Risk Of Later Disease Research Articles

Assessing Early Growth and Adiposity: Report from an EarlyNutrition Academy Workshop

This report provides a summary of a workshop organised by the European Commission-funded EarlyNutrition Project and the EarlyNutrition Academy. Accurate and reliable methods to assess body composition are needed in research on prenatal and early post-natal influences of nutrition on later health because common surrogate measures of maternal and offspring adiposity (body fat content), such as body mass index (BMI), have relatively poor predictive power for the risk of later disease. The key goals of the workshop were to discuss approaches to assess growth and body composition from pregnancy to adolescence, to summarise conclusions and to prepare a framework for research in the EarlyNutrition Project. The participants concluded that there is a pressing need to harmonise the methodologies for assessing body composition, recognising that each has advantages and limitations. Essential core measurements across studies assessing early growth and body composition were identified, including weight, length, BMI, waist and mid-upper arm circumference, subscapular and triceps skinfold thicknesses, and bioelectrical impedance analysis. In research settings with access to more sophisticated technologies, additional methods could include dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, ultrasound assessment of regional body fat, magnetic resonance imaging (MRI), air displacement plethysmography (ADP), and deuterium dilution. These provide richer data to answer research questions in greater depth but also increase costs. Where overall whole-body composition is the primary outcome measure, ADP or tracer dilution should be used whenever possible. Where regional distribution of body fat is of greater interest, an imaging technique such as MRI is preferred.

Early infantile growth and cardiovascular risks in adolescent Japanese women.

Objective: Early life events connected with the risk of later disease can occur not only in utero, but also in infancy. In study of the developmental origins of health and disease, the relationship between infantile growth patterns and adolescent body mass index and blood pressure is one of the most important issues to verify.Materials and Methods: We analyzed the correlation of current body mass index and systolic blood pressure of 168 female college students with their growth patterns in utero and in infancy.Results: Body mass index and systolic blood pressure in adolescence showed positive correlations with changes in weight-for-age z scores between 1 and 18 months but not with those between 18 and 36 months. Stepwise multiple regression analysis showed that both change in weight-for-age z scores from 1 to 18 months and body mass index at 1 month were significantly and independently associated with systolic blood pressure in adolescence. Body mass index at 36 months was positively correlated with body mass index in adolescence, while body mass index at birth was negatively correlated with body mass index in adolescence.Conclusion: Our findings shows that restricted growth in utero and accelerated weight gain in early infancy are associated with the cardiovascular risk factors of high systolic blood pressure and high body mass index in adolescence. In Japan, an increasing proportion of low birth weight infants and accelerated catch-up growth after birth have been observed in recent decades. This might be an alarming harbinger of an increase in diseases related to the developmental origins of health and disease in Japan.

Effects of in utero conditions on adult feeding preferences.

The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and experimental evidence demonstrating that the fetal environment may impact the individual's food preferences. In addition, we review the feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have implications in terms of public health and primary prevention during early ages.

The influence of maternal protein nutrition on offspring development and metabolism: the role of glucocorticoids

The consequences of sub-optimal nutrition through alterations in the macronutrient content of the maternal diet will not simply be reflected in altered neonatal body composition and increased mortality, but are likely to continue into adulthood and confer greater risk of metabolic disease. One mechanism linking manipulations of the maternal environment to an increased risk of later disease is enhanced fetal exposure to glucocorticoids (GC). Tissue sensitivity to cortisol is regulated, in part, by the GC receptor and 11β-hydroxysteroid dehydrogenase (11β-HSD) types 1 and 2. Several studies have shown the effects of maternal undernutrition, particularly low-protein diets, on the programming of GC action in the offspring; however, dietary excess is far more characteristic of the diets consumed by contemporary pregnant women. This study investigated the programming effects of moderate protein supplementation in pigs throughout pregnancy. We have demonstrated an up-regulation of genes involved in GC sensitivity, such as GC receptor and 11β-HSD, in the liver, but have yet to detect any other significant changes in these piglets, with no differences observed in body weight or composition. This increase in GC sensitivity was similar to the programming effects observed following maternal protein restriction or global undernutrition during pregnancy.

Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms.

Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.

