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A wide range of maternal dietary challenges have been linked to poor long term outcomes for children. Dietary alterations most closely linked to adverse intrauterine development include familiar examples of single micronutrient deficiencies—for example, low folic acid. Supplementation of folic acid during pregnancy is routinely advised in many countries and has been shown to reduce the incidence of spina bifida.2 Other maternal dietary challenges are context specific, such as low iodine, which is endemic in South East Asia and parts of Africa. Low maternal iodine levels impair fetal brain myelination, with established links to poor neurodevelopmental outcomes.3 Maternal iodine deficiency can be addressed through iodising food grade salt, a population-wide strategy successfully adopted in over 120 countries.4 Success in tackling isolated micronutrient deficiencies, either at individual or population level, shows that improving maternal nutrition is both possible and effective at improving lifelong health outcomes for children. However, any nutritional intervention, particularly at the population level, must be carefully considered to mitigate unintended effects. One example is iron supplementation in iron replete pregnant women, who may theoretically become more susceptible to infection.5 The World Health Organization recommends that iron supplementation in malaria endemic areas is accompanied by appropriate resources for prophylaxis and treatment.6 Moreover, tackling micronutrient deficiency is relatively straightforward compared with understanding and modifying diet as a whole.

Studies in animal models suggest that an array of dietary modifications, including high fat, high sugar, and calorie restriction, can influence the epigenetics of the fetus.7 A fascinating aspect of these studies is that despite the wide range of dietary variations tested in animal models, the physiological phenotype of the offspring is often similar. In adulthood the offspring typically have increased risk of metabolic dysfunction, consisting of early tissue ageing, oxidative stress, accumulation of fat mass, and inflammation. This is strikingly similar to phenotypes commonly observed in human populations worldwide as the incidence of metabolic disorders continues to accelerate (fig 1). Potential pathways of developmental programming. Evidence from animal models, primarily rodents, shows that the intrauterine environment influences fetal development at a cellular level, including β islet cells and pre-adipocytes. Disruptions to many of the same cellular pathways are also seen in human studies of adverse intrauterine environments

pmental programming. Evidence from animal models, primarily rodents, shows that the intrauterine environment influences fetal development at a cellular level, including β islet cells and pre-adipocytes. Disruptions to many of the same cellular pathways are also seen in human studies of adverse intrauterine environments However, translating the phenotypes programmed by nutritional manipulations in laboratory animals to humans is not straightforward, not least because of interspecies differences in developmental trajectories and timing. The associations between epigenetic programming of the fetus and maternal diet are, in theory, directly testable in human populations through trials of dietary modification. Unfortunately, trials of altering many aspects of diet and lifestyle during pregnancy have had disappointing results. In many large scale trials, compliance with planned changes to maternal dietary patterns can be challenging, showing the complexity of intervening in human eating behaviour.

als of dietary modification. Unfortunately, trials of altering many aspects of diet and lifestyle during pregnancy have had disappointing results. In many large scale trials, compliance with planned changes to maternal dietary patterns can be challenging, showing the complexity of intervening in human eating behaviour. Where change has been successful, many trials show lack of improvement in childhood metabolic endpoints, such as body mass index (BMI) or adiposity,8 even when mothers have been given intensive support for dietary change. A possible interpretation is that intervening to modulate maternal nutrition during pregnancy is too late to substantially influence maternal metabolic function or to produce sustained changes in eating habits. Shifting clinical focus towards optimising preconception family health, with a specific focus on reducing reliance on glucose heavy processed foods, is likely to be a more effective strategy for implementing research insights and preventing early onset metabolic disease. This strategy has the added benefit of encompassing dietary change in both prospective mothers and fathers, whose metabolic status also affects cardiometabolic risk in future generations.9

For many human populations around the world, food insecurity is an increasing concern. As climate change continues, food insecurity for pregnant women is likely to increase in many settings.10 Food insecurity encompasses both the direct effects of calorie restriction and limited food choices, such as a low protein diet, and indirect elements of associated maternal stress and other socioeconomic challenges (box 1). Some of these elements can be studied using animal models in which dietary calories and composition can be tightly controlled. However, exploring other elements of food insecurity, such as the interaction with increasing global temperatures and access to healthcare, requires novel population level experimental methods. Opportunistic studies in populations undergoing demographic transition globally, particularly those co-designed to have direct benefit within the population studied, should be a priority for research funders. Calorie restriction Specific nutritional deficiencies Vulnerability to anaemia or infection Poor fetal growth and preterm birth Maternal stress and anxiety Other unmet needs (housing, medical, financial, etc.)

