Impact of an integrated health, nutrition, and early child stimulation and responsive care intervention package delivered to preterm or term small for gestational age babies during infancy on growth and neurodevelopment: study protocol of an individually randomized controlled trial in India (Small Babies Trial).

BACKGROUND: Preterm and term small for gestational age (SGA) babies are at high risk of experiencing malnutrition and impaired neurodevelopment. Standalone interventions have modest and sometimes inconsistent effects on growth and neurodevelopment in these babies. For greater impact, intervention may be needed in multiple domains-health, nutrition, and psychosocial care and support. Therefore, the combined effects of an integrated intervention package for preterm and term SGA on growth and neurodevelopment are worth investigating. METHODS: An individually randomized controlled trial is being conducted in urban and peri-urban low to middle-socioeconomic neighborhoods in South Delhi, India. Infants are randomized (1:1) into two strata of 1300 preterm and 1300 term SGA infants each to receive the intervention package or routine care. Infants will be followed until 12 months of age. Outcome data will be collected by an independent outcome ascertainment team at infant ages 1, 3, 6, 9, and 12 months and at 2, 6, and 12 months after delivery for mothers. DISCUSSION: The findings of this study will indicate whether providing an intervention that addresses factors known to limit growth and neurodevelopment can offer substantial benefits to preterm or term SGA infants. The results from this study will increase our understanding of growth and development and guide the design of public health programs in low- and middle-income settings for vulnerable infants. TRIAL REGISTRATION: The trial has been registered prospectively in Clinical Trial Registry - India # CTRI/2021/11/037881, Registered on 08 November 2021.

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.

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.

Preconception and periconception interventions to prevent low birth weight, small for gestational age and preterm birth: a systematic review and meta-analysis.

BACKGROUND: Low birth weight (LBW), including preterm birth (PTB) and small for gestational age (SGA), contributes a significant global health burden. We aimed to summarise current evidence on the effect of preconception and periconception interventions on LBW, SGA and PTB. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library and WHO Global Index Medicus for randomised controlled trials and quasi-experimental studies published by 28 November 2020, which assessed interventions delivered in preconception and periconception or preconception and pregnancy. Primary outcomes were LBW, SGA and PTB. Studies were categorised by intervention type and delivery during preconception and periconception or during preconception and pregnancy. Estimates were pooled using fixed-effects or random-effects restricted maximum likelihood method meta-analyses. Quality of evidence for primary outcomes was assessed using the Grades of Recommendations, Assessment, Development and Evaluation approach. RESULTS: We included 58 studies. Twenty-eight studies examined nutrition interventions (primarily micronutrient or food supplementation). Thirty studies (including one reporting a nutrition intervention) provided health interventions (general preconception health, early adverse pregnancy outcome prevention, non-communicable disease and infectious disease prevention and management). One study assessed a social intervention (reproductive planning). Studies varied in terms of specific interventions, including delivery across preconception or pregnancy, resulting in few studies for any single comparison. Overall, the evidence was generally very uncertain regarding the impact of any intervention on LBW, SGA and PTB. Additionally, preconception and periconception nutritional supplementation containing folic acid was associated with reduced risk of birth defects (10 studies, N=3 13 312, risk ratio: 0.37 (95% CI: 0.24 to 0.55), I2: 74.33%). CONCLUSION: We found a paucity of evidence regarding the impact of preconception and periconception interventions on LBW, SGA and PTB. Further research on a wider range of interventions is required to clearly ascertain their potential effectiveness. TRIAL REGISTRATION NUMBER: This review was prospectively registered with PROSPERO (CRD42020220915).

Vitamin D status and associations with substance use patterns among people with severe substance use disorders in Western Norway.