Prenatal stress, glucocorticoids and the programming of adult disease

Numerous clinical studies associate an adverse prenatal environment with the development of cardio-metabolic disorders and neuroendocrine dysfunction, as well as an increased risk of psychiatric diseases in later life. Experimentally, prenatal exposure to stress or excess glucocorticoids in a variety of animal models can malprogram offspring physiology, resulting in a reduction in birth weight and subsequently increasing the likelihood of disorders of cardiovascular function, glucose homeostasis, hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety-related behaviours in adulthood. During fetal development, placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) provides a barrier to maternal glucocorticoids. Reduced placental 11β-HSD2 in human pregnancy correlates with lower birth weight and higher blood pressure in later life. Similarly, in animal models, inhibition or knockout of placental 11β-HSD2 lowers offspring birth weight, in part by reducing glucose delivery to the developing fetus in late gestation. Molecular mechanisms thought to underlie the programming effects of early life stress and glucocorticoids include epigenetic changes in target chromatin, notably affecting tissue-specific expression of the intracellular glucocorticoid receptor (GR). As such, excess glucocorticoids in early life can permanently alter tissue glucocorticoid signalling, effects which may have short-term adaptive benefits but increase the risk of later disease.

Experimental evidence for early nutritional programming of later health in animals

The developmental origins of adult disease represent a burgeoning area of research for which it has been suggested that up to 50% of the current incidence of later adult disease may be explained or even alleviated. Therefore, it is not surprising that there has been a substantial increase in the number of publications on this subject. In this review, some of the most important recent publications will be highlighted, particularly those focusing on the consequences for later cardiovascular control and obesity. The review will consider the extent to which both increased and decreased maternal nutrient intake in relevant animal models can result in offspring that are at greater risk of later disease, and will indicate the potential mechanisms involved. Particular focus will be given to effects on glucocorticoids, potential epigenetic effects, and the extent to which male or female offspring may be differentially programmed. In addition, the potential for nutritional or endocrine interventions during lactation in order to overcome these adverse outcomes will be covered. Inappropriate growth during pregnancy, lactation and/or childhood can result in individuals whose risk of later cardiovascular disease is greatly increased. By considering the critical importance of the maternal diet from before conception through to lactation, there is a clear potential to substantially improve the health of all children and adults.

Maternal nutrient restriction alters renal development and blood pressure regulation of the offspring

Studies have shown that the risk of hypertension in adulthood can be affected by the in utero environment. It is established that hypertension is linked to compromised kidney function and that factors affecting organogenesis can increase the risk of later disease. Prostaglandins (PG) and growth factors are known to play an important role in regulating kidney function and renal organogenesis. The extent, however, to which global energy restriction (where all nutrients are reduced) of the mother can programme later blood pressure control or renal PG and growth factor status is unknown. A study is described that aimed to examine the long-term effects of maternal nutrient restriction (NR) and elucidate their relationship with compromised kidney development. First, it was necessary to establish animal models. A sheep model of 50% NR during specific stages of gestation was used to investigate fetal renal development, whilst a rat model of 50% NR throughout pregnancy was used to investigate postnatal kidney development and adult functioning. Molecular analysis has shown that expression of the growth hormone-insulin-like growth factor (GH-IGF) axis is affected by NR in the fetal sheep kidneys, and that changes are dependent on the timing of NR and whether the fetus is a singleton or a twin. Analysis of the kidneys from the rat model has shown nutritional differences in the expression of PG receptors and the enzymes responsible for PG synthesis and degradation that persist into adulthood. In conclusion, NR does affect the GH-IGF and PG axes, and these changes may be important in the nutritional programming of renal functioning and adult blood pressure control.

The developmental origins of adult disease.

Epidemiological and clinical observations have led to the hypothesis that the risk of developing some chronic diseases in adulthood is influenced not only by genetic and adult lifestyle factors, but also by environmental factors acting in early life. These factors act through the processes of developmental plasticity and possibly epigenetic modification, and can be distinguished from developmental disruption. The concept of predictive adaptation has been developed to explain the relationship between early life events and the risk of later disease. At its base, the model suggests that a mismatch between fetal expectation of its postnatal environment and actual postnatal environment contribute to later adult disease risk. This mismatch is exacerbated, in part, by the phenomenon of "maternal constraint" on fetal growth, which implicitly provides an upper limit of postnatal nutritional environment that humans have adapted for and is now frequently exceeded. These experimental, clinical and conceptual considerations have important implications for prevention and intervention in the current epidemic of childhood obesity and adult metabolic and cardiovascular disorders.

