Child Health, Agriculture and Integrated Nutrition (CHAIN): a randomized trial to close the nutrient gap in rural Zimbabwe

Stunting (low height for a child's age) affects 155 million under-5 children around the world and leads to a higher risk of dying, poorer school performance and lower wages in adult life. Improving the quantity and quality of food for children under two years of age is the best approach we have to prevent stunting. We recently did a trial in rural Zimbabwe called SHINE, in which we showed that educating mothers about infant and young child feeding (IYCF) and giving the child a daily supplement (called Nutributter) to provide extra calories and vitamins, helped children grow taller. Despite this, many children still did not meet their daily nutrient requirements and over one-quarter remained stunted. In addition, the quantity of nutrients a child needs in developing countries is probably higher than in developed countries, because the gut is inflamed and less able to absorb nutrients. We therefore need to increase the nutrients children get and try to heal the gut, to help children grow better.

In this project, we will compare a new package of interventions against the SHINE approach, to see if we can close this nutrient gap. Almost 200 households with a 6-month-old child will be randomly allocated (like the flip of a coin) to receive the SHINE IYCF package (which we know reduces stunting) or the new package, which we call "IYCF-plus". Households receiving the SHINE IYCF package will receive 6 visits from a Village Health Worker to provide a series of lessons in how to feed a young child a healthy diet, including daily Nutributter. Households receiving the IYCF-plus package will receive an agriculture intervention and a more intensive feeding intervention. Families will receive three new varieties of crops (fortified maize, which is more resistant to drought and pests; moringa trees, which contain high amounts of protein, vitamins and calcium; and sugar beans, which contain easily digestible protein, zinc and iron) and will receive advice during planting and harvesting seasons. We hope this will increase the family's food availability, provide a more diverse range of food choices for the child and improve the nutrient content of the diet. The nutrients contained in these crops may also help the child's gut to heal, which should improve absorption of the food. Village Health Workers will visit households 12 times to give Nutributter and to provide more intensive messages about how to feed a young child, including use of the new crops. Families will also receive powdered versions of the crops that can immediately be used (for example, by adding to the child's porridge) before the family becomes self-sufficient by growing their own.

We will compare children in the IYCF and IYCF-plus groups at 18 months of age. The main outcome will be how many children in each group meet their daily nutrient requirements, using a detailed questionnaire that recalls and weighs all food the child ate in the previous day. We think that more children in the IYCF-plus group will meet their daily nutrient requirements. We will also measure their height, weight, blood count, the amount of muscle and fat in the body, and collect blood, urine and stool samples. We will use these samples to measure nutrient levels in the blood (such as iron and protein), to study the body's metabolism (how certain nutrients are broken down and used), and to test our theory that the children in the IYCF-plus group will have a less inflamed gut.

If we show that the IYCF-plus intervention leads to better nutrient intake, a healthier gut, and higher levels of nutrients in the blood, we would expect the combined agriculture-infant feeding approach to improve children's growth more than the SHINE intervention did. This approach has the advantage of being sustainable because families can grow and process their own crops for the child to eat, and health workers in rural areas can provide the advice needed to ensure infants receive the food they need to grow.

We aim to close nutrient gaps in young children at risk of stunting in rural Zimbabwe. In a recent trial we showed that improved infant and young child feeding (IYCF) reduces stunting by 20%. However, several key nutrient gaps remain, and nutrient uptake/utilization are altered by enteropathy, microbiome dysbiosis and chronic inflammation. We hypothesize that a combined agriculture-IYCF intervention will improve nutritional status and gut health, and ultimately reduce stunting.