Chronic and harmful substance use is associated with a cluster of harms to health, including micronutrient deficiencies. Maintaining adequate levels of vitamin D is important for musculoskeletal and other aspects of health. In this prospective longitudinal cohort study, 666 participants drawn from outpatient opioid agonist therapy (OAT) clinics and community care clinics for substance use disorder in Western Norway were assessed annually for determination of serum 25-hydroxyvitamin D [s-25(OH)D] levels. Fifty-seven percent were deficient at baseline (s-25(OH)D < 50 nmol/l), and 19% were severely deficient (s-25(OH)D < 25 nmol/l). Among those deficient/severely deficient at baseline, 70% remained deficient/severely deficient at the last measurement (mean duration 714 days). Substance use patterns and dosage of opioids for OAT were not associated with vitamin D levels. One exception was found for cannabis, where consumption on a minimum weekly basis was associated with lower levels at baseline (mean difference: -5.2 nmol/l, 95% confidence interval [CI]: -9.1, - 1.3), but without clear time trends (mean change per year: 1.4 nmol/l, CI: - 0.86, 3.7). The high prevalence of sustained vitamin D deficiency in this cohort highlights the need for targeted monitoring and supplementation for this and similar at-risk populations.

Enteral Low-Dose Vitamin A Supplementation in Preterm or Low Birth Weight Infants to Prevent Morbidity and Mortality: a Systematic Review and Meta-analysis.

OBJECTIVES: To assess effects of enteral "low" dose (daily doses of ≤10 000 international unit) vitamin A supplementation compared with no vitamin A supplementation in human milk-fed preterm and low birth weight (LBW) infants. DATA SOURCES: Cochrane Central Register of Controlled Trials; Medline, Embase, Scopus, Web of Science, CINAHL from inception to 16 March 2021. STUDY SELECTION: Randomized trials were screened. Primary outcomes were mortality, morbidity, growth, neurodevelopment. Secondary outcomes were feed intolerance and duration of hospitalization. We also assessed the dose and timing of vitamin A supplementation. Data were extracted and pooled with fixed and random-effects models. RESULTS: Four trials including 800 very LBW <1.5 kg or <32 weeks' gestation infants were found. At latest follow-up, we found little or no effect on: mortality, sepsis, bronchopulmonary dysplasia, retinopathy of prematurity, duration of hospitalisation. However, we found a increased level of serum retinol mean difference of 4.7 µg/ml (95% CI 1.2 to 8.2, I2 =0.00%, one trial, 36 participants,). Evidence ranged from very low to moderate certainty. There were no outcomes reported for length, head circumference or neurodevelopment. LIMITATIONS: Heterogeneity and small sample size in the included studies. CONCLUSIONS: Low-dose vitamin A increased serum retinol concentration among very LBW and very preterm infants but had no effect on other outcomes. More trials are needed to assess effects on clinical outcomes and to assess effects in infants 1.5 to 2.4 kg or 32 to 26 weeks' gestation.

Enteral Calcium or Phosphorus Supplementation in Preterm or Low Birth Weight Infants: a Systematic Review and Meta-analysis.

OBJECTIVES: To assess effects of calcium or phosphorous supplementation compared with no supplementation in human milk-fed preterm or low birth weight infants. METHODS: Data sources include Cochrane Central Register of Controlled Trials, Medline and Embase. We included Randomized controlled trials (RCTs) and non-randomized trials (quasi-randomized). RESULTS: Three studies (4 reports; 162 infants) were included. At latest follow-up (38 weeks), there was reduction in osteopenia (3 studies, 159 participants, relative risk 0.68, 95% confidence interval [CI] 0.46-0.99). At latest follow-up (6 weeks), there was no effect on weight (1 study, 40 participants, mean difference [MD] 138.50 g, 95% CI -82.16 to 359.16); length (1 study, 40 participants, MD 0.77 cm, 95% CI -0.93 to 2.47); and head circumference (1 study, 40 participants, MD 0.33 cm, 95% CI -0.30 to 0.96). At latest follow-up, there was no effect on alkaline phosphatase (55 weeks) (2 studies, 122 participants, MD -126.11 IU/L, 95% CI -298.5 to 46.27, I2 = 73.4%); serum calcium (6 weeks) (1 study, 40 participants, MD 0.54 mg/dL, 95% CI -0.19 to 1.27); and serum phosphorus (6 weeks) (1 study, 40 participants, MD 0.07 mg/dL, 95% CI -0.22 to 0.36). The certainty of evidence ranged from very low to low. No studies reported on mortality and neurodevelopment outcomes. CONCLUSIONS: The evidence is insufficient to determine whether enteral supplementation with calcium or phosphorus for preterm or low birth weight infants who are fed mother's own milk or donor human milk is associated with benefit or harm.