Neonatal Nutrition and Consequences on Adult Health

After completing this article, readers should be able to: 1. Describe aberrations in adult health that can result from nutrition in the fetal period and in neonatal life. 2. Review the results of studies from human neonates regarding early nutritional interventions designed for “catch-up” growth. 3. Review results from animal studies regarding early nutrition and “programming” for adult metabolic syndrome. 4. Describe some of the potential epigenetic mechanisms that may be responsible for “programming.” 5. Examine methods for preventing growth delays, the consequences of undernutrition, and the metabolic syndrome related to adverse “programming.” One of the traditional goals of neonatal nutrition is to maintain growth within standardized limits. In the preterm infant, growth between the 10th and 90th percentiles of intrauterine rate has been an ideal goal. More recently, maintenance of lean body mass and bone density; prevention of complications such as chronic lung disease, necrotizing enterocolitis, and infection; and optimization of neurodevelopment and adult health through early nutritional programming have become recognized as more meaningful goals than mere somatic growth. To meet these goals, current nutritional practices require thorough scrutiny in terms of quantity and quality (composition) and how they are customized, if not for the individual patient (which would be ideal), at least for subgroups such as those who are small or appropriate for gestational age, sick or healthy, preterm or term, or male or female. Fetal nutrition and development frequently are used as a template for the low-birthweight infant. A large body of literature on the consequences of fetal undernutrition shows that infants born small for gestational age (SGA) not only have short-term morbidity, but long-term morbidity manifested in what has been termed the “metabolic syndrome.” This syndrome includes abdominal obesity, arterial hypertension, and insulin resistance. Other clinical manifestations can be observed, including thyroid dysfunction, hirsutism, ovarian hyperandrogenism and infertility, dyslipidemia (increased …

A discussion of some statistical methods for separating within‐pair associations from associations among all twins in research on fetal origins of disease

Twin data can be used to gain insights into the origin of associations between factors arising in fetal life and the risk of later disease. This is because twin data afford an opportunity to conduct paired analyses that take the influence of shared factors into account. When an association that is present in an unpaired analysis is present also in a paired analysis, there is evidence that the causal pathway linking the fetal factor and the disease may have a fetal origin. If the association disappears in the paired analysis, there is evidence that it may have has arisen from a shared source such as the mother. The relevant factors include diet and socio-economic status. There are several statistical approaches to this. The simplest involves comparing, say, a coefficient from a regression of an outcome on a fetal factor for all subjects in a twin sample, with the coefficient obtained from regressing the within-pair difference in the outcome on the within-pair difference in the fetal factor. Alternative approaches involve simultaneously estimating regression parameters for between- and within-pair components. These approaches permit similar inferences about whether the association is due to individual (fetal) or shared (maternal) factors, and are valid in the circumstances that non-shared factors missing from the regression model do not influence the regression estimates.

Modeling Postnatal Exposures and Their Interactions with Birth Size

The fetal origins of adult disease hypothesis postulates that the inverse association between birth weight and later adverse outcome reflects fetal programming that increases the risk of later disease. However, low birth weight is associated with catch-up after birth, and weight gain is itself a risk factor for later disease. It is difficult to disentangle the effects on outcome of the size and growth components of weight change through time. This paper presents the life course plot, a device to display both size and growth effects simultaneously. It is based on the multiple-regression analysis of the outcome on the various weights, expressed as z-scores, and the plot displays the coefficients plotted against the corresponding ages of measurement. Examples from Brazil (Pelotas) and the Phillippines (Cebu) relate blood pressure in adolescence to weight through childhood. They show small inverse weight effects in infancy, but early weight is less important than weight and weight gain during adolescence. In addition, birth length in the Cebu study affects the strength of the relationship between weight and blood pressure in adolescence. This suggests a fetal programming effect, with children who were relatively long at birth having a more sensitive relationship between blood pressure and weight at age 15. Whether this is a good or a bad thing is not immediately clear.

Pathways of infant and childhood growth that lead to type 2 diabetes.

