Developing a data repository to support interdisciplinary research into childhood stunting: a UKRI GCRF Action Against Stunting Hub protocol paper.

INTRODUCTION: As a topic of inquiry in its own right, data management for interdisciplinary research projects is in its infancy. Key issues include the inability of researchers to effectively query diverse data outputs and to identify potentially important synergies between discipline-specific data. Equally problematic, few semantic ontologies exist to better support data organisation and discovery. Finally, while interdisciplinary research is widely regarded as beneficial to unpacking complex problems, non-researchers such as policy-makers and planners often struggle to use and interrogate the related datasets. To address these issues, the following article details the design and development of the UKRI GCRF Action Against Stunting Hub (AASH)'s All-Hub Data Repository (AHDR). METHODS AND ANALYSIS: The AHDR is a single application, single authentication web-based platform comprising a data warehouse to store data from across the AASH's three study countries and to support data querying. Four novel components of the AHDR are described in the following article: (1) a unique data discovery tool; (2) a metadata catalogue that provides researchers with an interface to explore the AASH's data outputs and engage with a new semantic ontology related to child stunting; (3) an interdisciplinary aid to support a directed approach to identifying synergies and interactions between AASH data and (4) a decision support tool that will support non-researchers in engaging with the wider evidence-based outputs of the AASH. ETHICS AND DISSEMINATION: Ethical approval for this study was granted by institutional ethics committees in the UK, India, Indonesia and Senegal. Results will be disseminated via publications in peer-reviewed journals; presentations at international conferences and community-level public engagement events; key stakeholder meetings; and in public repositories with appropriate Creative Commons licences allowing for the widest possible use.

Eggs for Improving Nutrition, cognitive development and reducing linear growth retardation among Infants and young Children (ENRICH): protocol of an egg supplementation trial among children aged 9-18 months in Hyderabad, India.

INTRODUCTION: Evidence on the impact of nutrient-rich animal source foods such as eggs for improving child growth and cognition is inconsistent. This study aims to examine the impact of an egg intervention in children, along with behaviour change communication (BCC) to the mother, on linear growth and cognition, and nutritional status in children aged 9-18 months. METHODS AND ANALYSIS: A 9-month open-labelled randomised controlled trial will be conducted in three urban slums in Hyderabad, India, as a substudy of an observational cohort study (n=350) following pregnant women and their children until 18 months of age in a population at risk of stunting. The children born to women enrolled during the third trimester of pregnancy will be block randomised in a 1:4 ratio into the intervention (n=70) and control (n=280) groups. Children in the intervention group will be supplemented with one egg per day starting from 9 months until 18 months of age. BCC designed to enhance adherence to the intervention will be used. The control group will be a part of the observational cohort and will not receive any intervention from the study team. The primary outcome will be length-for-age z-scores, and the secondary outcomes will include cognition, blood biomarkers of nutritional status including fatty acid profile and epigenetic signatures linked with linear growth and cognition. Multivariate intention-to-treat analyses will be conducted to assess the effect of the intervention. ETHICS AND DISSEMINATION: The study is approved by the Institutional ethics committees of ICMR-National Institute of Nutrition, Hyderabad, India and London School of Hygiene and Tropical Medicine, UK. The results will be published in peer-reviewed journals and disseminated to policy-makers. Findings will also be shared with study participants and community leaders. TRIAL REGISTRATION NUMBER: CTRI/2021/11/038208.

Impact of SARS-CoV-2 infection and mitigation strategy during pregnancy on prenatal outcome, growth and development in early childhood in India: a UKRI GCRF Action Against Stunting Hub protocol paper.

INTRODUCTION: The COVID-19 pandemic has offset some of the gains achieved in global health, particularly in relation to maternal, child health and nutrition. As pregnancy is a period of plasticity where insults acting on maternal environment have far-reaching consequences, the pandemic has had a significant impact on prenatal outcomes, intrauterine and postnatal development of infants. This research will investigate both the direct and indirect impacts of the COVID-19 pandemic during pregnancy on prenatal outcomes, growth and development in early childhood. METHODS AND ANALYSIS: Community and hospital data in Hyderabad and Gujarat, India will be used to recruit women who were pregnant during the COVID-19 pandemic and contracted SARS-CoV-2 infection. In comparison with women who were pregnant around the same time and did not contract the virus, the study will investigate the impact of the pandemic on access to healthcare, diet, nutrition, mental health and prenatal outcomes in 712 women (356 per study arm). Children born to the women will be followed prospectively for an 18-month period to investigate the impact of the pandemic on nutrition, health, growth and neurocognition in early childhood. ETHICS AND DISSEMINATION: Ethics approval was granted from the institutional ethics committees of the Indian Institute of Public Health Gandhinagar (SHSRC/2021/2185), Indian Council of Medical Research-National Institute of Nutrition (EC/NEW/INST/2021/1206), and London School of Hygiene and Tropical Medicine (72848). The findings of the study will be disseminated to policy and research communities through engagements, scientific conferences, seminars, and open-access, peer-reviewed publication.