For many human populations around the world, food insecurity is an increasing concern. As climate change continues, food insecurity for pregnant women is likely to increase in many settings.10 Food insecurity encompasses both the direct effects of calorie restriction and limited food choices, such as a low protein diet, and indirect elements of associated maternal stress and other socioeconomic challenges (box 1). Some of these elements can be studied using animal models in which dietary calories and composition can be tightly controlled. However, exploring other elements of food insecurity, such as the interaction with increasing global temperatures and access to healthcare, requires novel population level experimental methods. Opportunistic studies in populations undergoing demographic transition globally, particularly those co-designed to have direct benefit within the population studied, should be a priority for research funders. Calorie restriction Specific nutritional deficiencies Vulnerability to anaemia or infection Poor fetal growth and preterm birth Maternal stress and anxiety Other unmet needs (housing, medical, financial, etc.) India is one of the fastest growing economies in the world, but food security remains a major concern, with 195 million people classified by the United Nations as undernourished.11 Around one fifth of women aged 15-49 years are underweight (BMI <18.5). The National Food Security Act (2013) legally entitles about two thirds of India’s 1.4 billion population to receive heavily subsidised foodgrains through a targeted public distribution system, with a special focus on delivering macronutrients to pregnant women, breastfeeding mothers, and children aged 6 months to 14 years. This is particularly important, as evidence from a Mumbai based trial of micronutrient supplementation in pregnancy suggested that mothers who are better nourished respond better to micronutrient supplementation given before conception and throughout pregnancy.12 However, in keeping with the multifactorial nature of food insecurity, single intervention trials (eg, micronutrient supplementation) have shown only modest benefits for pregnancy and child outcomes.

are better nourished respond better to micronutrient supplementation given before conception and throughout pregnancy.12 However, in keeping with the multifactorial nature of food insecurity, single intervention trials (eg, micronutrient supplementation) have shown only modest benefits for pregnancy and child outcomes. A newer approach is to study multidimensional interventions, reflecting the diversity of challenges faced by populations with poor nutrition. An example of this approach is The Healthy Life Trajectories Initiative,13 which aims to improve population health through studying multiple simultaneous interventions starting in preconception and continuing through the early years of life. The scale, scope, and ambition of new trials of nutritional interventions in pregnancy must be sufficient to observe the longer term outcomes in childhood and beyond.

As populations undergo economic development and demographic transitions, food availability and dietary patterns often change radically within one or two generations. In tandem, patterns of childbearing also change; mothers tend to have fewer children and to be older at first pregnancy. With obesity and maternal age both increasing in pregnant populations worldwide, the incidence of diabetes in pregnancy is also rising, and it already affects up to 40% of pregnant women in some setttings.14 Left untreated, gestational diabetes has significant implications for the health of future generations, as well as the mother (fig 2). Short term outcomes of gestational diabetes on the mother, placenta, and fetus. Placentally derived hormones such as human placental lactogen (hPL) and placental growth hormone (pGH), contribute to maternal insulin resistance. The distribution of glucose transporter (Glut) subtypes on the maternal and fetal surface of the placenta means that glucose concentrations in the maternal circulation are reflected in the fetus, which leads to hyperinsulinaemia, adiposity, and macrosomia and increases risks to the fetus during delivery and in the neonatal period (NICU=neonatal intensive care unit)

subtypes on the maternal and fetal surface of the placenta means that glucose concentrations in the maternal circulation are reflected in the fetus, which leads to hyperinsulinaemia, adiposity, and macrosomia and increases risks to the fetus during delivery and in the neonatal period (NICU=neonatal intensive care unit) There is also considerable evidence that gestational diabetes influences metabolic outcomes for the child across the lifecourse, particularly increasing the risk of obesity and cardiovascular dysfunction.15 Short term adverse outcomes of gestational diabetes have been shown to be modifiable with maternal dietary changes, but it is less clear whether this is true for long term effects, the drivers of which could potentially be established in the fetus before maternal diagnosis.16 Diet and lifestyle modification are the mainstay of gestational diabetes therapy but are most effective when tailored to the individual. Recent initiatives to provide dietary advice that is more relevant to specific ethnic groups, especially those with a high risk of gestational diabetes, have been effective at improving both gestational weight gain17 and engagement with care.18 Clinicians providing dietary and lifestyle therapy should look closely at the specific needs of their local population to provide customised dietary advice.

