had lower socio-emotional scores (MD - 1·40, 95 % CI: -2·43, -0·37) and higher scores on Infant Temperament Scale (MD 2·05, 95 % CI: 0·62, 3·48) when compared with modest-protein group. At 24 months, no significant differences in any of the neurodevelopment scores between the three study groups was found. In conclusion, supplementation with modest amount of protein and multiple micronutrients may lead to short-term small improvements in motor function and infant temperament. There appears no advantage of supplementing with high protein, rather negative effects on infant behaviour were observed.

Harmonization of maternal balanced energy-protein supplementation studies for individual participant data (IPD) meta-analyses - finding and creating similarities in variables and data collection.

BACKGROUND: Public health and clinical recommendations are established from systematic reviews and retrospective meta-analyses combining effect sizes, traditionally, from aggregate data and more recently, using individual participant data (IPD) of published studies. However, trials often have outcomes and other meta-data that are not defined and collected in a standardized way, making meta-analysis problematic. IPD meta-analysis can only partially fix the limitations of traditional, retrospective, aggregate meta-analysis; prospective meta-analysis further reduces the problems. METHODS: We developed an initiative including seven clinical intervention studies of balanced energy-protein (BEP) supplementation during pregnancy and/or lactation that are being conducted (or recently concluded) in Burkina Faso, Ethiopia, India, Nepal, and Pakistan to test the effect of BEP on infant and maternal outcomes. These studies were commissioned after an expert consultation that designed recommendations for a BEP product for use among pregnant and lactating women in low- and middle-income countries. The initiative goal is to harmonize variables across studies to facilitate IPD meta-analyses on closely aligned data, commonly called prospective meta-analysis. Our objective here is to describe the process of harmonizing variable definitions and prioritizing research questions. A two-day workshop of investigators, content experts, and advisors was held in February 2020 and harmonization activities continued thereafter. Efforts included a range of activities from examining protocols and data collection plans to discussing best practices within field constraints. Prior to harmonization, there were many similar outcomes and variables across studies, such as newborn anthropometry, gestational age, and stillbirth, however, definitions and protocols differed. As well, some measurements were being conducted in several but not all studies, such as food insecurity. Through the harmonization process, we came to consensus on important shared variables, particularly outcomes, added new measurements, and improved protocols across studies. DISCUSSION: We have fostered extensive communication between investigators from different studies, and importantly, created a large set of harmonized variable definitions within a prospective meta-analysis framework. We expect this initiative will improve reporting within each study in addition to providing opportunities for a series of IPD meta-analyses.

Government-led initiative increased the effective use of Kangaroo Mother Care in a region of North India.

AIM: To learn how to achieve high-quality, effective coverage of Kangaroo Mother Care (KMC), defined as 8 hours or more of skin-to-skin contact per day and exclusive breastfeeding in district Sonipat in North India, and to develop and evaluate an implementation model. METHODS: We conducted implementation research using a mixed-methods approach, including formative research, followed by repeated, rapid cycles of implementation, evaluation and refinement until a model with the potential for high and effective coverage was reached. Evaluation of this model was conducted over a 12-month period. RESULTS: Formative research findings informed the final implementation model. Programme learning was critical to achieve high coverage. The model included improving the identification of small babies, creating KMC wards, modification in hospitalisation criteria, private sector engagement and in-built programme learning to refine implementation progress. KMC was initiated in 87% of eligible babies. At discharge, 85% received skin-to-skin contact care, 60% effective KMC and 80% were exclusively breastfed. At home, 7-day post discharge, 81% received skin-to-skin care and 79% were exclusively breastfed in the previous 24 hours. CONCLUSION: Achieving high KMC coverage is feasible in the study setting using a model responsive to the local context and led by the Government.

Vitamin B12 and/or folic acid supplementation on linear growth; a 6 years follow-up study of a randomised controlled trial in early childhood in North India.