Assessment of the role of gut health in childhood stunting in a multisite, longitudinal study in India, Indonesia and Senegal: a UKRI GCRF Action Against Stunting Hub protocol.

INTRODUCTION: Childhood stunting has a complex aetiology, with poor gut health being an important contributor. This study will assess inter-relationships between maternal and infant gut health indices and infant linear growth. Inter-relationships between gut health indices, systemic inflammation and growth hormones in early childhood will also be assessed. METHODS AND ANALYSIS: A longitudinal observational study of cohorts of 600 newborns and their mothers in India, Indonesia and Senegal will be conducted. Women will be recruited during pregnancy and their children followed up to age 24 months. Stool, urine and blood samples will be collected from the women and children for assessments of helminthic and protozoal parasites, bacterial pathogens, faecal microbiota taxa, biomarkers of environmental enteric dysfunction, systemic inflammation and growth hormones. Child anthropometric measurements will be collected at birth and at ages 3, 6, 9, 12, 18 and 24 months. The gut health indices will be integrated with cohort data from other Action Against Stunting Hub (AASH) workstreams for interdisciplinary analyses of childhood stunting and the development of a new typology of stunting. DISCUSSION: This study will advance scientific understanding of the role of gut health in childhood stunting and will contribute to a broader knowledge of the complex aetiology of this condition as part of the interdisciplinary AASH research to reduce the global burden of childhood stunting. ETHICS AND DISSEMINATION: This study has been approved by the relevant Ethics Committees in Senegal, India, and Indonesia and LSHTM. The results will be submitted for publication in peer-reviewed journals.

Anthropometric, biochemical, dietary, morbidity and well-being assessments in women and children in Indonesia, India and Senegal: a UKRI GCRF Action Against Stunting Hub protocol paper.

INTRODUCTION: Child stunting has a complex aetiology, especially in the first 1000 days of life. Nutrition interventions alone have not produced expected impacts in reducing/preventing child stunting, indicating the importance of understanding the complex interplay between environmental, physiological and psychological factors influencing child nutritional status. This study will investigate maternal and child nutrition, health and well-being status and associated factors through the assessment of: (1) anthropometry, (2) biomarkers of nutrition and health status, (3) dietary intakes, (4) fetal growth and development, (5) infant morbidity, (6) infant and young child feeding (IYCF) and (7) perinatal maternal stress, depression and social support. METHODS: This study will be conducted in a prospective pregnancy cohort in India, Indonesia and Senegal. Pregnant women will be recruited in the second (Indonesia, Senegal) and third (India) trimester of pregnancy, and the mother and infant dyads followed until the infant is 24 months of age. During pregnancy, anthropometric measures will be taken, venous blood samples will be collected for biochemical assessment of nutrition and health status, dietary intakes will be assessed using a 4-pass-24-hour dietary recall method (MP24HR), fetal ultrasound for assessment of fetal growth. After birth, anthropometry measurements will be taken, venous blood samples will be collected, MP24HR will be conducted, infant morbidity and IYCF practices will be assessed and a sample of breastmilk will be collected for nutrient composition analyses. Perinatal maternal stress, depression, social support and hair cortisol levels (stress) will be measured. The results from this study will be integrated in an interdisciplinary analysis to examine factors influencing infant growth and inform global efforts in reducing child stunting. ETHICS AND DISSEMINATION: Ethical approval was granted by the Ethics Committee of the London School of Hygiene and Tropical Medicine (17915/RR/17513); National Institute of Nutrition (ICMR)-Ministry of Health and Family Welfare, Government of India (CR/04/I/2021); Health Research Ethics Committee, University of Indonesia and Cipto Mangunkusumo Hospital (KET-887/UN2.F1/ETIK/PPM.00.02/2019); and the Comité National d'Ethique pour la Recherche en Santé, Senegal (Protocole SEN19/78); the Royal Veterinary College (URN SR2020-0197) and the International Livestock Research Institute Institutional Research Ethics Committee (ILRI-IREC2020-33). Results will be published in peer-reviewed journals and disseminated to policy-makers and participating communities.

mRNA Levels of Placental Iron and Zinc Transporter Genes Are Upregulated in Gambian Women with Low Iron and Zinc Status.