Enteral Multiple Micronutrient Supplementation in Preterm and Low Birth Weight Infants: A Systematic Review and Meta-analysis.

OBJECTIVES: To assess effects of supplementation with 3 or more micronutrients (multiple micronutrients; MMN) compared to no MMN in human milk-fed preterm and low birth weight (LBW) infants. RESULTS: Data on a subgroup of 414 preterm or LBW infants from 2 randomized controlled trials (4 reports) were included. The certainty of evidence ranged from low to very low. For growth outcomes in the MMN compared to the non-MMN group, there was a small increase in weight-for-age (2 trials, 383 participants) and height-for-age z-scores (2 trials, 372 participants); a small decrease in wasting (2 trials, 398 participants); small increases in stunting (2 trials, 399 participants); and an increase in underweight (2 trials, 396 participants). For neurodevelopment outcomes at 78 weeks, we found small increases in Bayley Scales of Infant Development, Version III (BISD-III), scores (cognition, receptive language, expressive language, fine motor, gross motor) in the MMN compared to the non-MMN group (1 trial, 27 participants). There were no studies examining dose or timing of supplementation. CONCLUSIONS: Evidence is insufficient to determine whether enteral MMN supplementation to preterm or LBW infants who are fed mother's own milk is associated with benefit or harm. More trials are needed to generate evidence on mortality, morbidity, growth, and neurodevelopment.

Enteral Iron Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Iron is needed for growth and development of infants globally, but preterm and low birth weight (LBW) infants are at risk for severe iron deficiencies. To assess the effect of enteral iron supplementation on mortality, morbidity, growth, and neurodevelopment outcomes in preterm or LBW infants fed human milk. Secondary objectives were to assess the effect on biomarkers and dose and timing. METHODS: Data sources include PubMed, Embase and Cochrane Library databases to March 16, 2021. Study Selection includes controlled or quasi experimental study designs. Two reviewers independently extracted data. RESULTS: Eight trials (eleven reports; 1093 participants, 7 countries) were included. No trials reported mortality. At latest follow-up, there was little effect on infection (very low certainty evidence, 4 studies, 401 participants, relative risk [RR] 0.98, 95% confidence interval [95% CI] 0.56 to 1.73, I2 = 0.00%) and necrotising enterocolitis (3 studies, 375 participants, RR 1.47, 95% CI 0.68 to 3.20, I2 = 0.00%). There was an increase in linear growth (length) (moderate certainty evidence, 3 studies, 384 participants, mean difference 0.69 cm, 95% CI 0.01 to 1.37, I2 = 0%) but little effect on weight, head circumference, or cognitive development. There was an improvement in anemia (moderate certainty evidence, 2 studies, 381 participants, RR 0.25, 95% CI 0.10 to 0.62, I2 = 0.00%) but no effect on serum ferritin. Limitations include heterogeneity in the included studies. CONCLUSIONS: There are important benefits for human milk-fed preterm and LBW infants from enteral iron supplementation. However, more randomized control trials are required to improve the certainty of evidence.

