Fetal development and risk of cardiovascular diseases and diabetes type 2 in adult life
Rozwój płodu a ryzyko chorób sercowo-naczyniowych i cukrzycy typu 2 w wieku dorosłym
Dorota Szostak-Wegierek1, Katarzyna Szamotulska2,
1Department of Preventive Medicine and Hygiene, Medical University of Warsaw, Poland
Head: prof. dr hab. med. L. Kłosiewicz-Latoszek
2Department of Epidemiology, Institute of Mother and Child,, Warsaw, Poland
Head: dr n. med. K. Szamotulska
Director: S. Janus
The fetal origin hypothesis of adult cardiovascular diseases, type 2 diabetes, hypertension and dyslipidemia in persons born with low birthweight, independently of their extrauterine risk factors, has been well established in the last decade of the twentieth century. However, mechanisms responsible for this relationship are still under investigation. Insulin resistance resulting from the restriction of intrauterine development of skeletal muscles and other organs is considered as the most important cause of metabolic disturbances and their cardiovascular complications in adult subjects born with intrauterine growth retardation (IUGR). Decline of insulin secretion, overactivation of the hypothalamo-pituitary-adrenal axis, reduced glucose uptake in the liver and raised lipid oxidation in the muscles may also explain this association. On the other hand, abnormal vascular development , increased activity of the sympathetic nervous system, defective endothelial function and/or impaired renal function in growth restricted newborns may contribute to hypertension in their later life. With respect to maternal conditions and life-style factors that may increase cardiovascular risk in adult offspring born with IUGR, the most consistent results concern pregnancy induced hypertension, preeclampsia, undernutrition, smoking during pregnancy, hypercholesterolemia, inflammation and/or enhanced glucocorticoid secretion. Macrosomia of the newborn, a frequent sequel to maternal diabetes and/or obesity, also increases the risk of diabetes and cardiovascular diseases in adulthood. Maternal overnutrition, and particularly high fat and sugar intake, seem to play a key role in fetal programming of cardiovascular risk in subjects born with macrosomia. Epigenetic imprinting underlies the described pathomechanisms. The presented associations are illustrated, among others, with the results of studies performed by the authors of this review.
Key words: low birthweight, IUGR, macrosomia, maternal nutrition, cardiovascular risk, hypertension risk, diabetes type 2 risk
W ostatniej dekadzie dwudziestego wieku powstała koncepcja dotyczšca wewnštrzmacicznego programowania ryzyka chorób układu sercowo-naczyniowego, cukrzycy typu 2, nadcinienia i dyslipidemii u osób urodzonych z małš masš ciała, zwłaszcza z wewnštrzmacicznym zahamowaniem wzrastania płodu (IUGR). Stanowi to stan zagrożenia, niezależnie od działania w póniejszym okresie życia innych czynników ryzyka. Obecnie prowadzone sš szeroko zakrojone prace nad mechanizmami, które odpowiadajš za wystšpienie tego typu ryzyka. Jako najczęstszš przyczynę zaburzeń metabolicznych prowadzšcych do powikłań sercowo-naczyniowych w wieku dorosłym uważa się opornoć na insulinę zwišzanš z wewnštrzmacicznym niedorozwojem mięni szkieletowych a także innych narzšdów. Zwraca się uwagę na obniżone wydzielanie insuliny, podwyższonš aktywnoć osi podwzgórze-przysadka- nadnercza, zmniejszony wštrobowy wychwyt glukozy i nasilony proces oksydacji lipidów. W powstawaniu nadcinienia w póniejszym okresie życia rolę odgrywać może także nieprawidłowy rozwój naczyń, zwiększona aktywnoć współczulnego układu nerwowego, upoledzenie funkcji ródbłonka, a także zaburzenie funkcji nerek. Do matczynych czynników działajšcych na płód, mogšcych sprzyjać rozwojowi chorób sercowo-naczyniowych u dorosłych potomków urodzonych z IUGR, należy także nadcinienie indukowane cišżš, stan przedrzucawkowy, niedożywienie, palenie papierosów w czasie cišży, hipercholesterolemia, stany zapalne i nadmierne wydzielanie glikortykoidów. Ryzyko wystšpienia cukrzycy i chorób sercowo-naczyniowych w wieku dorosłym może być zwiększone także u osób urodzonych z makrosomiš, która jest częstym następstwem cukrzycy i/lub otyłoci u matki. Nadmierne odżywianie się matki, a zwłaszcza wysokie spożycie tłuszczu i cukru, wydaje się odgrywać kluczowš rolę w programowaniu ryzyka chorób sercowo-naczyniowych u osób urodzonych z nadmiernš masš ciała. U podstaw opisanych zwišzków leżš mechanizmy epigenetyczne. Przedstawione w pracy powišzania, zostały zilustrowane wynikami badań, w tym także badań prowadzonych przez autorów opracowania.
