Maternofetal interaction and modulation in creating a new population: a review of current evidence on the relationship between fetal nutrition and the development of chronic diseases later in life

The concept of fetal programming has found its place in science and keeps lighting the way to better understanding of fetal life and its impact on postnatal and adult life. Its capacity is much wider than a common recognition of the fact that different disorders in pregnancy impact fetal health, and these capacities keep being confirmed by various observational studies and experimental models. Another fact that makes fetal programming even harder to confirm and accept is the long period between the stimulus and its consequences, as well as various factors that can change and influence this period of one’s lifetime. Nevertheless, different hypotheses are present, concerning suboptimal fetal health and nutrition and their contribution to the development of chronic diseases during one’s lifetime - inadequate nutrition during intrauterine period and early childhood can permanently change one’s physiology and metabolism, which contributes to a possible development of chronic diseases (hypertension, coronary artery disease, stroke, diabetes, etc.). The aim of this paper is to review current evidence on the relationship between fetal nutrition and the risk of chronic diseases later in life.

A detailed review of current literature and the analysis of various studies aimed at following neonates to their adulthood in order to determine the significance of fetal programming.

An association between suboptimal fetal growth and a higher risk of metabolic syndrome, insulin resistance, diabetes type 2, and hypertension, has been proven by the studies conducted within different populations and age groups.

Based on the evidence presented in this paper, it can be concluded that fetal programming has been recognized as significant and is on the way to becoming the third contributing factor in the development of chronic diseases during one’s lifetime, along with a genetic predisposition and lifestyle.

INTRODUCTION

According to the fetal origins hypothesis, changes in fetal growth result in adaptations that determine vulnerability to cardiovascular, metabolic, and endocrine diseases during one’s lifetime. “Programming” is a phenomenon which implies long-term and irreversible alterations in metabolic structure and functions induced by short stimuli. During fetal development, changes in the milieu of nutrients and hormones of the conceptus during a critical period can alter fetal gene expression, which results in lasting effects on a group of physiological functions and structures. An important point of this definition is the fact that reprogramming can occur only during a certain window period when the person is sensitive. Programming reflects a general principle of developmental biology, and a large number of systems and organs can be determined by intrauterine development [1].

According to Barker’s early-origin hypothesis, suboptimal fetal growth and nutrition may lead to an increased risk of chronic diseases. According to this theory, in utero and early childhood “undernutrition” permanently alter physiology and metabolism leading to an increased predisposition to chronic diseases during one’s lifetime (hypertension, hyperlipidemia, obesity, diabetes, etc.), and it is also believed that the timing of dietary change during pregnancy is crucial. A small amount of nutrients during a critical period of fetal life may reduce fetal growth and permanently damage the development and functioning of the system leading to metabolic changes later in life such as reduced sensitivity to insulin [2] .The term “metabolic imprinting” rather than “programming” was used by Waterland and Garza to encompass adaptive responses to specific early nutrition [3]. Lucas emphasizes that fetal programming goes beyond resetting one’s metabolism, so he believes that “programming” is a more appropriate term than “imprinting”. This type of imprinting has a strong biological basis, and it involves temporary changes in DNA molecules that can expand their influence on several generations. Intergenerational effects, as observed in the offspring of individuals who had been exposed to starvation in utero, support the theory of genomic imprinting [4]. As Hales hypothesized, fetal condition may affect the residual functions of organs and the effects may occur not before midlife [5]. There is increasing evidence of a link between fetal growth and chronic diseases during one’s lifetime, and even if fetal programming did not support the theory of chronic diseases, it could represent an additional environmental risk that interacts with other determinants during life or modulates them. This could be an important policy that may have significant implications for the prevention of nutrition-related chronic diseases, especially in populations with high prevalence of low birth weight, which reflects poor maternal nutritional status. The aim of this paper is to review current evidence of the link between fetal nutrition and the risk of developing chronic diseases later in life, mechanisms and pathways based on epidemiological and experimental data, as well as to determine some of the implications for policies and strategies in developing countries. The focus is on fetal programming, but it is recognized that the process may extend into early postnatal life.