Background: The role of the placenta in regulating micronutrient transport in response to maternal status is poorly understood.Objective: We investigated the effect of prenatal nutritional supplementation on the regulation of placental iron and zinc transport.Methods: In a randomized trial in rural Gambia [ENID (Early Nutrition and Immune Development)], pregnant women were allocated to 1 of 4 nutritional intervention arms: 1) iron and folic acid (FeFol) tablets (FeFol group); 2) multiple micronutrient (MMN) tablets (MMN group); 3) protein energy (PE) as a lipid-based nutrient supplement (LNS; PE group); and 4) PE and MMN (PE+MMN group) as LNS. All arms included iron (60 mg/d) and folic acid (400 µg/d). The MMN and PE+MMN arms included 30 mg supplemental Zn/d. In a subgroup of ∼300 mother-infant pairs, we measured maternal iron status, mRNA levels of genes encoding for placental iron and zinc transport proteins, and cord blood iron levels.Results: Maternal plasma iron concentration in late pregnancy was 45% and 78% lower in the PE and PE+MMN groups compared to the FeFol and MMN groups, respectively (P < 0.001). The mRNA levels of the placental iron uptake protein transferrin receptor 1 were 30-49% higher in the PE and PE+MMN arms than in the FeFol arm (P < 0.031), and also higher in the PE+MMN arm (29%; P = 0.042) than in the MMN arm. Ferritin in infant cord blood was 18-22% lower in the LNS groups (P < 0.024). Zinc supplementation in the MMN arm was associated with higher maternal plasma zinc concentrations (10% increase; P < 0.001) than in other intervention arms. mRNA levels for intracellular zinc-uptake proteins, in this case zrt, irt-like protein (ZIP) 4 and ZIP8, were 96-205% lower in the PE+MMN arm than in the intervention arms without added zinc (P < 0.025). Furthermore, mRNA expression of ZIP1 was 85% lower in the PE+MMN group than in the PE group (P = 0.003).Conclusion: In conditions of low maternal iron and in the absence of supplemental zinc, the placenta upregulates the gene expression of iron and zinc uptake proteins, presumably in order to meet fetal demands in the face of low maternal supply. The ENID trial was registered at www.controlled-trials.com as ISRCTN49285450.

A randomized trial to investigate the effects of pre-natal and infant nutritional supplementation on infant immune development in rural Gambia: the ENID trial: Early Nutrition and Immune Development.

BACKGROUND: Recent observational research indicates that immune development may be programmed by nutritional exposures early in life. Such findings require replication from trials specifically designed to assess the impact of nutritional intervention during pregnancy on infant immune development. The current trial seeks to establish: (a) which combination of protein-energy (PE) and multiple-micronutrient (MMN) supplements would be most effective; and (b) the most critical periods for intervention in pregnancy and infancy, for optimal immune development in infancy. METHODS/DESIGN: The ENID Trial is a 2 x 2 x 2 factorial randomized, partially blind trial to assess whether nutritional supplementation to pregnant women (from < 20 weeks gestation to term) and their infants (from 6 to 12 months of age) can enhance infant immune development. Eligible pregnant women from the West Kiang region of The Gambia (pregnancy dated by ultrasound examination) are randomized on entry to 4 intervention groups (Iron-folate (FeFol = standard care), multiple micronutrients (MMN), protein-energy (PE), PE + MMN). Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination, including ultrasound. At delivery, cord blood and placental samples are collected, with detailed infant anthropometry collected within 72 hours. Infants are visited weekly thereafter for a morbidity questionnaire. From 6 to 12 months of age, infants are further randomized to a lipid-based nutritional supplement, with or without additional MMN. The primary outcome measures of this study are thymic development during infancy, and antibody response to vaccination. Measures of cellular markers of immunity will be made in a selected sub-cohort. Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age. DISCUSSION: The proposed trial is designed to test whether nutritional repletion can enhance early immune development and, if so, to help determine the most efficacious form of nutritional support. Where there is evidence of benefit from a specific intervention/combination of interventions, future research should focus on refining the supplements to achieve the optimal, most cost-effective balance of interventions for improved health outcomes.