Enteral Zinc Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Evidence on the effect of zinc supplementation on health outcomes in preterm or low birth weight (LBW) infants is unclear. We estimated the effect of enteral zinc versus no zinc supplementation in human milk fed preterm or LBW infants on mortality, growth, morbidities, and neurodevelopment. METHODS: Data sources include PubMed, Cochrane Central and Embase databases through March 24, 2021. Study selection was randomized or quazi-experimental trials. Two reviewers independently screened, extracted data, and assessed quality. We reported pooled relative risks (RR) for categorical outcomes, and mean differences (MD) for continuous outcomes. RESULTS: Fourteen trials with 9940 preterm or LBW infants were included. Moderate to low certainty evidence showed that enteral zinc supplementation had little or no effect on mortality (risk ratio 0.73, 95% confidence interval [CI] 0.46 to 1.16), but increased weight (MD 378.57, 95% CI 275.26 to 481.88), length (MD 2.92, 95% CI 1.53 to 4.31), head growth (MD 0.56, 95% CI 0.23 to 0.90), and decreased diarrhea (RR 0.81; 95% CI 0.68 to 0.97). There was no effect on acute respiratory infections, bacterial sepsis, and psychomotor development scores. The effect of zinc supplementation on mental development scores is inconclusive. There was no evidence of serious adverse events. Eight trials had some concerns or high risk of bias, small-sized studies, and high heterogeneity between trials led to moderate to very low certainty of evidence. CONCLUSIONS: Zinc supplementation in preterm or LBW infants have benefits on growth and diarrhea prevention. Further research is needed to generate better quality evidence.

Enteral Vitamin D Supplementation in Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Many preterm and low birth weight (LBW) infants have low vitamin D stores. The objective of this study was to assess effects of enteral vitamin D supplementation compared with no vitamin D supplementation in human milk fed preterm or LBW infants. METHODS: Data sources include Cochrane Central Register of Controlled Trials, Medline, and Embase from inception to March 16, 2021. The study selection included randomized trials. Data were extracted and pooled with fixed and random-effects models. RESULTS: We found 3 trials (2479 participants) that compared vitamin D to no vitamin D. At 6 months, there was increase in weight-for-age z-scores (mean difference 0.12, 95% confidence interval [CI] 0.01 to 0.22, 1 trial, 1273 participants), height-for-age z-scores (mean difference 0.12, 95% CI 0.02 to 0.21, 1 trial, 1258 participants); at 3 months there was decrease in vitamin D deficiency (risk ratio 0.58, 95% CI 0.49 to 0.68, I2=58%, 2 trials, 504 participants) in vitamin D supplementation groups. However, there was little or no effect on mortality, any serious morbidity, hospitalization, head circumference, growth to 6 years and neurodevelopment. The certainty of evidence ranged from very low to moderate. Fourteen trials (1969 participants) assessed dose and reported no effect on mortality, morbidity, growth, or neurodevelopment, except on parathyroid hormone and vitamin D status. No studies assessed timing. Limitations include heterogeneity and small sample size in included studies. CONCLUSIONS: Enteral vitamin D supplementation improves growth and vitamin D status in preterm and LBW infants.

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.

Characteristics, experiences and actions taken by women to address delayed conception: A mixed-methods cross-sectional study protocol.