THE ROLE OF FETAL GLUCOCORTICOIDS

The role of fetal glucocorticoids and potential longterm consequences in a fetus that has been exposed to high concentrations for a long period of time are considered within fetal programming. Apart from stimulating cell differentiation and increasing the rate of organ maturation, primarily the lungs, the heart, kidneys and the immune system, fetal glucocorticoids coordinate various adaptation mechanisms required for the transition from intrauterine to extrauterine life. Physiologically, concentrations of glucocorticoids in a fetus increase before birth, as a sign of tissue maturation, whereas in pathological conditions the concentrations increase earlier during pregnancy due to placental insufficiency (fetoplacental stress) or due to a lack of a placental enzyme that protects the fetus from the mother’s glucocorticoids [6]. This enzyme (11 β-Hydroxysteroid dehydrogenase), which is responsible for maintaining a lower level of cortisol in the fetus in comparison with the mother (in physiological conditions), rapidly converts cortisol into its inert form. The significance of this enzyme has been recognized in studies conducted on both humans and animals, as its dysfunction also occurs in individuals with insulin resistance and possibly resulting metabolic syndrome due to high levels of glucocorticoids [7]. Consequently, an inverse correlation between plasma cortisol concentrations and infant birth weight was demonstrated in three different populations. The study that proved this also linked high cortisol levels to high blood pressure, although the correlation was stronger in obese individuals [8]. Taking into account that higher cortisol concentrations are found in adults who had low birth weight, it can be assumed that fetal nephrogenesis also plays a role in potentially high blood pressure values (considering that babies with low birth weight have fewer nephrons at birth) with lifelong effects on renal function and cardiovascular control. A study that dealt with this in more detail was conducted on rats and showed that the offspring of mothers who had low-protein diet during pregnancy could have higher blood pressure due to impaired fetal nephrogenesis [9]. Another study that supports this finding is the one conducted by Langley-Evans and colleagues which implies that the sequence of events from glucocorticoid action in the fetus to hypertension in adulthood includes the development of sensitivity to glucocorticoids in adults, with the activation of the renin-angiotensin system and increased sensitivity of blood vessels to angiotensin II, all with reference to maternal malnutrition [10]. Having this in mind, it has been concluded that glucocorticoids may diminish vascular development and program the renal renin-angiotensin system. An early transition from cell proliferation to cell differentiation due to elevated cortisol together with irregular growth pattern for a given developmental stage, may lead to consequences later in life, some of which are high blood pressure and hyperglycemia. Another reason why excessive fetal exposure to glucocorticoids is significant is the fact that in adulthood it may lead to insulin resistance and glucose intolerance through various mechanisms – by altering the expression of glucoregulatory genes in tissues (e.g., in skeletal muscles), by regulating cortisol-induced gluconeogenesis in the kidney and the liver, and possible changes in pancreatic beta cells are also mentioned [11],[12].

THE ROLE OF INSULIN-LIKE GROWTH FACTORS (IGFS)

Insulin-like growth factors (IGFs) are now known to be the main mediators of prenatal growth in people, and their generation in utero appears to be independent from growth hormone. The role of growth hormone, which brings about growth, is mainly related to the postnatal period, whereas IGFs have a primary role in the prenatal period. According to Gluckman, IGF-2 is dominant early in gestation (during embryonic development) when the placenta does not limit substrate availability, while later during gestation (during the fetal period), as well as in the perinatal period, IGF-1 is dominant being strictly controlled by nutrition [13]. Various studies claim that the bioavailability and the activity of IGFs can be altered whenever fetal growth is compromised. Cianfarani and colleagues, among others, have studied the possibility of postnatal catch-up growth for children born with intrauterine growth restriction (IUGR) – it is estimated that 20% of children born with IUGR do not experience postnatal catch-up growth. It has been shown that intrauterine reprogramming of the hypothalamic-pituitary-adrenal axis can lead to a permanent modification of the neuroendocrine stress response and that children who had elevated cortisol level may be less likely to catch up postnatally. It is hypothesized that during the neonatal period cortisol limits proteolysis of IGF-binding protein-3 (IGFBP3) and thereby reduces the bioavailability of IGF [14]. Low levels of IGF-1 were also observed in children who were small for gestational age (SGA) but who did not experience catch-up growth and remained short (in comparison with children of normal and short stature who had had an adequate size for gestational age at birth). Low levels of IGFBP3 were also observed in these children and its proteolysis was believed to be the reason. A reduced rate and an abnormal pattern of growth hormone secretion were also present, suggesting that an ever-present defect in the growth hormone-IGF-1 axis may occur in those SGA children who do not catch up postnatally [15]. According to the “catch-up” growth hypothesis proposed by Cianfarani, Germani and Branca, tissues use up insulin and IGF-1 during fetal life, when there is a lack of substrate as IGF-1 is turned off. After birth, when both hormones are abundantly present, and due to an adequate supply of nutrients, it is assumed that insulin resistance develops a defense mechanism against hypoglycemia. Excessive activation of the IGF system determines early postnatal compensatory growth, but it also leads to insulin resistance as a metabolic adaptation with potentially harmful long-term effects [16].