hnic groups, especially those with a high risk of gestational diabetes, have been effective at improving both gestational weight gain17 and engagement with care.18 Clinicians providing dietary and lifestyle therapy should look closely at the specific needs of their local population to provide customised dietary advice. For women who require drug treatment for gestational diabetes, international guidelines vary regarding whether metformin or insulin should be the first choice. Ideally, sufficient evidence would be available to enable a personalised precision approach to this question. The ongoing uncertainty is partly because of the difficulty of conducting large scale clinical trials in pregnancy. Regulatory barriers to trials of therapeutics in pregnancy must be urgently re-evaluated and a more streamlined approach to evaluating potential therapies adopted. The prevalence of obesity in women of childbearing age has also increased worldwide; estimates suggest that up to 20% of all pregnant women may be living with obesity.19 In Brazil, which has undergone rapid demographic transition, the incidence of maternal obesity has increased to over 25% in the past decade despite national policies to promote healthy eating habits and monitor nutritional status during pregnancy. Pregestational obesity, excessive gestational weight gain, and increasingly sedentary lifestyles all contribute to a higher cardiometabolic risk for the next generation.14

increased to over 25% in the past decade despite national policies to promote healthy eating habits and monitor nutritional status during pregnancy. Pregestational obesity, excessive gestational weight gain, and increasingly sedentary lifestyles all contribute to a higher cardiometabolic risk for the next generation.14 As the role of postnatal nutrition has become clearer, a major aspect of national policy to combat the effects of high and rising rates of maternal obesity and gestational diabetes in Brazil has been promotion of breastfeeding. Breast milk has a complex and variable composition determined by a multitude of factors, including gestational age, maternal nutrition status, maternal genetics, and infant health. Evidence suggests that breast milk composition can influence the epigenetic status of the newborn—for example, through the presence of microRNAs.20 Research is ongoing into the impact of maternal nutritional status on the composition of microRNAs and other components of breast milk, such as specific oligosaccharides, with the hope of developing either biomarkers or therapeutic targets to improve long term metabolic health.21 However, these research findings have not yet translated to substantial improvements in population health or altered Brazilian breastfeeding rates. Education and promotion initiatives may not be enough to effect population-wide change in infant feeding practices, particularly when populations start with low breastfeeding rates and thus low availability of experienced peer support. Translation of these novel findings into healthier populations is likely to require investment in specialised clinical services, including those that support infant feeding.

The nutritional status of mothers correlates strongly with childhood health outcomes, and in many cases these effects persist into later life. Multiple facets of nutrition can influence the intrauterine environment, from isolated micronutrient deficiencies to food insecurity to chronic overnutrition, and the effect on the fetus can be initiated from preconception nutrition. However, advances in understanding of the links, have not yet translated into widespread benefits for population health. Box 2 lists priorities for policy makers, research funders, and clinical services to accelerate change in this area. Multidimensional lifestyle interventions targeted at the family unit Scalable pragmatic interventions, co-designed with populations at risk Incorporating population environmental challenges (eg, food security, climate change) Longitudinal follow-up throughout childhood (ideally through adolescence and beyond) Bidirectional benefits of participation (including for control groups—eg, family support) Alignment with studies in other global settings to improve generalisability and validation

Incorporating population environmental challenges (eg, food security, climate change) Longitudinal follow-up throughout childhood (ideally through adolescence and beyond) Bidirectional benefits of participation (including for control groups—eg, family support) Alignment with studies in other global settings to improve generalisability and validation Multiple studies show that while targeting a single facet of diet, such as folic acid or iodine supplementation, is achievable, attempts to make sweeping changes to dietary patterns in pregnancy are less successful. A key consideration is that intervention within pregnancy may be too little, too late. Pre-conception family health is a more effective target for public health initiatives. It is also clear that educational public health initiatives regarding nutrition should be backed up by support services to help with practical implementation of these positive changes. Wider availability of local services to support nutritional policies, for example infant feeding support, should be prioritised. A vital element of effectively translating nutritional advice into health behavioural change is recognising that dietary patterns within populations vary widely and are often interwoven with cultural, financial, and environmental factors. Nutritional recommendations, for example management of diabetes in pregnancy, are more likely to be followed if advice is attuned to the needs of the local population and support is available for implementation. Successful action has the potential to improve population health and reduce the burden on health systems.

s. Nutritional recommendations, for example management of diabetes in pregnancy, are more likely to be followed if advice is attuned to the needs of the local population and support is available for implementation. Successful action has the potential to improve population health and reduce the burden on health systems. Maternal nutrition during pregnancy affects cellular and molecular development of the fetus Nutritional exposures in early life influence long term health, including risk of cardiovascular disease, type 2 diabetes, and obesity Interventions to achieve broad changes to diet during pregnancy are difficult and may be too late Specific policy interventions and more research investment are urgently required to translate new molecular insights into improved population health outcomes