Early Malnutrition in the Mother Affects the Development of the Baby's: Heart. Brain. Lungs. A and B

Nestle Nutr Inst Workshop Ser. Writer manuscript; bachelor in PMC 2016 Oct 26.

Published in final edited form as:

PMCID: PMC5081104

EMSID: EMS69666

Fetal malnutrition and long-term outcomes

Caroline HD Fall

MRC Lifecourse Epidemiology Unit, University of Southampton, Great britain

Abstract

Epidemiological studies accept shown that lower birthweight is associated with a wide range of agin outcomes in subsequently life, including poorer 'human capital' (shorter stature, lower cognitive operation); increased risk factors for afterward illness, (higher blood pressure and reduced glucose tolerance, and lung, kidney and immune role); clinical illness (diabetes, coronary center illness, chronic lung and kidney disease); and increased all-cause and cardiovascular mortality. Higher birthweight is associated with an increased risk of cancer, and (if caused past gestational diabetes) obesity and diabetes. The "developmental origins of health and affliction" (DOHaD) hypothesis proposes that fetal nutrition has permanent furnishings on growth, structure and metabolism ('programming'). This is supported past studies in animals showing that maternal under- and over-nutrition during pregnancy tin produce similar abnormalities in the adult offspring. Common chronic diseases could potentially exist prevented by achieving optimal fetal nutrition, and this could accept boosted benefits for survival and human capital. Recent follow-up of children born afterwards randomised nutritional interventions in pregnancy provides weak show of beneficial effects on growth, vascular function, lipid concentrations, glucose tolerance and insulin resistance. Brute studies indicate that epigenetic phenomena may be an important mechanism underlying programming, and that nutritional interventions may need to showtime pre-conceptionally.

Fetal undernutrition and long-term outcomes

The beginning convincing show that fetal undernutrition could accept a long-term influence on human being health came from the follow-upwards of adults who were in utero during the Dutch Famine ('Hunger Winter') of 1944-45. Immature men whose mothers lived in famine-affected areas of kingdom of the netherlands during early pregnancy had an increased risk of obesity compared to men whose mothers lived in non-famine areas (2.vii% versus 1.five%) [i]. Men whose mothers were exposed to famine in late pregnancy or early on post-natal life had lower rates of obesity. The authors speculated that these findings reflected permanent effects of nutritional deprivation on fetal hypothalamic centres, causing lifelong changes in food intake and growth.

The science of 'developmental origins of health and disease' (DOHaD) started to attract intense interest some 20 years after, when Barker and Osmond linked birthweight (collected by health visitors in the Great britain from 1911-1930) with expiry certificate data and discovered that men and women who had a lower birthweight were at increased risk of death from cardiovascular and chronic lung illness [2]. Following on from this, a large number of nascency cohort studies have now linked lower birthweight to other adverse outcomes in later life. These include reduced 'human capital' (shorter stature, lower lean body mass, and poorer cognition, educational accomplishment, work chapters, income and reproductive performance) [iii]; increased adventure factors for later on affliction, (higher blood force per unit area [3], primal adiposity [4], insulin resistance [iii] and stress responses [v], and reduced glucose tolerance [6], lung part [seven], glomerular filtration rate [viii] and allowed office [ix]); increased clinical disease (blazon 2 diabetes, coronary heart illness, chronic renal affliction and chronic lung disease) [3,6,seven]; and increased all-cause and cardiovascular bloodshed [10]. The associations with take a chance factors for disease have been shown in children besides equally adults. The associations extend beyond the range of birth weight, and are not express to low birthweight (<2500 one thousand), although in some studies an upturn in risk is observed at loftier birthweights for some outcomes (meet below, fetal 'over-nutrition'). Well-nigh studies have been carried out in predominantly full-term births, suggesting that the phenomenon is linked to low birthweight for gestational age (interpreted as an indicator of fetal diet) rather than depression birthweight due to pre-term birth. Withal, there is some prove that pre-term nascence is too a take a chance cistron for cardio-metabolic outcomes like hypertension, insulin resistance and the metabolic syndrome [11].

Enquiry in animals had already shown that transient ecology conditions, including diet, in early life could permanently alter or "programme" the body'southward structure and role [12]. Subsequent piece of work in animal models has shown that fetal under-diet, achieved either by under-nourishing the mother during pregnancy, or by impairing the fetal supply line (uterine artery ligation, placental reduction or factor knock-out models that impair placental growth), produces permanent effects on a broad range of tissues and systems [13–15]. For instance, there are several maternal under-nutrition models in animals that produce obesity, insulin resistance and diabetes in the offspring, who show changes at whole brute level (eg. sedentary behaviour), tissue level (eg. altered organization of cell types in hepatic lobules, reduced prison cell numbers and vascularisation of pancreatic islets), and molecular level (eg. altered expression of genes in the insulin signalling pathway). This show from animal studies suggests that the associations between birthweight and later wellness in humans are likely to reflect the programming of a variety of tissues past intra-uterine nutrition (Effigy 1). The associations with birthweight occur because the same factors that perturb/programme metabolic function tin also reduce fetal growth; animal studies have shown that programming tin occur in the absence of reductions in birth size [13–15].