BACKGROUND: The impact of infertility on mental, emotional, physical and sexual health is grave, particularly in a pronatalist society. Literature is replete with evidence of wide ranging psychosocial consequences of infertility in women, indicating the need for identifying the gaps and designing appropriate context specific interventions to improve access and utilization of services. Data that are accessible, primarily from infertility clinics and women visiting hospitals for infertility treatment; information from community settings is rare. This is a protocol paper for a study to understand women's experiences and actions taken by them to cope with delayed conception. METHODS: Mixed-methods cross-sectional design is used to obtain deep insights into the experiences of delayed conception, coping mechanisms, medical assistance and other help sought. Information is also being obtained on socio-demographic profile, fertility intentions, fertility quality of life, general medical history, obstetric, gynecological and sexual history, substance use and mental health status. A sample of 1530 women will be administered 4 modules of a quantitative survey. Focus group discussions, about four or till saturation point, will be conducted using purposive sampling. The study is recruiting from a population of women who previously participated in the 'Women and Infants Integrated Interventions for Growth Study (WINGS) and failed to conceive during 18 months follow up period. Data collected through questionnaire will be assembled, cleaned, analyzed and reported. The findings will be disseminated through reports with the ethics review committee, government entities, academic and research publications. DISCUSSION: This study will provide insights on the experiences and coping strategies of women with delayed conception in the study community. Results will assist in designing appropriate interventions to meet the holistic health and psychosocial needs of women with delayed conception and promote sexual and reproductive health within the broader framework of Sustainable Development Goals and Universal health coverage. TRIAL REGISTRATION: Trial registration number: CTRI/2020/03/023955.

Impact of supplementation with milk-cereal mix during 6-12 months of age on growth at 12 months: a 3-arm randomized controlled trial in Delhi, India.

BACKGROUND: A large proportion of infants in low- and middle-income countries are stunted. These infants are often fed complementary foods that are low-quality, primarily in terms of protein and micronutrients. OBJECTIVES: We aimed to test 2 milk-cereal mixes supplemented with modest and high amounts of protein during 6-12 mo of age, compared with no supplementation, for their effect on length-for-age z score (LAZ) at 12 mo of age. METHODS: Eligible infants (6 mo plus ≤29 d) were randomly assigned to either of the 2 interventions (modest- and high-protein) or a no supplement group. The milk-cereal mixes provided ∼125 kcal, 30%-45% energy from fats, and 80%-100% RDA of multiple micronutrients (MMN). The modest-protein group received 2.5 g protein [protein energy ratio (PER): 8%; 0.75 g from milk source] and the high-protein group received 5.6 g protein (PER: 18%, 1.68 g from milk source). One packet was given daily for 180 d. Counseling on continued breastfeeding and optimal infant-care practices was provided to all. RESULTS: We enrolled 1548 infants (high-protein: n = 512; modest-protein: n = 519; and no supplement: n = 517). Compared with the no supplement group, there was an improvement in LAZ [adjusted mean difference (MD): 0.08; 95% CI: 0.01, 0.15], weight-for-age z score (MD: 0.12; 95% CI: 0.06, 0.19), weight-for-length z score (MD: 0.11; 95% CI: 0.02, 0.19), and midupper arm circumference z score (MD: 0.10; 95% CI: 0.02, 0.18) in the high-protein group at 12 mo of age. No significant differences for these anthropometric indicators were noted between the modest-protein and no supplement groups or between the high- and modest-protein groups. CONCLUSIONS: Cereal mixes with higher amounts of milk-based protein and MMN may lead to improvement in linear growth and other anthropometric indexes in infants, compared with no supplementation.This trial was registered at ctri.nic.in as CTRI/2018/04/012932.

Screening and management options for severe thinness during pregnancy in India.

This paper answers research questions on screening and management of severe thinness in pregnancy, approaches that may potentially work in India, and what more is needed for implementing these approaches at scale. A desk review of studies in the last decade in South Asian countries was carried out collating evidence on six sets of strategies like balanced energy supplementation (BEP) alone and in combination with other interventions like nutrition education. Policies and guidelines from South Asian countries were reviewed to understand the approaches being used. A 10-point grid covering public health dimensions covered by World Health Organization and others was created for discussion with policymakers and implementers, and review of government documents sourced from Ministry of Health and Family Welfare. Eighteen studies were shortlisted covering Bangladesh, India, Nepal, and Pakistan. BEP for longer duration, preconception initiation of supplementation, and better pre-supplementation body mass index (BMI) positively influenced birthweight. Multiple micronutrient supplementation was more effective in improving gestational weight gain among women with better pre-supplementation BMI. Behavior change communication and nutrition education showed positive outcomes on dietary practices like higher dietary diversity. Among South Asian countries, Sri Lanka and Nepal are the only two countries to have management of maternal thinness in their country guidelines. India has at least nine variations of supplementary foods and three variations of full meals for pregnant women, which can be modified to meet additional nutritional needs of those severely thin. Under the National Nutrition Mission, almost all of the globally recommended maternal nutrition interventions are covered, but the challenge of reaching, identifying, and managing cases of maternal severe thinness persists. This paper provides four actions for addressing maternal severe thinness through available public health programs, infrastructure, and human resources.