Folate and vitamin B12 are essential for growth. Our objective was to estimate their long-term effects on linear growth in North Indian children. This is a follow-up study of a factorial designed, double-blind, randomized placebo-controlled trial in 1,000 young children. Starting at 6-30 months of age, we gave folic acid (∼2 RDAs), vitamin B12 (∼2 RDAs), both vitamins, or a placebo daily for six months. Six years after the end of supplementation, we measured height in 791 children. We used the plasma concentrations of cobalamin, folate, and total homocysteine to estimate vitamin status. The effect of the interventions, the association between height-for-age z-scores (HAZ) and baseline vitamin status, and the interactions between supplementation and baseline status were estimated in multiple regression models. Mean (SD) age at follow-up was 7.4 (0.7) years (range 6 to 9 years). There was a small, non-significant effect of vitamin B12 on linear growth and no effect of folic acid. We observed a subgroup-effect of vitamin B12 supplementation in those with plasma cobalamin concentration < 200 pmol/L (P interaction = 0.01). The effect of vitamin B12 supplementation in this group was 0.34 HAZ (95% CI: 0.11-0.58). We found an association between cobalamin status and HAZ in children not given vitamin B12 (P interaction = 0.001). In this group, each doubling of the cobalamin concentration was associated with 0.26 (95% CI: 0.15 to 0.38) higher HAZ. Suboptimal B12 status in early childhood seemingly limits linear growth in North Indian Children.

Burden, risk factors and outcomes associated with gestational diabetes in a population-based cohort of pregnant women from North India.

BACKGROUND: The burden of gestational diabetes mellitus (GDM) appears to be increasing in India and may be related to the double burden of malnutrition. The population-based incidence and risk factors of GDM, particularly in lower socio-economic populations, are not known. We conducted analyses on data from a population-based cohort of pregnant women in South Delhi, India, to determine the incidence of GDM, its risk factors and association with adverse pregnancy outcomes (stillbirth, preterm birth, large for gestational age babies) and need for caesarean section. METHODS: We analyzed data from the intervention group of the Women and Infants Integrated Interventions for Growth Study (WINGS), an individually randomized factorial design trial. An oral glucose tolerance test (OGTT) was performed at the time of confirmation of pregnancy, and for those who had a normal test (≤140 mg), it was repeated at 24-28 and at 34-36 weeks. Logistic regression was performed to ascertain risk factors associated with GDM. Risk ratios (RR) were calculated to find association between GDM and adverse pregnancy outcomes and need for caesarean section. RESULTS: 19.2% (95% CI: 17.6 to 20.9) pregnant women who had at least one OGTT were diagnosed to have GDM. Women who had prediabetes at the time of confirmation of pregnancy had a significantly higher risk of developing GDM (RR 2.08, 95%CI 1.45 to 2.97). Other risk factors independently associated with GDM were woman's age (adjusted OR (AOR) 1.10, 95% CI 1.06 to 1.15) and BMI (AOR 1.04, 95% CI 1.01 to 1.07). Higher maternal height was found to be protective factor for GDM (AOR 0.98, 95% CI 0.96 to 1.00). Women with GDM, received appropriate treatment did not have an increase in adverse outcomes and no increased need for caesarean section CONCLUSIONS: A substantial proportion of pregnant women from a low to mid socio-economic population in Delhi had GDM, with older age, higher BMI and pre-diabetes as important risk factors. These findings highlight the need for interventions for prevention and provision of appropriate management of GDM in antenatal programmes. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry - India, #CTRI/2017/06/008908 ( http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339&EncHid=&userName=society%20for%20applied%20studies ).

Early child stimulation, linear growth and neurodevelopment in low birth weight infants.

BACKGROUND: Children with low birth weight (LBW) are at risk of linear growth faltering and developmental deficits. Evidence suggests that early child stimulation and care reflected as responsive caregiving and opportunities for learning can promote development. The current analysis aimed to measure the extent to which linear growth and early child stimulation modify each other's association with neurodevelopmental outcomes among LBW infants. METHODS: This is a secondary data analyses from a randomized controlled trial on the effect of community-initiated kangaroo mother care in LBW infants on their neurodevelopment at 12 months of corrected age. Bayley Scales of Infant and Toddler Development was used to assess cognitive, motor and language scores. Stimulation at home was assessed by the Pediatric Review of Children's Environmental Support and Stimulation (PROCESS) tool. PROCESS scores were categorized into three groups: < Mean-1SD (low stimulation); Mean ± 1 SD (moderate stimulation) and > mean + 1SD (high stimulation). RESULTS: A total of 516 infants were available for neurodevelopment assessments. Interactions were observed between length for age z-score (LAZ) and PROCESS score categories. In the low stimulation group, the adjusted regression coefficients for the association between LAZ and cognitive, motor and language scores were substantially higher than in the moderate and high stimulation group. Stimulation was positively associated with neurodevelopmental outcomes in both stunted and non-stunted infants; however, the association was twice as strong in stunted than in non-stunted. CONCLUSION: Moderate to high quality stimulation may alleviate the risk of sub-optimal development in LBW infants with linear growth deficits. CLINICAL TRIAL REGISTRATION: The primary trial whose data are analysed is registered at clinicaltrials.gov ( https://clinicaltrials.gov/ct2/show/NCT02631343 ).

