OPTIMISE: Optimal preconception nutrition to offset inflammation and non-communicable disease risk in pregnant women and their children

Non-communicable diseases (NCDs) such as heart disease and diabetes rapidly increasing in low- and middle-income countries (LMICs). These diseases are occurring at younger ages in LMICs compared with high-income countries with accompanying economic and societal costs. Between 1980 and 2014, the prevalence of diabetes doubled in sub-Saharan Africa, India and China and is now higher there than in many high-income countries. 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. With rapid socio-economic transition, LMICs are experiencing not only undernutrition and low birth weight, but also increased weight gain during later childhood and adolescence. The consequence of this combination results in women in these countries entering pregnancy with poorer nutrition and increased rates of diabetes during pregnancy. It is therefore possible that measures to improve the nutrition of young women before and during pregnancy may have long-term beneficial effects.

Research has also shown that chronic inflammation (a normally protective response of the body to injury or infection) has been associated with NCDs including diabetes and heart disease. Nutrition plays a key role in the regulation of this inflammatory response. It has been shown that diets consisting of a greater intake of red meat, high-fat products, refined grains, and simple carbohydrates can result in higher levels of markers of inflammation, even in the absence of injury or infection.
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 maternal nutrition and well-being 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. As part of the main study, we will collect a range of biological samples (blood, buccal and vaginal swabs, urine, stool, cord blood and placenta) from the women/mothers, fathers and children.

In this study, we will undertake analyses of a selection of these biological samples. We aim to understand the nutritional factors (such as body size and diet) that affect inflammation in young women in three countries (China, India and South Africa). We will explore whether inflammation is related to maternal complications such as diabetes during pregnancy, and whether it affects fetal growth. We will also assess whether the intervention reduces inflammation and the risk of maternal complications, and improves fetal growth. Finally, we will explore the pathways by which nutrition, inflammation and NCDs are related. The findings will have important global policy implications for maternal and child health as the studies cover urban and rural populations in various stages of socio-economic transition.

Chronic low-grade inflammation, characterised by persistent elevation of circulating pro-inflammatory cytokines, has been associated with the development of non-communicable diseases (NCDs). Animal studies show that both maternal under- and over-nutrition can programme the offspring for increased inflammatory load and adiposity, and cause metabolic abnormalities, and that both maternal inflammation and its impact in offspring can be reversed by nutritional interventions. Human studies have similarly shown that both maternal under- and over-nutrition are associated with offspring metabolic deficits. Some studies have shown that higher maternal inflammatory load in pregnancy is associated with greater newborn and child adiposity. We therefore hypothesise that nutritional status (dietary intake, adiposity, micronutrients) is a critical driver of inflammatory load during the preconception and pregnancy periods, which in turn, increases risk for pregnancy complications and adverse offspring outcomes, leading to increased NCD risk.

The Healthy Life Trajectories Initiative programme consist of four separate but harmonised intervention studies in India, South Africa, China and Canada. The studies will test multi-faceted interventions spanning from preconception into the postnatal period, to improve maternal, infant and child health. Exposure and outcome data variables and biospecimen collection methodologies have been harmonised. In this study, we will investigate the relationship between nutrition, inflammation and risk factors for NCDs, and examine whether these associations are influenced by the intervention. We will measure selected inflammatory markers, fatty acids and micronutrients at baseline and post intervention. We will also undertake more detailed mechanistic studies to define the role of the placenta in programming of NCDs by examining inflammatory load and nutrient transport. The intervention platform will strengthen causal inference.

The burden of non-communicable diseases (NCDs) falls disproportionately on low- and middle-income countries (LMICs). Rates of type 2 diabetes have doubled in LMICs including India, China and sub-Saharan Africa. Application of developmental origins of health and disease (DOHaD) principles may prevent intergenerational transmission of non-communicable disease (NCD) risk by developing and delivering novel interventions in an integrated manner across the lifecourse. We hypothesise that a greater chronic inflammatory load before and during pregnancy due to sub-optimal nutrition increases rates of pregnancy complications and exacerbates NCD risk in both women and her offspring. Further, that an integrated intervention starting preconceptionally and at appropriate points across the lifecourse (pregnancy, infancy and childhood) to optimise nutrition will decrease the incidence of pregnancy complications, improve fetal growth and reduce NCD risk markers in mother and offspring.
The Healthy Life Trajectories Initiative (HeLTI) programme comprises four separate but harmonised intervention studies in India, South Africa, China and Canada. The studies are 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 diverse populations from a range of settings, the findings will have significant impact on global health policy. The results will help assess and guide the development of integrated maternal and child interventions incorporating nutrition.

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 the inflammatory 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. An understanding of the mechanisms will strengthen evidence for making policy recommendations.

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 require the adoption of measures beyond current strategies and our results will allow policy makers to re-evaluate their current approaches. 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. It will also enable UK investigators to gain experience of global health research. 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 that it will substantially increase 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.