Mechanisms of intergenerational nutritional programming of non-communicable diseases in three countries: a Healthy Life Trajectories Initiative study.

Non-communicable diseases (NCDs) such as heart disease and diabetes are rapidly increasing in low- and middle-income countries (LMICs). These diseases are occurring at younger ages in LMICs compared to high-income countries, with accompanying economic and societal costs. There are now ~166 million people with diabetes in India and China alone (40% of the world's total). Current approaches to preventing diabetes or heart disease focus on weight reduction and increased physical activity in middle-aged adults with existing risk factors such as obesity or high blood pressure. While such approaches offer some benefit to the individual, they do little to address the risk in future generations.

Research from many countries across the world has shown that low birth weight and poor growth of the fetus in the womb is related to an increased risk of developing diabetes and heart disease in later life. These effects are exacerbated by greater weight gain during childhood, adolescence or adulthood. It is suggested that undernutrition during critical periods of early development permanently alters the structure and function of the body's tissues and organs ('programming'), leading to an increased vulnerability to disease in later life. It is therefore possible that measures to optimise the health of young women before and during pregnancy, and measures to optimise the growth of infants and young children may have long-term beneficial effects on the health of the children.

In this context, the Healthy Life Trajectories Initiative (HeLTI) programme was set up as a joint initiative funded by the Canadian Institutes of Health Research, Department of Biotechnology (India), Medical Research Council (South Africa) and the National Natural Science Foundation (China), in collaboration with the World Health Organisation. There are four separate but harmonised intervention studies in Mysore (India), Johannesburg (South Africa), Shanghai (China) and two provinces in Canada. The studies will test the concept that interventions addressing multiple domains of health spanning from before pregnancy, and continued through pregnancy and after birth will improve maternal and child health including the long-term well-being of the child. Our main outcome is a measure of adiposity (fat mass in relation to height) at five years of age in the child. While the exact intervention packages vary by country to ensure cultural and contextual appropriateness, they are all unified by both the overall aim of the intervention and approach. The studies are at slightly different points - two of the studies are in the preparatory phase while the other two have started the main study.

As part of the main study, we will be collecting a range of biospecimens (blood, buccal and vaginal swabs, urine, stool, cord blood and placenta) from the women/mothers, fathers and children. Under this grant, we would like to undertake analyses of a selection of these biological samples, in order to understand how early life factors impact long-term health. In this outline call, we will standardise our procedures for processing biological samples, and finalise our plans for analyses. The results will help us in understanding the mechanisms by which poor fetal growth and undernutrition leads to NCDs in later life. The findings will have important global policy implications as the studies comprise Asian, African and Caucasian populations.

Non-communicable diseases (NCDs) including cardiovascular disease (CVD) and type 2 diabetes (T2D) are rapidly increasing in low- and middle-income countries (LMICs). Current approaches to preventing cardiometabolic disease mainly target lifestyle factors in high-risk adults. While offering some benefit to the individual, such approaches do little to address the risk in future generations. The developmental origins of health and disease (DOHaD) concept offers an alternative paradigm to tackling NCDs by developing and delivering novel interventions in an integrated manner across the lifecourse, starting preconceptionally.

The Healthy Life Trajectories Initiative (HeLTI) programme was set up as a joint initiative comprising four separate but harmonised intervention studies in Mysore (India), Johannesburg (South Africa), Shanghai (China) and two provinces in Canada. The studies will test evidence-based multi-faceted interventions spanning from preconception into the postnatal period, to improve maternal, infant and child health, including cardiometabolic and neurocognitive well-being. Exposure and outcome data variables and collection methodologies have been harmonised. A harmonised set of core biospecimens has been developed by the HeLTI teams, together with guidelines for governing biospecimen collection, biobanking and access. Samples that will be biobanked include blood, urine, buccal and vaginal swabs, stool/rectal swabs, cord blood and placenta, meconium, and heel stick cards. Core funding allows sample collection. Under this grant, we will augment sample collection in India, China and South Africa. We intend to undertake mechanistic examination of the contribution of genetic and epigenetic factors, the microbiome and physiological pathways to poor developmental outcomes and cardiometabolic risk in relation to maternal, fetal and infant health. In the development phase, we will standardise biospecimen processing and storage, and develop the full proposal.

The burden of non-communicable diseases (NCDs) falls disproportionately on low- and middle-income countries (LMICs). Application of developmental origins of health and disease (DOHaD) principles may prevent intergenerational transmission of NCD risk. We hypothesise that an integrated intervention starting preconceptionally and at appropriate points across the lifecourse (pregnancy, infancy and childhood) will reduce childhood adiposity and the risk for NCDs as well as improve measures of child neurodevelopment. The Healthy Life Trajectories Initiative (HeLTI) programme comprises four separate but harmonised intervention studies based on DOHaD concepts in Mysore (India), Johannesburg (South Africa), Shanghai (China) and two provinces in Canada. The package of multi-faceted interventions is a response to the modest/negative findings, in relation to long-term benefits, found in single intervention trials. It is also not biologically plausible that multiple risk factors would respond to a single intervention. While the respective intervention packages vary by country to ensure cultural, contextual and policy appropriateness, they are all unified by both the overarching aim of the intervention and approach. Each study is powered individually but sufficiently harmonised to facilitate meta-analyses across countries. Given that the countries span African, Asian and Caucasian populations from a range of settings, the findings will have significant impact on global health policy.

The mechanisms by which developmental programming occurs is still poorly understood. As part of the MRC grant, we intend to undertake mechanistic examination of the contribution of genetic and epigenetic factors, the microbiome and physiological pathways to poor developmental outcomes and cardiometabolic risk in relation to maternal, fetal and infant health. A number of these outcomes have been linked to life-long risk for development of NCDs. Our intervention studies are particularly suitable for such analyses as they allow robust causal inference.

The information will benefit international and national agencies responsible for improving maternal and child health, and reducing NCDs. Reducing NCDs by optimising maternal and child health requires the adoption of measures beyond current strategies, and our results will allow policy makers to re-evaluate their strategies. Our mechanistic work will provide proof of causation to support policy decisions. Our process evaluation will help to provide insight into what worked or did not in each trial. Our economic evaluation will help policy makers assess the scalability of the intervention.

Our study will provide valuable information to colleagues on undertaking multi-faceted interventions starting preconceptionally in limited-resource settings. Capacity building has been a major focus of our work previously and this project will particularly enable young researchers in India, China and South Africa to develop transferable research skills and contribute to capacity building. Exchange visits between researchers in these three countries, and the UK and Canada will be supported, contributing to knowledge transfer. Our community engagement activities will help in increasing the knowledge-base of the wider public in the topics of maternal and child health.

We believe ours is the first study of its kind and will contribute to increasing the competitiveness of the research groups participating in this project. It would also open opportunities for other interested research groups working in the field of maternal and child health to collaborate with us. We have established governance arrangements for data sharing and we will build a biorepository in each of the sites which will be available for future analyses. We expect the project to lead to high quality publications.