Impact of nutritional interventions among lactating mothers on the growth of their infants in the first 6 months of life: a randomized controlled trial in Delhi, India.

BACKGROUND: In lower-middle-income settings, growth faltering in the first 6 mo of life occurs despite exclusive breastfeeding. OBJECTIVE: The aim was to test the efficacy of an approach to improve the dietary adequacy of mothers during lactation and thus improve the growth of their infants. METHODS: Eligible mother-infant dyads (infants ≤7 d of age) were randomly assigned to either intervention or control groups. Mothers in the intervention group received snacks that were to be consumed daily, which provided 600 kcal of energy-with 25-30% of energy derived from fats (150-180 kcal) and 13% of energy from protein (80 kcal). Micronutrients were supplemented as daily tablets. We provided counseling on breastfeeding and infant-care practices to mothers in both groups. The primary outcome was attained infant length-for-age z scores (LAZ) at 6 mo of age. Secondary outcomes included exclusive breastfeeding proportion reported by the mother, maternal BMI and midupper arm circumference (MUAC), hemoglobin concentrations in mothers and infants, and the proportion of anemic infants at 6 mo of age. RESULTS: We enrolled 816 mother-infant dyads. The intervention did not achieve a significant effect on LAZ at 6 mo (adjusted mean difference: 0.09; 95% CI: -0.03, 0.20). Exclusive breastfeeding at 5 mo was higher (45.1% vs. 34.5%; RR: 1.31; 95% CI: 1.04, 1.64) in the intervention group compared with the controls. There were no significant effects on mean hemoglobin concentration or the proportion of anemic infants at 6 mo of age compared with the control group. We noted significant effects on maternal nutritional status (BMI, MUAC, hemoglobin concentration, and proportion anemic). CONCLUSIONS: Postnatal supplementation of 600 kcal energy, 20 g protein, and multiple micronutrients daily to lactating mothers did not affect infant LAZ at age 6 mo. Such supplementation may improve maternal nutritional status. This trial was registered at Clinical Trials Registry-India as CTRI/2018/04/013095.

Impact of an integrated nutrition, health, water sanitation and hygiene, psychosocial care and support intervention package delivered during the pre- and peri-conception period and/or during pregnancy and early childhood on linear growth of infants in the first two years of life, birth outcomes and nutritional status of mothers: study protocol of a factorial, individually randomized controlled trial in India.

