In spite of improving life expectancy over the course of the previous century, the health of the U.S. population is now worsening. Recent increasing rates of type 2 diabetes, obesity and uncontrolled high blood pressure predict a growing incidence of cardiovascular disease and shortened average lifespan. The daily >$1billion current price tag for cardiovascular disease in the United States is expected to double within the next decade or two. Other countries are seeing similar trends. Current popular explanations for these trends are inadequate. Rather, increasingly poor diets in young people and in women during pregnancy are a likely cause of declining health in the U.S. population through a process known as programming. The fetal cardiovascular system is sensitive to poor maternal nutritional conditions during the periconceptional period, in the womb and in early postnatal life. Developmental plasticity accommodates changes in organ systems that lead to endothelial dysfunction, small coronary arteries, stiffer vascular tree, fewer nephrons, fewer cardiomyocytes, coagulopathies and atherogenic blood lipid profiles in fetuses born at the extremes of birthweight. Of equal importance are epigenetic modifications to genes driving important growth regulatory processes. Changes in microRNA, DNA methylation patterns and histone structure have all been implicated in the cardiovascular disease vulnerabilities that cross-generations. Recent experiments offer hope that detrimental epigenetic changes can be prevented or reversed. The large number of studies that provide the foundational concepts for the developmental origins of disease can be traced to the brilliant discoveries of David J.P. Barker.

The early embryo and periconceptional period is a window during which environmental factors may cause permanent change in the pattern and characteristics of development leading to risk of adult onset disease. This has now been demonstrated across small and large animal models and also in the human. Most evidence of periconceptional ‘programming’ has emerged from maternal nutritional models but also other in vivo and in vitro conditions including assisted reproductive treatments, show consistent outcomes. This short review first reports on the range of environmental in vivo and in vitro periconceptional models and resulting long-term outcomes. Second, it uses the rodent maternal low protein diet model restricted to the preimplantation period and considers the stepwise maternal-embryonic dialogue that comprises the induction of programming. This dialogue leads to cellular and epigenetic responses by the embryo, mainly identified in the extra-embryonic cell lineages, and underpins an apparently permanent change in the growth trajectory during pregnancy and associates with increased cardiometabolic and behavioural disease in adulthood. We recognize the important advice of David Barker some years ago to investigate the sensitivity of the early embryo to developmental programming, an insight for which we are grateful.

Understanding the role and importance of nutrition in early postnatal life, as an influence on lifelong vulnerability to poor health, is an important part of current research. We need to be able to define optimal patterns of infant feeding, not just to support growth and development in infancy, but also as determinants of later health. To date, much of the focus on the long-term effects of infant nutrition has been on milk feeding, to compare breast and formula feeding and to evaluate the effects of exclusivity, timing and duration of feeding different types of milk in infancy; other aspects of infant feeding such as age at introduction of solid foods and type of weaning diet have received less attention, and relatively little is known about their links to later health. Contemporary data are needed to enable us to move beyond explanation of historical infant feeding data in order to understand and predict health outcomes in future generations. Ongoing and new population studies, that include infants from diverse settings, will be key to providing generalizable data that can be used to define optimal feeding practice. There are some methodological challenges ahead, although significant progress has already been made, and further progress is envisaged in the future. In particular, the opportunity to bring together epidemiological studies and new mechanistic insights that will help identify key aspects of infant nutrition and their causal effects offer great promise both in moving this field forward as well as the potential for health benefits for future generations.

David Barker established growth as a seminal link between early development and later health attainment and disease risk. This was nothing less than a paradigm shift in health and medicine, turning the focus of disease causality away from contemporary environmental influences to earliest growth as a time when functional anatomy and physiology sets in place critical structures and function for a lifetime.

Barker’s prodigious work investigated time- and place-specific interactions between maternal condition and exogenous environmental influences, focusing on how growth unfolds across development to function as a mechanistic link to ensuing health. Subsequent applications do not always attend to the specificity and sensitivity issues included in his original work, and commonly overlook the long-standing methods and knowledge base of auxology. Methodological areas in need of refinement include enhanced precision in how growth is represented and assessed. For example, multiple variables have been used as a referent for ‘growth,’ which is problematic because different body dimensions grow by different biological clocks with unique functional physiologies. In addition, categorical clinical variables obscure the spectrum of variability in growth experienced at the individual level. Finally, size alone is a limited measure as it does not capture how individuals change across age, or actually grow.

The ground-breaking notion that prenatal influences are important for future health gave rise to robust interest in studying the fetus. Identifying the many pathways by which size is realized permits targeted interventions addressing meaningful mechanistic links between growth and disease risk to promote health across the lifespan.

Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

The theory of developmental programming is supported by accumulating evidence, both observational and experimental. The direct application of the principles of developmental programming by clinicians to benefit pregnant women remains an area of limited attention. Examining a selection of inpatients at an obstetric referral center, I searched for situations in which clinical decision making could be driven by the principles of developmental programming. I also looked for situations in which the clinical research agenda could be dictated by these concepts. In the decision to undertake preventive measures to avoid preeclampsia, the offspring’s perspective may support more liberal application of calcium and aspirin. Consideration of the long-term health perspective of the offspring could drive choices in the management of obesity and diabetes in pregnancy. The administration of corticosteroids in women delivering by elective cesarean at term may have modest short-term benefits, but additional trials are necessary to investigate long-term offspring health. The offspring of women suffering hyperemesis gravidarum may benefit from nutritional therapy. The long-term health of the offspring could affect couples’ choice for IVF or expectant management. Applying the principles of developmental programming to the management of pregnant women could drive clinical decision making and is driving the clinical research agenda. Increasingly, developmental programming concepts are becoming an integral part of clinical practice, as well as determining the choice of outcomes in trials in obstetrics and fertility medicine. The presented cases underscore the need for more research to guide clinical practice.

The recognition of ‘fetal origins of adult disease’ has placed new responsibilities on the obstetrician, as antenatal care is no longer simply about ensuring good perinatal outcomes, but also needs to plan for optimal long-term health for mother and baby. Recently, it has become clear that the intrauterine environment has a broad and long-lasting impact, influencing fetal and childhood growth and development as well as future cardiovascular health, non-communicable disease risk and fertility. This article looks specifically at the importance of the developmental origins of ovarian reserve and ageing, the role of the placenta and maternal nutrition before and during pregnancy. It also reviews recent insights in developmental medicine of relevance to the obstetrician, and outlines emerging evidence supporting a proactive clinical approach to optimizing periconceptional as well as antenatal care aimed to protect newborns against long-term disease susceptibility.

In 1969, David Barker, his wife and four children moved to Uganda to work at Makerere Medical School in the capital Kampala. During the 1960s, Makerere had become a research and teaching centre with an international reputation based on the work of Trowell, Burkitt, Hutt and many others who had pioneered studies explaining the disease patterns in the West Nile area on the basis of the local climate, nutrition and lifestyle. David Barker was funded by the Medical Research Council to carry out research on a poorly understood disease, Buruli ulcer, joining Scottish surgeon Wilson Carswell, who was later to achieve fame as the role model for Dr Garrigan in Giles Foden’s novel The Last King of Scotland.

A developmental approach to public health focuses attention on better nourishing girls and young women, especially those of low socio-economic status, to improve mothers’ nutrition and thereby the health of future generations. There have been significant advances in the behavioural sciences that may allow us to understand and support dietary change in young women and their children in ways that have not previously been possible. This paper describes some of these advances and aims to show how they inform this new approach to public health. The first of these has been to work out what is effective in supporting behaviour change, which has been achieved by careful and detailed analysis of behaviour change techniques used by practitioners in intervention, and of the effectiveness of these in supporting change. There is also a new understanding of the role that social and physical environments play in shaping our behaviours, and that behaviour is influenced by automatic processes and ‘habits’ as much as by reflective processes and rational decisions. To be maximally effective, interventions therefore have to address both influences on behaviour. An approach developed in Southampton aims to motivate, support and empower young women to make better food choices, but also to change the culture in which those choices are being made. Empowerment is the basis of the new public health. An empowered public demand for better access to better food can go a long way towards improving maternal, infant and family nutrition, and therefore the health of generations to come.

Professor David Barker, CBE, FRS, made an enormous contribution to biomedical research, which helped to change its direction and assisted translation to clinical medicine in the area of non-communicable disease (NCD). In this paper, I briefly note some of the studies, which led to his work, and describe how the underlying mechanisms came to be investigated by fetal physiologists. This is a unique aspect of the change in scientific emphasis, from a gene-centric and adult lifestyle view of NCD to a more holistic perspective, which placed emphasis on the importance of development that took place in the late 20th century. Early this century, the DOHaD Society was formed: I discuss some aspects of the formation of the Society and note the important role it is now playing in addressing the need to find early-life interventions to reduce NCD. This forms part of the unique legacy that David Barker has left to science and medicine.