THE IMPACT OF NUTRITION

The concept of programming is much wider than a common recognition of the fact that conditions in pregnancy influence fetal health. What makes the hypothesis of fetal programming even more difficult to confirm or accept is the fact that the period between the stimulus and its consequences is rather long, then numerous factors that may alter this link during life, as well as the possibility that reduced fetal growth and chronic diseases are not linked but have a common origin, such as low socioeconomic status or a genetic predisposition. Nevertheless, fetal programming hypothesis is gaining ground as evidence from observational studies and especially experimental models accumulates.

Data on the effects of maternal nutrition on the size and proportions at birth are rather limited. Data on the intake of micronutrients from food and supplements in pregnancy are still scarce, and the timing of inadequate nutrition or supplementation should be considered, along with the type of nutrients and maternal condition. Several micronutrients appear to be crucial for fetal growth and possibly for fetal programming, although the mechanisms remain unclear. Based on existing evidence, vitamins B2, B6, B12 as well as folic acid, through DNA methylation, affect the fetal genome and are thus part of fetal programming. Vitamin A, iron, chromium, zinc, and vitamin C probably also play an important role in fetal programming, but further research is needed concerning their significance [17]. Even fewer studies link maternal nutrition to the child’s body measurements except for weight and size at birth. In Southern England, a prospective study which included 693 primiparous singleton women showed that placental weight and full-term birth weight were not associated with the intake of any micronutrient. In the second trimester, vitamin C was the only micronutrient that independently correlated with birth weight, considering maternal height and possible tobacco consumption. Vitamin C, Vitamin E and folic acid were all associated with placental weight after adjusting for maternal characteristics, but only vitamin C remained predictive in simultaneous regression, although the correlation was weak [18]. Nowadays it is necessary to emphasize the impact of the environment and the quality of food consumed on one’s life. With respect to this, it has been shown that the intake of food rich in pesticides (prenatally or postnatally) can lead to puberty disorders (pesticides affect the onset, progression, and completion of puberty), considering that they act as substances than can alter the functions of the endocrine system (endocrine disrupting chemicals - EDCs) [19]. Studies have shown a positive correlation between EDC exposures and pregnancy complications (ectopic pregnancies, miscarriages, gestational diabetes mellitus, hypertension in pregnancy, premature birth), as well as children born with IUGR, small for gestational age or large for gestational age [20]. It is also important to mention maternal predictors. Based on a large body of evidence, the main maternal anthropometric predictors of birth weight appear to be their weight (the strongest correlation), height, mid-upper arm circumference, and BMI. A study conducted by Mohanty and colleagues grouped these parameters in women by color, and it is considered that women whose parameters are in “the red zone” are more likely to give birth to children with low body weight [21]. Besides, maternal anthropometric parameters can be taken into account in early pregnancy and when predicting gestational diabetes mellitus, which has also been researched [22].