The fetal programming hypothesis; adult chronic disease resulting from the effects of fetal under-nutrition on the development of different tissues

Fetal under-nutrition can occur because of an inadequate maternal nutrition, inability of the mother to mobilise and send sufficient nutrients, or an dumb vascular and placental supply line to the fetus. It tin also occur if there is high fetal demand, for example because of faster growth. Changes in fetal structure and physiology could occur because of a elementary lack of the nutrients or building blocks required to construct loftier-quality organs and tissues, or because of adaptations to reduce food need eg past slowing fetal growth or prioritising essential organs. Endocrine systems (especially for hormones that regulate fetal growth and maturation) are re-gear up, and tissues are supported or sacrificed differentially. It is hypothesised that the resulting metabolic changes persist and increase the risk of developing diabetes and cardiovascular disease, especially if boosted stressors are acquired in later life (such as obesity and physical inactivity).

A consistent feature of the homo studies is that that the highest risk of cardio-metabolic disease and its risk factors is in children or adults who had a low birthweight only became relatively heavy (Figure 2). This 'modest becoming big' design is besides seen in animal models, in which post-natal high-energy or high-fatty feeding amplifies the agin cardio-metabolic furnishings of pre-natal under-diet [13–fifteen]. It fits with the concept that the fetus programmed by under-nutrition develops metabolic traits (higher blood pressure, insulin resistance, fundamental adiposity) that make them vulnerable to disease when exposed to additional stressors in subsequently life such as inadequate exercise, excess energy intake and obesity. It could also explain the recent ascent in cardio-metabolic affliction in depression-income countries undergoing rapid economic transition. This has raised the question of whether paediatricians should attempt and limit post-natal weight-gain in lower birthweight infants. Even if this were possible, at that place is no evidence to back up such a strategy in infancy; current evidence from low and middle-income countries suggests that greater infant weight gain is associated with benefits for survival and human being capital, and is neutral in terms of later cardio-metabolic chance [3].

Lower birthweight followed by the development of above average weight or BMI in babyhood or adulthood is associated with increased insulin resistance and impaired glucose tolerance (data from 3 Indian nascence cohorts)

Nutritional interventions in under-nourished meaning women

The DOHaD concept has stimulated enormous scientific involvement, merely has had little bear on on how the 'common women' thinks almost diet in pregnancy, or on national policies on maternal nutrition. Human evidence for fetal programming is all the same largely based on observational information and on nativity measurements, which are only crude indicators of fetal nutrition. However, the DOHaD hypothesis is offset to exist tested past studying children of undernourished women who took part in nutrition supplementation trials in pregnancy (Table ane). If maternal under-diet is an important cause of fetal under-nutrition, better outcomes would be expected in children whose mothers were supplemented. The published trials include a diversity of interventions and ages at follow-up, just fall into iii groups (mainly poly peptide-energy supplementation [16–xviii], multiple micronutrient supplementation [19–21]), or both [22]). All started in pregnancy, usually in the 2d or 3rd trimester, and the offspring outcomes most oft studied were growth and cardio-metabolic risk factors.

In the INCAP trial in Guatemala, villages were randomised to receive either a protein-energy drink (Atole) or a low-energy drink (Fresco) which were supplied daily to pregnant women and children <7 years of age [16]. There was no significant difference between Atole and Fresco villages in birthweight. This is the oldest trial and the only 1 with adult follow-up data. It showed lower triglyceride and college HDL cholesterol concentrations in men and women who received Atole before the historic period of 24 months (either given to the female parent in pregnancy or to the children themselves mail service-natally). There were no significant effects on adult claret pressure or fasting glucose. In the Gambian trial, women received a daily high energy biscuit, from twenty weeks of pregnancy (intervention grouping) or during lactation merely (controls). The intervention certainly influenced fetal nutrition, increasing birthweight past a mean 136 k and halving perinatal mortality. In the adolescent offspring (11-17 years), in that location was a small reduction in fasting plasma glucose concentrations (mean -0.05 mmol/l) merely no differences in adiposity, blood pressure, insulin concentrations or serum lipids [17]. In India, pregnant mothers and children under 6 years of age in intervention villages received nutrient-based energy and protein supplements. At sixteen years, the children had lower insulin resistance and arterial stiffness compared to children born in control villages [xviii]. There were no differences in their blood force per unit area or lipid concentrations. In both the Republic of guatemala and Indian trial, offspring of intervention mothers were taller, and in Guatemala an increase in height was as well observed in the next generation.