Effect of community-initiated kangaroo mother care on breastfeeding performance in low birthweight infants: A randomized clinical trial.

This individually randomized trial was conducted to estimate the effect of promoting community-initiated kangaroo mother care (ciKMC) in low birthweight (LBW) infants on infant breastfeeding performance. It was designed as a substudy within a larger primary trial on ciKMC and infant survival. Five hundred fifty stable LBW mother-infant dyads (1500-2250 g) who provided consent, were consecutively enroled for breastfeeding performance assessment. The ciKMC intervention included promotion and support of continuous skin-to-skin contact and exclusive breastfeeding (EBF) through home visits during the neonatal period. The primary outcome was effective breastfeeding performance indicated by an infant breastfeeding assessment tool score of ≥10 after the end of the neonatal period. As secondary outcomes, we reported maternal satisfaction related to infant breastfeeding, and EBF after the end of the neonatal period. We completed outcome assessments in 96% of participants. In the ciKMC arm, 92% of the infants showed effective breastfeeding performance against 81% in the control arm [adjusted prevalence ratio (aPR): 1.24, 95% confidence interval (CI): 1.16-1.32]. In the ciKMC arm, 65% of the mothers reported to be very satisfied with their infants' breastfeeding against 51% in the control arm (aPR: 1.22, 95% CI: 1.05-1.41). The proportion of infants practicing EBF was 89% in the ciKMC arm against 45% in the control arm (aPR: 1.62, 95% CI: 1.45-1.81). Our study findings suggest that promotion of ciKMC can improve effective breastfeeding, EBF and maternal satisfaction related to breastfeeding in LBW infants.

Health equity impact of community-initiated kangaroo mother care: a randomized controlled trial.

BACKGROUND: Kangaroo mother care (KMC) can substantially enhance overall survival of low birthweight babies. In a large randomized controlled trial, we recently showed that supporting mothers to provide community initiated KMC (ciKMC) can reduce mortality among infants up to 180 days of life by 25% (hazard ratio (HR) 0.75). With the current analysis, we aimed to explore if ciKMC promotion leads to increased inequity in survival. METHODS: In the trial we randomized 8402 low birthweight babies to a ciKMC (4480 babies) and a control (3922 babies) arm, between 2015 and 2018 in Haryana, India. We estimated the difference in concentration indices, which measure inequality, between babies in the ciKMC and control arms for survival until 180 days of life. Further, we compared the effect of ciKMC promotion across subgroups defined by socioeconomic status, caste, maternal literacy, infant's sex, and religion. RESULTS: Our intervention did not increase survival inequity, as the concentration index in the ciKMC arm of the trial was 0.05 (95% CI -0.07 to 0.17) lower than in the control arm. Survival impact was higher among those belonging to the lower two wealth quintiles, those born to illiterate mothers and those belonging to religions other than Hindu. CONCLUSIONS: We found that ciKMC promotion did not increase inequity in survival associated with wealth. The beneficial impact of ciKMC tended to be larger among vulnerable groups. Supporting mothers to provide KMC at home to low birthweight babies will not increase and could indeed reduce inequities in infant survival. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02653534 . Registered January 12, 2016-Retrospectively registered.

Diagnostic measures for severe acute malnutrition in Indian infants under 6 months of age: a secondary data analysis.

BACKGROUND: Weight for length z-score (WLZ) < - 3 is currently used to define severe acute malnutrition (SAM) among infants. However, this approach has important limitations for infants younger than 6 months of age as WLZ cannot be calculated using WHO growth standards if infant length is < 45 cm. Moreover, length for age z-score (LAZ) and weight for length z-score (WLZ) are least reliable measures, with high chances of variation, and less chances of detecting undernutrition in under 6 months infants. The objective of the current analysis was to compare WLZ with WAZ and LAZ in a cohort of Indian infants in predicting the deaths between 6 weeks and 6 months of age. METHODS: The data was from an individually randomized trial conducted in slums of Delhi, India in which infants' weight and length were measured at 6 weeks of age (at the time of the first immunization visit). Vital status of the infants was documented from 6 weeks to 6 months of age. The sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated for WAZ < -3, WLZ < -3, and LAZ < -3 for deaths between 6 weeks and 6 months of age. The receiver operating characteristics curve was calculated for each of the above anthropometric indicators. RESULTS: For deaths occurring between 6 weeks to 6 months of age, the specificity ranged between 85.9-95.9% for all three anthropometric indicators. However, the sensitivity was considerably higher for WAZ; it was 64.6% for WAZ < -3, 39.1% for LAZ < -3, and 25.0% for WLZ < -3. WAZ < -3 had higher area under curve (0.75; 95% CI: 0.68, 0.82) and hence, better discriminated deaths between 6 weeks and 6 months of age than WLZ < -3. The adjusted relative risk (RR 10.6, 95% CI 5.9, 18.9) and the population attributable fraction (PAF 57.9, 95% CI 38.8, 71.0%) of mortality was highest for WAZ < -3. CONCLUSIONS: We found WAZ < -3 at 6 weeks of age to be a better predictor of death in the 6 weeks to 6 months of life in comparison to WLZ < -3 and LAZ < -3 and propose that it should be considered to diagnose SAM in this age group.