We examined developmental programming studies that reported sex-specific effects published between 2012 and 2014, and examined whether the authors reported a statistical approach to explicitly test whether the effect of treatment differed between the sexes, for example, a sex by treatment interaction term. Less than half of the studies that reported sex-specific effects described explicitly testing whether effects were indeed sex-specific; in most cases, an effect was considered ‘sex-specific’ if it was significant in one sex but not the other. This is not a robust approach, since significance in one sex and lack of significance in the other sex does not imply a significant difference between the sexes. However, sample size often limits statistical power to detect interactions. We suggest that if the effect is significant in only one sex, but the interaction term is not significant, alternative solutions would be to present the confidence intervals for the effect size for each sex, or using Bayesian approaches to calculate the probability that the effect sizes differ between the sexes. We present a simple example of a Bayesian analysis to illustrate that this approach is reasonably easy to implement and interpret.

Fetal programming hypothesis presupposes that stimulus or insult acting during critical periods of uterine growth and development may permanently alter tissue structure and function. Ricinus communis oil (RCO) has been reported to possess/used as laxative, labor-inducing and estrogenic properties. Generational reproductive effects of maternal exposure to RCO was investigated in rats. A total of 25 pregnant rats randomly assigned to five equal groups were treated with distilled water (control, group 1), RCO (950 mg/kg p.o.) during gestation days (GD) 1–7, 7–14, 14–21 and 1–21, respectively. Birth weight, morphometric data, anogenital distance (AGD), pubertal age, sperm parameters, hormonal profile, organ weight and histopathology were determined in the first (F1) and second (F2) filial generations. Results showed a significant decrease (P<0.05) in birth weight/morphometric data in male pups from the GD 1–7 and 7–14 groups. AGD decreased significantly in RCO-treated F1 males. Pubertal age of F1 females decreased significantly (P<0.05) compared with controls. At postnatal day 90, F1 males from the RCO-treated group showed significant decrease in testis weight, body weight, sperm count, motility and normal morphology. Testosterone levels were significantly decreased in RCO-treated F1 males, which also showed testicular interstitial edema and epididymal hypospermia. Only pubertal indexes were altered in F2 rats. Maternal exposure to RCO at early gestation periods impaired androgen-mediated reproductive end points in the first generation of rats. RCO exhibits endocrine disrupting capabilities.

Intrauterine growth restriction (IUGR) is associated with adverse perinatal outcomes and late-onset diseases in offspring. Eating disorders, voluntary caloric restriction and maternal undernutrition can all induce IUGR but a relevant model is required to measure all its possible consequences. In this work, pregnant rabbits were used as an IUGR model. Control females (n=4) received ad libitum diet throughout pregnancy, whereas underfed females (n=5) were restricted to 50% of their daily requirements. Offspring size was measured by ultrasonography and in vivo at birth. Hemodynamic features of the umbilical cords and middle cerebral arteries (systolic peak velocity, end diastolic velocity, pulsatility index and resistance index) were characterized by Doppler ultrasonography. At day 21, maternal underfeeding resulted in a significant reduction of fetal size (occipito-nasal length). At birth, the size of kits from the underfed group was significantly lower (lower crown-rump length, biparietal and transversal thoracic diameters) and a reduced weight with respect to the control group. Feed restriction altered blood flow perfusion compared with does fed ad libitum (significant higher systolic peak, time-averaged mean velocities and lower end diastolic velocity). Fetuses affected by IUGR presented with compensative brain-sparing effects when compared with the control group. In conclusion, the present study supports using rabbits and the underfeeding approach as a valuable model for IUGR studies. These results may help to characterize IUGR alterations due to nutrient restriction of mothers in future research.

Stress during rat gestation can elicit depression-like physiological and behavioral responses in the offspring. However, human clinical depression is more prevalent among females than males. Accordingly, we examined how repeated variable prenatal stress (PS) alters rat anxiety- and depression-like behavior as well as circadian patterning of motor activity in both male and female offspring. For this purpose, we exposed pregnant Sprague–Dawley rats to multiple stressors during gestational days 13–21. Subsequently, we monitored locomotor and rearing/climbing activities in home-like cages for 24 h and measured anxiety- (elevated plus maze, EPM) and depression-like (forced swim test, FST) behaviors in the offspring at a young adult age. As a stressful event later in life (in addition to PS) may be needed to actually trigger an episode of clinical depression, half of the animals were exposed to an acute stressor (elevated platform) before EPM testing. Dams exposed to the stressor battery had increased plasma corticosterone levels compared with controls. Male PS offspring displayed changes in locomotor and rearing/climbing activity relative to controls. Additionally, anxiety measures in the EPM were affected in control animals after acute stressor exposure, however, this response was blunted in PS offspring. Moreover, FST immobility, as an indicator of depressive-like behavior, was increased in female but not male PS rats. Altogether, our results identify both sex- and circadian phase-specific effects of PS. These findings indicate that the PS rat model reflects multiple clinical depression characteristics, including elevated female vulnerability.