Although a link between small body size at birth and later type 2 diabetes has been repeatedly documented, less is known about the associations between the disease and growth during infancy. The aim of this study was to explore the pathways of infant and early growth that lead to type 2 diabetes in adult life. We carried out a longitudinal study of 8760 subjects born in Helsinki from 1934 to 1944. On average, they had 8 measurements of height and weight between birth and 1 year of age and another 10 measurements between 1 and 12 years of age. We identified people with type 2 diabetes using a national register. Among babies whose birth weights were <or=3.5 kg, the rate of infant growth was unrelated to later type 2 diabetes. Among babies with birth weights >3.5 kg, slow growth in length between birth and 3 months of age predicted later disease. Rapid gain in BMI after age 2 years increased the risk of later disease in both groups of babies, but this effect was greatest among children who had slow growth in length between birth and 3 months of age. In children whose Z-scores for length decreased, an SD increase in BMI at age 12 years was associated with an odds ratio (OR) for type 2 diabetes of 1.77 (95% CI 1.50-2.09). The corresponding OR in subjects whose Z-scores for length increased was 1.42 (95% CI 1.20-1.69). Rapid gain in childhood BMI was associated with high maternal BMI and socioeconomic factors (fewer people in the home and lower social class). Babies with above-average birth weights may develop type 2 diabetes later in life if poor living conditions lead to faltering growth in length in the first few months after birth. We speculate that growth faltering at this time is associated with lifelong impairment of insulin metabolism and inability to meet the challenge of rapid childhood increase in BMI.

Use of a virtual reality car-driving stressor in cardiovascular reactivity research

Eighteen subjects (11 males, 7 females) completed a virtual reality car-driving stressor on two occasions several weeks apart. Immediately before and throughout task performance, blood pressure, cardiac output, and total peripheral resistance were assessed. Reactivity scores were calculated for each parameter for each subject as the arithmetic difference between task level and baseline level. The task elicited considerable hemodynamic activation on each occasion of testing, as well as high levels of self-reported task realism, engagement, excitement, and nervousness. Correlation analyses of both absolute and reactivity scores revealed evidence of test-retest reliability. Males were found to exhibit greater absolute levels of and greater increases in systolic blood pressure. The development of tasks suitable for inclusion in a battery of behavioral stressors, responses to which may help identify those at risk for later disease, is of considerable interest in cardiovascular behavioral medicine. The present findings suggest that the virtual reality car-driving task may be useful in this context.

Role of glucocorticoids in programming of maternal diet-induced hypertension in the rat

A rat model of hypertension induced by in utero exposure to maternal low protein diets has previously been described. Low protein exposed rat pups are of lower weight at birth and have large associated placentas. Such animals are proposed, therefore, to mirror individuals in the human population perceived to be at greater risk of cardiovascular disease in adulthood. Recent work has suggested that maternal glucocorticoids may programme this increased risk of later disease. The role of glucocorticoids in programming the hypertensive state was assessed by administration of the 11β-hydroxylase inhibitor, metyrapone, to pregnant rats consuming 18 (control) or 9% (low protein) casein diets. At day 14 of pregnancy, fetuses and placentas of low protein-fed rats were significantly larger than those of controls. Metyrapone significantly inhibited corticosterone synthesis in both dietary groups, and attenuated the more rapid growth of fetus and placenta in the low protein fed group. Systolic blood pressures of rats exposed to the low protein diet in utero were significantly higher (29 mmHg) than those exposed to the control diet. Metyrapone abolished the hypertensive state of low protein exposed rats, but in the control group significantly elevated blood pressure by 15 mm Hg. Maternal and fetal glucocorticoid interactions in utero clearly have an important role in determining future regulation of blood pressure. Maternal-diet induced hypertension in the rat would appear to be a glucocorticoid-dependent phenomenon.

The healthy Seventh-day Adventist lifestyle: what is the Norwegian experience?

The health effect of being a Seventh-day Adventist was studied by computer-linking the official church rosters with National Health Registries. Birth weight in children born by Seventh-day Adventist mothers was 99 g higher (P < 0.001) than that of matched control subjects. Total cholesterol was 0.86 mmol/L lower in the Seventh-day Adventist men (P < 0.001) and 0.48 mmol/L lower in women (P < 0.001). Cancer incidence was not significantly lower in Seventh-day Adventists [standardized incidence ratio (SIR) in men, 91; women, 97]. Total mortality was significantly lower only in Seventh-day Adventist men [standardized mortality ratio (SMR), 82; P < 0.001], especially cardiovascular mortality. Entering the church at an early age had a large effect on later mortality. The study supports previous findings in Seventh-day Adventists, with the exception of cancer incidence and mortality. An early establishment of a healthy lifestyle seems to be of decisive importance in the risk of later disease.

Patterns of food intake in childhood and adolescence and risk of later disease or "the awful food kids eat nowadays must be bad for them".

Patterns of food intake in childhood and adolescence and risk of later disease or "the awful food kids eat nowadays must be bad for them".