We will conduct a randomized controlled trial of integrated agriculture-IYCF ("IYCF-plus") compared to our current gold standard ("IYCF") in 192 rural Zimbabwean households. Interventions will be delivered by government cadres and outcomes measured by research staff. IYCF will comprise i) 6 Village Health Worker (VHW) visits from 6-18mo of age, with interactive behaviour-change messages; and ii) a daily lipid-based nutrient supplement. IYCF-plus will comprise all IYCF interventions plus i) provision of new crop varieties (bio-fortified stress-tolerant maize; moringa trees; and bio-fortified sugar beans), with support and advice from Agricultural Extension Workers; ii) higher intensity behaviour-change communication (12 VHW visits from 6-18mo of age); iii) powdered supplements of sugar beans, moringa leaf and whole egg powder, as a bridging intervention before families become self-sufficient; and iv) embedded gender-sensitive programming to ensure that messages reach mothers.

The primary outcome is nutrient intake by 24hr dietary recall at 18 months. Secondary outcomes are anthropometry, haemoglobin, fat mass and fat-free mass. Laboratory studies will assess key nutrients (circulating amino acids, choline and polyphenol metabolism, iron and folate status, serum retinol); microbiome composition by shotgun whole-genome sequencing; metabolic profiles by untargeted urinary and faecal metabolomics; and markers of environmental enteric dysfunction, inflammation and innate immune function.

Our ambition is to improve child survival, health and potential by finding new ways of tackling undernutrition, to help reach the Sustainable Development Goals. In sub-Saharan Africa, stunting prevalence remains stagnant and, due to population growth, absolute numbers of stunted children are increasing. Low-income countries have more stunted children today than 15 years ago. An estimated 43% of children fail to reach their developmental potential due to stunting and poverty, and in sub-Saharan Africa this rises to 66%. It is estimated that children at risk of poor development due to stunting and poverty forego around one-quarter of average annual adult income, thereby trapping many populations into reduced long-term potential, poverty and social inequality.

The key beneficiaries of this work will therefore be children at risk of stunting in developing countries, by finding ways to improve nutrient intake, utilization and growth. Focusing interdisciplinary expertise on new nutrition-specific solutions to promote healthy growth has the potential to benefit around one-quarter of children in low-income countries. Effective interventions will enhance health and wellbeing, educational attainment, economic prosperity and resilience across the life-course, conferring enormous individual and societal benefits, including national economic growth and stability. Improving child growth and development would be an effective way of preventing inequality, enhancing productivity and reducing poverty. We have already demonstrated the impact of infant and young child feeding for stunting, anaemia and child development in the SHINE trial. In the current proposal we aim to optimize nutrient intake even further to achieve greater linear growth gains. Given the large number of stunted children, even interventions that have a small effect on growth at the individual level have the potential for large benefits at the population level.

We have worked in rural Zimbabwe for the past decade and our research agenda is therefore based on local priorities, mindful of context and respectful of community perceptions. We aim to identify and include the most hard-to-reach populations in our research, and target both male and female community members. Through our outcome measures, we will evaluate the impact of our programme on communities, including quantitative and qualitative indicators of welfare and economic development. In designing this trial, we have considered scalability and sustainability of our intervention approaches from the start. Our ultimate goal is to translate effective interventions from research tools to policy recommendations, to benefit children with stunting. To maximise impact, we work in partnership with the Ministry of Health and Child Care and the Food & Nutrition Council, to bridge the evidence-action divide.

Our research has potential to enhance the economy in Zimbabwe by building a research agenda that requires human resources; training researchers in new skills; and enhancing the research ecosystem to retain talented individuals in the country. Academics in the UK will benefit from experience in interdisciplinary working; knowledge exchange to appreciate epistemic and methodological differences; new research partnerships; and high-calibre academic outputs. The global health community will benefit from new insights into prevention of undernutrition to improve growth and development, which is relevant to many settings.

UK taxpayers, who fund this work, will be engaged through school visits run by the Centre of the Cell at QMUL (www.centreofthecell.org) - a unique, state-of-the-art science education centre housed within our institute. We are currently developing a game called Baby Grow, which introduces malnutrition by engaging players in the challenge of helping a baby to grow. This will also be reformatted for tablet version and introduced to communities in rural Zimbabwe as a novel means of public engagement in science.