Guidelines for Reporting Trial Protocols and Completed Trials Modified Due to the COVID-19 Pandemic and Other Extenuating Circumstances: The CONSERVE 2021 Statement.

Importance: Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective: As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence: A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings: The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance: CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

Effect of community-initiated kangaroo mother care on survival of infants with low birthweight: a randomised controlled trial.

BACKGROUND: Coverage of kangaroo mother care remains very low despite WHO recommendations for its use for babies with low birthweight in health facilities for over a decade. Initiating kangaroo mother care at the community level is a promising strategy to increase coverage. However, knowledge of the efficacy of community-initiated kangaroo mother care is still lacking. We aimed to assess the effect of community-initiated kangaroo mother care provided to babies weighing 1500-2250 g on neonatal and infant survival. METHODS: In this randomised controlled, superiority trial, undertaken in Haryana, India, we enrolled babies weighing 1500-2250 g at home within 72 h of birth, if not already initiated in kangaroo mother care, irrespective of place of birth (ie, home or health facility) and who were stable and feeding. The first eligible infants in households were randomly assigned (1:1) to the intervention (community-initiated kangaroo mother care) or control group by block randomisation using permuted blocks of variable size. Twins were allocated to the same group. For second eligible infants in the same household as an enrolled infant, if the first infant was assigned to the intervention group the second infant was also assigned to this group, whereas if the first infant was assigned to the control group the second infant was randomly assigned (1:1) to the intervention or control group. Mothers and infants in the intervention group were visited at home (days 1-3, 5, 7, 10, 14, 21, and 28) to support kangaroo mother care (ie, skin-to-skin contact and exclusive breastfeeding). The control group received routine care. The two primary outcomes were mortality between enrolment and 28 days and between enrolment and 180 days. Analysis was by intention to treat and adjusted for clustering within households. The effect of the intervention on mortality was assessed with person-time in the denominator using Cox proportional hazards model. This study is registered with ClinicalTrials.gov, NCT02653534 and NCT02631343, and is now closed to new participants. FINDINGS: Between July 30, 2015, and Oct 31, 2018, 8402 babies were enrolled, of whom 4480 were assigned to the intervention group and 3922 to the control group. Most births (6837 [81·4%]) occurred at a health facility, 36·2% (n=3045) had initiated breastfeeding within 1 h of birth, and infants were enrolled at an average of about 30 h (SD 17) of age. Vital status was known for 4470 infants in the intervention group and 3914 in the control group at age 28 days, and for 3653 in the intervention group and 3331 in the control group at age 180 days. Between enrolment and 28 days, 73 infants died in 4423 periods of 28 days in the intervention group and 90 deaths in 3859 periods of 28 days in the control group (hazard ratio [HR] 0·70, 95% CI 0·51-0·96; p=0·027). Between enrolment and 180 days, 158 infants died in 3965 periods of 180 days in the intervention group and 184 infants died in 3514 periods of 180 days in the control group (HR 0·75, 0·60-0·93; p=0·010). The risk ratios for death were almost the same as the HRs (28-day mortality 0·71, 95% CI 0·52- 0·97; p=0·032; 180-day mortality 0·76, 0·60-0·95; p=0·017). INTERPRETATION: Community-initiated kangaroo mother care substantially improves newborn baby and infant survival. In low-income and middle-income countries, incorporation of kangaroo mother care for all infants with low birthweight, irrespective of place of birth, could substantially reduce neonatal and infant mortality. FUNDING: Research Council of Norway and University of Bergen.

Linear Growth between Early and Late Childhood and Cognitive Outcomes at 6-9 Years of Age.