BACKGROUND: The period from conception to two years of life denotes a critical window of opportunity for promoting optimal growth and development of children. Poor nutrition and health in women of reproductive age and during pregnancy can negatively impact birth outcomes and subsequent infant survival, health and growth. Studies to improve birth outcomes and to achieve optimal growth and development in young children have usually tested the effect of standalone interventions in pregnancy and/or the postnatal period. It is not clearly known whether evidence-based interventions in the different domains such as health, nutrition, water sanitation and hygiene (WASH) and psychosocial care, when delivered together have a synergistic effect. Further, the effect of delivery of an intervention package in the pre and peri-conception period is not fully understood. This study was conceived with an aim to understand the impact of an integrated intervention package, delivered across the pre and peri-conception period, through pregnancy and till 24 months of child age on birth outcomes, growth and development in children. METHODS: An individually randomized controlled trial with factorial design is being conducted in urban and peri-urban low- to mid-socioeconomic neighbourhoods in South Delhi, India. 13,500 married women aged 18 to 30 years will be enrolled and randomized to receive either the pre and peri-conception intervention package or routine care (first randomization). Interventions will be delivered until women are confirmed to be pregnant or complete 18 months of follow up. Once pregnancy is confirmed, women are randomized again (second randomization) to receive either the intervention package for pregnancy and postnatal period or to routine care. Newborns will be followed up till 24 months of age. The interventions are delivered through different study teams. Outcome data are collected by an independent outcome ascertainment team. DISCUSSION: This study will demonstrate the improvement that can be achieved when key factors known to limit child growth and development are addressed together, throughout the continuum from pre and peri-conception until early childhood. The findings will increase our scientific understanding and provide guidance to nutrition programs in low- and middle-income settings. TRIAL REGISTRATION: Clinical Trial Registry - India #CTRI/2017/06/008908; Registered 23 June 2017, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339&EncHid=&userName=society%20for%20applied%20studies.

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.

Setting research priorities on multiple micronutrient supplementation in pregnancy.

Prenatal micronutrient deficiencies are associated with negative maternal and birth outcomes. Multiple micronutrient supplementation (MMS) during pregnancy is a cost-effective intervention to reduce these adverse outcomes. However, important knowledge gaps remain in the implementation of MMS interventions. The Child Health and Nutrition Research Initiative (CHNRI) methodology was applied to inform the direction of research and investments needed to support the implementation of MMS interventions for pregnant women in low- and middle-income countries (LMIC). Following CHNRI methodology guidelines, a group of international experts in nutrition and maternal health provided and ranked the research questions that most urgently need to be resolved for prenatal MMS interventions to be successfully implemented. Seventy-three research questions were received, analyzed, and reorganized, resulting in 35 consolidated research questions. These were scored against four criteria, yielding a priority ranking where the top 10 research options focused on strategies to increase antenatal care attendance and MMS adherence, methods needed to identify populations more likely to benefit from MMS interventions and some discovery issues (e.g., potential benefit of extending MMS through lactation). This exercise prioritized 35 discrete research questions that merit serious consideration for the potential of MMS during pregnancy to be optimized in LMIC.

Vitamin D deficiency and mild to moderate anemia in young North Indian children: A secondary data analysis.

OBJECTIVES: The aim of this study was to examine the association between vitamin D deficiency and anemia status among young children in the resource-poor setting of northern urban India. METHODS: We used data from a randomized controlled trial of daily supplementation with folic acid, vitamin B12, or both for 6 mo in children 6 to 30 mo of age conducted in Delhi, India. We measured serum vitamin D status, hemoglobin, plasma vitamin B12, folate, soluble transferrin receptor, and homocysteine levels at baseline. Children with severe anemia (hemoglobin [Hgb] <7 g/dL) were excluded from enrollment. Multivariable logistic and multinomial logistic regressions were used to examine the association between vitamin D and anemia status at baseline. RESULTS: 25-Hydroxyvitamin-D (25 OHD) concentration was measured for 960 (96%) children. Of the children, 331 (34.5%) were vitamin-D deficient (<10 ng/mL). Approximately 70% of the enrolled children were anemic, with ∼46% having moderate (Hgb 7-9.9 g/dL) and 24% mild (Hgb 10-10.9 g/dL) anemia. There was no association between vitamin D and anemia status after adjusting for confounders; however, the risk for moderate anemia was significantly higher among vitamin D-deficient children than those who were vitamin-D replete (relative risk, 1.58; 95% confidence interval, 1.09-2.31). CONCLUSIONS: Vitamin D deficiency was associated with moderate anemia among young children and the effect was independent of iron deficiency. The causal association of vitamin D deficiency with anemia risk remains debatable. The role of vitamin D in risk for anemia needs to be examined in further studies.