TENDENCY TO METABOLIC SYNDROME

The strongest correlation between birth weight and chronic diseases later in life is probably observed through the development of metabolic syndrome (syndrome X), including the occurrence of high blood pressure, hypertriglyceridemia, often obesity, as well as insulin resistance and diabetes. The significance of the potential development of diabetes in later life is emphasized as there is an increasing trend in its prevalence in adults (including women) because of a potential pregnancy burdened by this comorbidity. The prevalence of pregestational diabetes in pregnant women has increased in the past decade in Belgrade and it is expected to continue rising, and even to double by 2050 [23]. Also, it has been shown that women with type 1 diabetes have an increased risk of pregnancy complications and unfavorable neonatal outcomes compared to those with type 2 diabetes or gestational diabetes mellitus [24]. As shown in numerous studies, maternal undernutrition in critical periods of fetal development is associated with fetal programming towards obesity, insulin resistance, metabolic syndrome, and type 2 diabetes in later life, especially if these children have a more complex diet postnatally. Adipogenesis, which begins in utero and is accelerated in neonatal period, is most responsible for this [25]. According to the previously mentioned Hales’ theory, maternal undernutrition during the critical periods in fetal development leads to compensatory changes in the fetus including its ability to store adipose tissue, which contributes to the development of central obesity later in life when there is a mismatch between predicted and actual postnatal nutrition [5]. It has been shown that a higher risk of abdominal obesity and a higher percentage of body fat correlate with low birth weight, which was also confirmed by Jaquet and colleagues, among others, in a study that included 25-year-old men and women. They concluded that insulin-stimulated glucose uptake was reduced in children with IUGR with diminished suppression of free fatty acids in adipose tissue. This suggests that adipose tissue plays a role in insulin resistance of children with IUGR as well as that reduced fetal growth probably leads to an increased level of fat in the liver during life with no significant changes in body fat [26]. They also believe that children with IUGR in first years of life, as part of their growth compensation, have higher concentrations of leptin, but that it loses its effect on BMI and gender (this is considered to be the result of adaptive resistance to leptin which is in accordance with their attempt to catch up) [27]. Furthermore, a systematic review and meta-analysis of children with low birth weight (LBW and SGA) and potential development of type 2 diabetes in adulthood showed that these children were 2.3 times more likely to develop type 2 diabetes and that they had a higher risk of insulin resistance as such [28]. These children have also been shown to develop resistance to growth hormone and IGF-1 in first days of life as part of their insulin resistance, so the authors believe that this could account for their difficulties in catching up during their childhood and for a greater tendency to metabolic syndrome later in life [29]. In Australia, Flanagan and colleagues observed that short birth length alone, not thinness, correlated with insulin resistance and that this was so only in men. They examined insulin sensitivity and insulin secretion in relation to body size at birth in 20-year-old men and women born at term, by using the intravenous glucose tolerance test wih minimal glucose loss. It was shown that small size at birth (only in men in this particular study) was associated with an increased risk of insulin resistance and hyperinsulinemia, regardless of their body mass or body fat percentage, so it is assumed that glucose tolerance decreases with age in people who were born small for gestational age owing to insufficiency of compensatory mechanisms [30]. In a Hertfordshire