Two of the multiple micronutrient (MMN) trials (both in Nepal) showed a small increase in birth weight in the MMN groups [19,20]. Two-year old children whose mothers received multiple micronutrient supplements during pregnancy were heavier and had larger caput, chest and mid-arm circumferences and larger skinfold thickness, only lower systolic blood force per unit area, than children of control women, who received only iron and folic acrid [19]. In the other trial, seven-year quondam children whose mothers received vitamin A, fe, folic acid and zinc were taller and less adipose than children of control mothers (vitamin A lonely) and had lower triglyceride concentrations, while children whose mothers received folic acrid had a lower prevalence of metabolic syndrome than controls [twenty]. At that place were no effects on blood pressure, other lipids, glucose or insulin. In a trial in Peru, infants of mothers who were supplemented with fe, folic acid and zinc were heavier and had larger chest circumference and calf musculus expanse than those of women who received atomic number 26 and folic acid without zinc [21].

The People's republic of bangladesh 'Minimat' trial combined protein-energy and MMN interventions; women were randomised to receive food supplements 'early on' (~9 weeks gestation) or at the usual time (~xiv weeks), with (in a factorial design) either additional MMN or fe+folic acid. This is the just trial that attempted to correct both macronutrient and micronutrient deficiencies in the mother, and started in the kickoff trimester of pregnancy, but it is so far published simply in abstract form [22]. Early food supplements were associated with less stunting and lower LDL-cholesterol concentrations in the children. Multiple micronutrient supplementation was associated with lower insulin concentrations, and, interestingly, more stunting.

These studies provide some testify that improving the nutrient intake of nether-nourished homo mothers in pregnancy has benefits for growth and cardio-metabolic risk in the children, simply it cannot be called strong evidence. All took place in low-income populations, where levels of cardio-metaboli risk factors are still relatively depression and where the opportunity for 'condign big' postal service-natally is low compared with loftier-income settings. This would tend to reduce any differences between children from intervention and control groups. If early pregnancy is a disquisitional time for nutritional programming of adiposity, as suggested past animal studies [23] and the Dutch Famine studies [24], furnishings of supplements started afterwards in pregnancy may be limited. The only report with developed follow-up (Guatemala) had a very small sample size, and the age at follow-up in the other trials (either in immature children or adolescents) was not ideal for examining programming furnishings. Longer follow-upwards of these trials is needed, and data are required from studies in other populations and of other interventions, including pre-conceptional trials, before conclusions can be reached.

Fetal 'over-nutrition' and long-term outcomes

Maternal diabetes during pregnancy exposes the fetus to an excess of nutrients. Diabetic mothers are not simply hyperglycaemic, but also have elevated circulating lipids and amino acids. The fetal pancreas and liver are stimulated to secrete increased insulin and insulin-like growth factors, resulting in the macrosomic infant of the diabetic mother. Freinkel suggested 30 years agone that this could crusade obesity and diabetes in later life ("fuel mediated teratogenesis") [25] and information technology is at present established that gestational diabetes is a gamble gene for afterward diabetes in the offspring [4]. At that place are therefore bug at both extremes of birthweight. In almost populations, the predominant association of birthweight with later diabetes risk is linear and inverse, except in very large studies such as the US Nurses' Study, in which gestational diabetes produces a pocket-sized upturn in risk at high birthweights [six]. In populations with a very high prevalence of gestational diabetes, such equally the Pima Indians, the bend becomes U-shaped [six].

Lesser degrees of maternal glucose intolerance may besides be associated with increased adiposity in the children. In a US study of 9439 women routinely screened for gestational diabetes, at that place was a positive clan, fifty-fifty in the not-diabetic grouping, betwixt maternal glucose concentrations and overweight in the children [26]. Maternal insulin resistance and glycaemia class role of the normal process of fetal nutrition, and we exercise not nonetheless know the optimal levels of glucose and other fuels and nutrients in the female parent. There is besides increasing involvement in whether maternal obesity, in the absence of diabetes, causes fuel-mediated teratogenesis and programmes cardio-metabolic risk in the children. In beast models, maternal obesity, or high-fatty feeding during pregnancy, crusade obesity, insulin resistance and diabetes in the offspring [15]. Like the diabetic mother, an obese mother has increased circulating glucose, insulin, lipids and pro-inflammatory factors. Maternal obesity is associated with an increased take chances of obesity and metabolic syndrome in the children [27], and children built-in to obese mothers before they underwent biliopancreatic featherbed surgery take a lower run a risk of obesity than siblings born before surgery [28], just better evidence of a causal intra-uterine consequence is awaited.

Another important affliction to mention in relation to higher birthweight (and thus possibly to a fetal 'over-diet' event) is cancer. There is consistent bear witness that chest cancer and leukaemia are more common amid people of higher birthweight, and cancer bloodshed is college in men of higher birth weight [ten].