Słowa kluczowe: mała masa urodzeniowa, wewnatrzmaciczne zahamowanie wzrastania płodu (IUGR), makrosomia, zywienie matki, ryzyko sercowo-naczyniowe, ryzyko nadcisnienia, ryzyko cukrzycy typu 2
Conditions of development during fetal period of life may have a great impact on health not only in infancy and childhood, but also in adult life. It concerns mainly the risk of type 2 diabetes, arterial hypertension, dyslipidemia and cardiovascular diseases (1, 2). The concept of the relationship between impaired fetal development and accelerated progression of atherosclerosis was created in the late 80-ties of the twentieth century by DJP Barker. He had shown that the regions of the Great Britain where in the beginning of the last century high infant mortality was observed, several decades later were characterized by high cardiovascular mortality (3). As in some areas of England and Wales obstetrical documentation at the beginning of the twentieth century still available, Barker and coworkers decided to perform research aiming at investigation of the relationship between low birthweight, a marker of fetal undernutrition, and later metabolic and cardiovascular risk. They invited, in the series of studies, the subjects whose birthweight were known. In the cases who had died earlier, the data on the causes of death were collected. It was shown that those who were born with low birthweight had higher risk of cardiovascular death (4). They also developed arterial hypertension, type 2 diabetes, hypercholesterolemia, dyslipidemia, and metabolic syndrome more often than those who were born with normal birthweight (5, 6, 7, 8). It was proposed that intrauterine growth retardation (IUGR), which may result among other factors from maternal malnutrition, markedly increases metabolic and cardiovascular risks. Barkers observation was later supported by himself and other investigators. The literature of this topic consists of several hundreds of scientific papers and several books. For example, it was demonstrated that every 1-kg increase in birthweight was associated with the reduction of coronary heart disease risk of about 20% (9), about 2 mm Hg lower systolic blood pressure (10) and decrease in markers of impaired carbohydrate metabolism (11). In the recent years the intima-media thickness (IMT) measurement that enables to detect early stages of atherosclerosis, has been used in the research of the relationship between intrauterine growth retardation (IUGR) and the risk of the artery disease. A number of studies using carotid IMT measurements support the concept that in subjects born small for gestational age (SGA), progression of atherosclerosis may be more pronounced than in those born with normal birthweight (12, 13).