meta-analysis, it was shown that birth weight correlated with the rate of type 2 diabetes and chronic diseases in later life in a J curve and that it was more pronounced in female children [31]. Also, an earlier Hertfordshire cohort study examined mortality outcomes in adults who had had low birth weight and it was shown that men were more likely to die from cardiovascular disease and accidental falls, whereas women were more prone to cardiovascular disease, musculoskeletal disorders, pneumonia, and diabetes. What presents the ever-increasing significance of low birth weight and what this cohort study proved is the fact that a one-standard-deviation increase in birth weight reduced all-cause mortality rate by age 75 by 0.86% in the entire population [32]. In Finland, a study including 7086 individuals with low birth weight showed a cumulative incidence of 7.9% for men and 5.4% for women and the incidence increased as body weight, length, fetal ponderal index, and placental weight decreased. It was also noted that offspring of mothers who had had high BMI in pregnancy experienced accelerated growth during childhood and thus had a higher incidence of type 2 diabetes [33]. A cohort study conducted in India showed that the components of insulin resistance were “programmed” in utero, as well as that they may become visible as early as childhood. In the group of almost 400 children aged 4, those who weighed ≥ 2.5 kg at birth had significantly higher plasma insulin concentration 30 minutes after glucose intake regardless of the current body size. Plasma glucose and insulin were independently and reversely related to birth weight, although the current weight and skinfold thickness were positively related to glucose and insulin. At the age of 8, low birth weight in all children was associated with a group of disorders within insulin resistance, although the current weight was a strong predictor as well [34]. Similarly, in a study conducted in South Africa, in children aged 7 a negative correlation between birth weight and insulin secretion or blood glucose was noted upon the oral glucose tolerance test. There was a negative correlation between length at birth and insulin resistance as well. Children who were small for gestational age and experienced intense growth by the age of 7 more often developed insulin resistance compared to children who remained small [35]. This correlation was confirmed in Sweden where Carlsson and colleagues discovered that men whose birth weight was below 3 kg and who had a family history of diabetes were ten times more likely to develop diabetes compared to those whose birth weight was higher (the risk for those with a positive family history was 5.4, whereas for those without a family history it was 2.3). The effects of weight gain were greater in those whose length or weight during the first year of life were low [36]. Even in the Pima Indians, who have a high prevalence of type 2 diabetes, a positive correlation between low birth weight and insulin resistance later in life has been noted. It has been shown that children with low birth weight are thinner in the period between ages 5 and 29 but have more pronounced insulin resistance (indicated by the 2-hour plasma glucose level) compared to children with normal body weight. Children who had high birth weight were more overweight in this period of their lives, but their insulin resistance was less pronounced than what would be expected according to their obesity. There was a positive correlation between birth weight and the current weight and height, adjusted for age and sex, in all examined age groups [37]. Also, a potential link between birth weight and the development of diabetes before the age of 40 was studied in the Pima Indians. In this high-risk population, both low and high birth weight were associated with the development of diabetes in the period of adolescence (between ages 10 and 19), but only low birth weight was associated with the development of this disease in early life (between ages 20 and 39) [38].