OBJECTIVES: To assess the extent to which linear growth beyond the early years of life determines later cognitive development. STUDY DESIGN: We revisited children from New Delhi, India, who had participated in a randomized controlled trial 6 years before and assessed neurodevelopment using standardized and validated psychometric tools (Wechsler Intelligence Scale for Children, 4th edition; Crichton Vocabulary Scales; and Neuropsychological test battery). The associations of change in height for age z scores between early (12-36 months) and late (6-9 years) childhood with cognitive outcomes at 6-9 years of age were explored using linear regression models, after adjustment for appropriate confounders. RESULTS: Out of the 1000 North Indian children who were enrolled in the original study, 791 consented to participate in this follow-up. Height for age z scores in the first 2 years of life was significantly associated with both the Wechsler Intelligence Scale for Children-Crichton Vocabulary Scales (standardized ß coefficient [ß], 0.15; 95% CI, 0.08-0.23), and the Neuropsychological test battery-II z-score (ß, 0.09; 95% CI, 0.03-0.18) at 6-9 years of age. There were no significant associations between change in height for age z scores between early and later childhood and Wechsler Intelligence Scale for Children-Crichton Vocabulary Scales (ß, -0.03; 95% CI, -0.11 to 0.04) or Neuropsychological test battery-II z-scores (ß, -0.04; 95% CI, -0.12 to 0.06). CONCLUSIONS: Linear growth between early and late childhood is not associated with later cognitive outcomes. Our findings support the current practice of investing public health efforts to accelerate linear growth in the first 2-3 years of life.

Antenatal Uterotonics as a Risk Factor for Intrapartum Stillbirth and First-day Death in Haryana, India: A Nested Case-control Study.

BACKGROUND: Use of uterotonics like oxytocin to induce or augment labor has been shown to reduce placental perfusion and oxygen supply to the fetus, and studies indicate that it may increase the risk of stillbirth and neonatal asphyxia. Antenatal use of uterotonics, even without the required fetal monitoring and prompt access to cesarean section, is widespread, yet no study has adequately estimated the risk of intrapartum stillbirth and early neonatal deaths ascribed to such use. We conducted a case-control study to estimate this risk. METHODS: We conducted a population-based case-control study nested in a cluster-randomized trial. From 2008 to 2010, we followed pregnant women in rural Haryana, India, monthly until delivery. We visited all live-born infants on day 29 to ascertain whether they were alive. We conducted verbal autopsies for stillbirths and neonatal deaths. Cases (n = 2,076) were the intrapartum stillbirths and day-1 deaths (early deaths), and controls (n = 532) were live-born babies who died between day 8 and 28 (late deaths). RESULTS: Antenatal administration of uterotonics preceded 74% of early and 62% of late deaths, translating to an adjusted odds ratio (95% confidence interval [CI]) for early deaths of 1.7 (95% CI = 1.4, 2.1), and a population attributable risk of 31% (95% CI = 22%, 38%). CONCLUSIONS: Antenatal administration of uterotonics was associated with a substantially increased risk of intrapartum stillbirth and day-1 death. See video abstract: http://links.lww.com/EDE/B707.

Effect of prebiotic and probiotic supplementation on neurodevelopment in preterm very low birth weight infants: findings from a meta-analysis.

BACKGROUND: Preterm very low birth weight (VLBW) infants are at risk of gut dysbiosis and neurodevelopmental deficits. Prebiotics and probiotics may modulate gut microbiota and influence brain functions. This review synthesizes literature on effect of prebiotic and/or probiotic supplementation in preterm VLBW on their neurodevelopmental outcomes. METHODS: Search was done using PubMed and CENTRAL. Randomized controlled trials (RCTs) in preterm infants (<37 weeks gestation) and/or infants with birth weight <1500 g that evaluated the effect of prebiotic and/or probiotic supplementation on neurodevelopmental outcomes were included. Weighted mean difference in cognitive and motor scores; pooled relative risks for cognitive and motor impairment, cerebral palsy, hearing, and visual impairment were estimated. Quality of evidence was assessed using the GRADE criteria. RESULTS: Out of 275 articles identified, seven were included for review. All, except one, were done in preterms <33 weeks of gestation. Age of assessment of outcomes was ≥18-22 months of corrected age in five studies. Interventions did not decrease or increase the risk of cognitive and motor impairment, cerebral palsy, visual, and hearing impairment. Quality of evidence was "low" to "very low." CONCLUSIONS: Limited evidence from RCTs does not demonstrate a difference in neurodevelopmental outcomes between prebiotic/probiotic treated and untreated control groups.