IUGR and metabolic disturbances in adult life
The mechanisms underlying the relationship between intrauterine growth retardation (IUGR) and the later increased cardiovascular risk have been investigated by many researchers. Insulin resistance was found to be one of the most important disorders linking fetal hypotrophy with the later metabolic risk. It was shown in a number of studies that SGA subjects develop this condition more often than those whose birthweight was appropriate for gestational age (AGA) (14). It concerns especially those who became overweight in later life. Also in our study (15), that was performed in males aged 24-29 years born at term, a weak but significant inverse relationship between bithweight and insulin resistance, measured by HOMA-IR (r=-0.164, p<0.05) was revealed. We demonstrated that adult males who had higher HOMA-IR, in comparison with those with lower value if this index (=>3.00 vs <3.00), had been born with significantly lower mean birthweight (3184ą511 vs 3457ą572, p=0.012). However, insulin resistance is not the only mechanism that may be responsible for carbohydrate metabolism disturbances and subsequent increased risk of type 2 diabetes in subjects born with low birthweight. It was shown in animal models that intrauterine growth retardation may be followed by the decrease in beta-cells mass and decline of insulin secretion in adult life (16, 17). The enhanced risk of metabolic syndrome development in subjects born with IUGR may be also related to the overactivation of the hypothalamo.pituitary.adrenal (HPA) axis (17). Increased cortisol release may contribute to the central fat distribution, insulin resistance and metabolic syndrome (18, 19). Some authors attempt to explain the physiological sense of the relationship between fetal growth retardation, insulin resistance and/or decreased insulin production. As insulin is a growth factor during fetal life, the decrease in its action leads to the restriction of development of such organs as skeletal muscles, pancreas or kidneys. This in turn enables redistribution of important nutrients for the needs of development of the key body parts, such as the brain. This mechanism seems to be particularly important under the condition of inadequate food supply during pregnancy or in the case of placental insufficiency (20). As inadequate intrauterine nutrient supply brings information of adverse life conditions in the extrauterine environment, it may enable to reprogramme metabolic pathways of the growing conceptus to prepare it to the shortage of food in later life. Forming the thrifty phenotype, that is beneficial under scarcity conditions, is usually detrimental in the case of eventual later abundance and may result in obesity and metabolic syndrome (17). It was shown that IUGR subjects are of increased risk of obesity in their adult life. One of the possible explanations of this phenomenon is decreased lean body mass, resulting from insulin resistance, that is followed by the decreased basal metabolic rate. This in turn enables to spare energy and may contribute to overweight and obesity (21). As far as overweight and obesity in adult life enhances the relationship between fetal growth restriction and cardiovascular risk factors in adult life, including metabolic disturbances, some investigators studied the trajectories of growth during infancy and childhood of persons born with IUGR. It appeared, that fetal growth restricted babies experience the catch-up growth during first years of life (22), which has been interpreted as a permanent liberation - in extrauterine life - from maternal constraints during pregnancy and was confirmed in experimental animal studies (23). The existence of catch-up growth phenomenon leads some authors to the negation of the causal relationship between birth weight and cardiovascular risk factors in adult life, promoting as a main explanatory mechanism rapid growth in early childhood that favours adiposity. Fetal undernutrition may affect also other organs and tissues. In the liver it may reduce glucose uptake and increase gluconeogenesis. In the muscles, except for the adverse influence on insulin sensitivity, it may raise lipid oxidation. In the adipose tissue fetal malnutrition may reduce insulin inhibition of lipolysis. All the described metabolic disturbances may enhance the risk of type 2 diabetes (17).
IUGR and hypertension in adult life
The processes discussed above, that are responsible for development of the metabolic syndrome, are not the only disturbances that may explain the increased cardiovascular risk in adult IUGR subjects. Also other classic risk factors, such as lipid disorders that may be a consequence of the liver dysfunction, and arterial hypertension should be considered (17). Among mechanisms that may take part in the development of hypertension in IUGR subjects there are: abnormal vascular development, increased activity of the sympathetic nervous system and defective endothelial function, resulting probably from the decreased nitric oxide activity. There is a growing body of evidence that also renal mechanisms may play an important role in the pathogenesis of hypertension. Low birthweight is often accompanied by the reduced number of nephrons and raise of the rennin-angiotensin-aldosterone system activity. Some authors also discuss the possible role of the decreased conversion of cortisol to inactive cortisone in the distal tubule cells. This in turn is followed by the enhanced activation of mineralocorticoid receptors by cortisol (17, 24). It was also demonstrated that low birthweight may be related to altered baroreflex activity, that also contributes to hypertension (25).