TENDENCY TO CARDIOVASCULAR DISEASE

A negative correlation between birth weight and blood pressure, especially systolic blood pressure, has been found in all age groups, within cohort, retrospective, and longitudinal studies, in industrial countries and developing countries. Law and Shiell reviewed 34 studies (25 cohort studies, 4 case-control or comparative studies, and 5 longitudinal studies) which described the relationship between blood pressure and birth weight quantitatively and in non-pathological subjects and which included 66.000 individuals. Almost all of them noted a negative correlation, except for a few exceptions with newborns and adolescents. Around half of all studies used multiple regression analysis, and all adjusted for current weight, which was considered the most important confounding variable. Blood pressure typically declined in the range of 2 to 3 mm Hg per kilo of body weight gain. Only in one study involving adolescents in Israel, and only in girls, was there a positive correlation between birth weight and blood pressure [39]. An inverse correlation between size at birth (weight, length, or fetal ponderal index) and cardiovascular disease, hypertension, type 2 diabetes, and insulin resistance syndrome was observed in all continents. Potential confounding factors include sex, age, current body size, as well as socioeconomic status, but they are all adjusted in studies. A negative correlation between fetal growth and markers for cardiovascular risk and insulin resistance was observed in children and adolescents [40]. In another previous cohort study with male subjects, Sheffield, Barker and colleagues confirmed that an increased risk of chronic diseases was associated with fetal growth retardation, as well as an inverse correlation between fetal ponderal index at birth and chronic disease mortality. These cohorts showed that stroke deaths were associated with low birth weight, as well as with low birth weight in male babies [41]. A study that included men born between 1924 and 1933 in Helsinki, revealed that chronic disease (CHD) mortality rate was higher in those who had had low ponderal index (PI) and small birth weight but who had caught up by the age of 7. This showed that poor fetal nutrition followed by improved nutrition postnatally may further increase the risk of CHD. As the initial measurements were made at the age of 7, it was possible to assess childhood growth and examine the relationship with CHD, adjusted for body weight. The highest risk of death due to cardiovascular disease (5.3) was found in individuals who had the lowest PI at birth combined with the highest BMI in the period between ages 7 and 11. This is compared with the risk of 1.2 in those who had high BMI in childhood but were not small for gestational age. The fact that the risk is higher if birth weight was low is explained by the harmful action of rapid postnatal weight gain or by changed body structure later in life due to fetal programming. Another possibility is that rapid growth is associated with cardiovascular disease through induced changes in GH-IGF-1 axis [42]. The main potential confounding variables of negative correlation between blood pressure and birth weight are the current body size and socioeconomic status in most chronic diseases, as well as gestational age at birth and maternal blood pressure, during pregnancy and outside pregnancy. Walker and colleagues found a negative correlation between birth weight and blood pressure in young adults aged 16 to 26 years. After correction for maternal blood pressure 9 to 19 years postpartum (where maternal blood pressure correlated positively with blood pressure of the offspring and negatively with their weight), a negative correlation was weaker, which implies the inherited predisposition to hypertension as a confounding variable to LBW [43]. Other numerous studies have supported this trend. In a study conducted in Japan in 3-year-old children, systolic blood pressure corelated positively with maternal systolic pressure during pregnancy, while there was a negative correlation to birth weight [44]. The study conducted by Bonamy and colleagues showed that children born with SGA were 54% more likely to develop hypertension later in life compared to children who had adequate weight for gestational age [45]. In a meta-analysis of 1571 adults born with very small birth weight (<1500g) compared to 777 controls it was shown that children who had been born with very low birth weight had 3.4 mm Hg higher systolic blood pressure and 2.1 mm Hg higher diastolic blood pressure. The only perinatal event associated with high blood pressure was maternal pre-eclampsia [46]. The significance of elevated blood pressure and its adequate control is reflected in the data showing that the reduction of systolic blood pressure by 2 mm Hg reduced population-level mortality from ischemic heart disease by 7% to 14% and from stroke by 9% to 19% [45]. It has also been emphasized that in children who had low birth weight (who were either born prematurely or were small for gestational age) breastfeeding has proved to be a protective factor for the development of arterial hypertension. There was lower prevalence of hypertension in children who weighed less than 2500g and were breastfed. It has been shown that both breastfeeding and avoiding rapid weight gain in childhood can reduce the risk of obesity, dyslipidemia, and glucose intolerance [46].

CONCLUSION

1. Based on the evidence presented, it can be concluded that fetal programming has been recognized as significant and is on its way to becoming the third contributing factor in the development of chronic diseases during life, together with a genetic predisposition and lifestyle. However, there are large gaps, especially in the field of programming, the role of maternal nutrition in the specific period, the assessment of fetal (and placental) growth, and effective measures for reducing the risk in children who have experienced growth retardation.
2. The fact that children who had low birth weight have a higher risk of chronic diseases in adulthood when growing rapidly in childhood and especially if they become obese, is a special implication for programs. In this regard, it has been concluded that children with low birth weight should be the target population for the promotion of healthy diet and obesity prevention, especially through the education system.
3. Further incentives to improve maternal nutrition are emphasized – unlike genetic theories, fetal programming of most common chronic diseases of adulthood justifies, if necessary, focusing on optimal fetal growth and development. Long-term consequences of fetal malnutrition represent an additional argument towards focusing more attention on the nutrition of young girls and women, preferably before pregnancy, or during pregnancy. The importance of the environmental influence and the quality of food consumed are also emphasized due to the potentially harmful effect of the substances that may alter the functions of the endocrine system (EDCs) to the course of pregnancy, with further short-term and long-term consequences to neonates. Indeed, prevention of fetal growth restriction could improve child survival and development, as well as contribute to reducing the risk of chronic diseases, especially obesity, diabetes, and other chronic diseases which have reached epidemic proportions worldwide. Certainly, the prevention of chronic diseases through lifestyle and adequate nutrition can be a huge challenge in countries where malnutrition in mothers and children is high.
4. There is a serious need to better assess the further impact of fetal growth restriction in developing countries and populations in transition. Further research of various aspects of the early origin of disease must fit into appropriate healthcare policy.