As mothers get heavier in most all populations, the incidence of diabetes in pregnancy is increasing, and this is likely to make an increasing contribution to the burden of obesity and diabetes in future generations. This may be a particularly important phenomenon in transitioning populations, in which mothers who themselves had a low birthweight are at increased gamble of developing gestational diabetes and thus exposing their offspring to fuel-mediated teratogenesis (Figure 3). Improved direction of diabetes in pregnancy reduces fetal macrosomia simply it is not yet known whether this prevents subsequently effects in the children.

Inter-generational effects of fetal nutrition on diabetes risk.

Intergenerational under-nutrition results in low birthweight, and a number of adverse after outcomes, including impaired human capital (left-hand circle). Rapid childhood or adult weight gain on a background of low birthweight is associated with an increased chance of cardio-metabolic disease (left to right arrow), and (in women) with gestational diabetes, which exposes her fetus to excess fuel mediated teratogenesis, some other route to increased diabetes chance (right-hand circle).

Mechanisms linking fetal nutrition to long-term outcomes

Possible mechanisms for the long-term programming of health and disease past fetal diet have been extensively reviewed [xv,29,30]. The simplest mechanism is inadequate growth and/or re-modelling of tissues, due to inadequate substrates at critical periods of development. Fetal tissues develop during specific times and in a specific order, and inadequate nutrients at these times could atomic number 82 to permanently reduced prison cell numbers, and/or altered construction due to selection of more than 'robust' alternative cell types. At that place is good show for this in the kidney; protein deprivation in significant animals during fetal nephrogenesis results in smaller offspring nephron number, and later on hypertension [xxx]. At that place is also evidence from animal studies of tissue re-modelling in the pancreas, liver and hypothalamus in response to fetal nether-nutrition.

Re-modelling of tissues that regulate endocrine and metabolic pathways could have broad-ranging effects. For case, the hypothalamus is the master encephalon heart regulating appetite and feeding behaviour, and monitors and responds to signals about nutritional state (the presence of nutrient in the gut, circulating fuels, stored fatty and glycogen). Dissimilar populations of hypothalamic cells stimulate or suppress food intake via projections to other brain areas, for example altering feeding behaviour. Animate being inquiry shows that the cell proliferation, migration, differentiation, growth and apoptosis required to make these projections can be contradistinct by the nutritional environment during fetal evolution [31]. Leptin and insulin, which are important fetal growth hormones and answer to fetal diet, are thought to regulate this hypothalamic evolution.

The above mechanisms would have to involve changes in gene expression, and there is neat involvement currently in effects of fetal diet on epigenetic phenomena, such as Dna methylation, that have a part in switching genes on and off. Patterns of DNA methylation are substantially established during embryogenesis and fetal development, and are sensitive to the nutritional environment. For example, maternal protein brake during pregnancy, which causes hypertension and increased adiposity in rat offspring, appears to human action, at least partially, through altered methylation and expression of specific genes involved in free energy and lipid metabolism [32]. Both the altered methylation and the later on abnormalities are prevented past supplementing the maternal diet with folic acid. Human data is limited, but epigenetic changes have been shown in newborns whose mothers took part in a randomised controlled trial of pre-conceptional multiple micronutrient supplements; in Gambian children conceived in the 'hungry' versus the 'harvest' flavor; and in adult offspring of women exposed to the Dutch famine [33]. Epigenetic variation in umbilical cord tissue has also been related to later outcomes such as childhood adiposity [34].

Epigenetic patterns can be inherited, which could explicate how transient alterations in fetal nutrition can change body composition and metabolic parameters beyond more one generation [29]. Epigenetic perturbations in a limited number of primal metabolic genes could besides explicate the striking phenomenon in animal models whereby widely differing nutritional interventions in the mother (from global nutrient restriction to loftier-fatty feeding) apparently result in the same 'metabolic syndrome' phenotype in the offspring [30]. Nutritional furnishings on epigenetic characteristics could produce the 'plasticity' of phenotype in early life that is inherent to the concept of fetal programming. Furthermore, this blazon of plasticity means that the programming of long-term outcomes may non crave major nutritional deficits during organogenesis and differentiation, but could result from short-lived and subtle changes in the nutritional environment at stages of development when nutrient demands for growth are still quite small, such as during the peri-conceptional catamenia and early on embryogenesis [23]. A farther intriguing aspect of epigenetic programming is that it could act through paternal besides as maternal nutrition. Offspring of male mice fed a depression-protein nutrition from weaning until sexual maturity had increased hepatic expression of genes involved in lipid and cholesterol biosynthesis [35]. In time to come nosotros may demand to consider the nutrition of fathers, as much as that of mothers, amidst the inter-generational determinants of health and disease.

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