Properties of arteries in persons born as IUGR infants and with atherosclerosis in adult life
It should be emphasized that also non classic risk factors should be taken into consideration as the possible explanation of the influence of intrauterine growth retardation on the cardiovascular risk. Martyn et al. (12) showed a strong inverse relationship between birthweight and the risk of carotid atherosclerosis in elderly subjects. The association persisted after adjustment for classic cardiovascular risk factors and gestational age at birth. Also our study (26) supported this observation. In this investigation, performed in young males aged 27-32 years, in those with higher CIMT (carotid intima media thickness) value (>0.6 mm vs =<0.6 mm) we showed higher intensity of classic risk factors, such as lower mean concentration of HDLcholesterol (1.19ą0.27 vs 1.36ą0.33 mmol/l, p=0.012), higher TC/HDL ratio (4.36ą1.40 vs 3.71ą1.04, p=0.009), higher fasting glucose level (5.48ą0.42 vs 5.28ą0.44 mmol/l, p=0.045), and higher HbA1c% (5.63ą0.54 vs 5.40ą0.50, p=0.044). Also metabolic syndrome was significantly more common in this group (43.3% vs 22.5%, p=0.031). Subjects with higher CIMT were born with significantly lower mean birthweight (3224 ą539 vs 3556 ą430 g, p=0.001). It should be stressed that the relationship between birthweight and CIMT value persisted after adjustment for current adiposity measurements, classic risk factors and the presence of metabolic syndrome. In conclusion, it seems that there are some other than "classic" mechanisms that may account for the influence of fetal growth retardation on atherosclerosis development. Among the potential "non classic" mechanisms that may explain the existing relationship between IUGR and the atherosclerosis risk there are: altered artery structure, endothelial dysfunction, enhanced inflammation processes intensity, and also increased oxidative stress. Burkhardt et al (27) showed that umbilical arteries of newborns with IUGR were thinner, stiffer and narrower than those whose birthweights were appropriate for gestational age. Also in a study that was performed in children of about 8 years of age (28) it was shown that IUGR was related to the increased abdominal aortic stiffness. Similarly, in 50-year-old adults it was found that lower birthweight was associated with reduced arterial compliance (29). Other authors (30) observed that IUGR was associated with narrower retinal arteriolar caliber. It should be emphasized that this preclinical condition is regarded to be related to endothelial dysfunction. It was also demonstrated in a number of studies that subjects born with IUGR were often characterized by endothelial dysfunction (31, 32, 33, 34). In children and adolescents it was also shown that lower birthweight was related to chronic low-grade inflammation (35). The results of the ARIC study demonstrated that IUGR was associated with enhanced inflammation and endothelial activation in adult life (36). Oxidative stress seems to play a particularly important role in programming endothelial dysfunction and may contribute to atherosclerosis. It was postulated that it may modulate gene expression (37). It was demonstrated that IUGR infants were characterized by increased oxidative stress in comparison with those born with normal weight (38). It was also shown that in newborns with IUGR levels of antioxidants and antioxidant enzyme activity were reduced and lipid peroxidation was augmented (39).
Oxidative stress accompany a number of conditions, such as preeclampsia, gestational hypertension, gestational diabetes, smoking, hypercholesterolemia, infections and inflammation, and malnutrition (37). Most of these disorders may result in IUGR.
Maternal factors in development of risk of cardiovascular diseases in adult life
Pregnancy - induced hypertension and preeclampsia
Preeclampsia is a complex, multifactoral disease which influences the mother and the placenta by vascular dysfunction and induces IUGR in the fetus. Although the cause of the condition remains largely unknown, the predisposing factors are poor placentation and maternal cardiovascular and metabolic syndrome-like disorders leading to placental and systemic inflammation and oxidative stress. The relationship between maternal pregnancy induced hypertension or preeclampsia and SBP=>140 mm Hg in the non-low birthweight offspring aged 29-41 years was observed by Mogren et al. (40) who presented odds ratio of 1.43 (95% CI: 1.04-1.97) in a cohort of nearly 8 thousand Swedes. Also Vatten et al. in their study of over 4 thousand Norwegian girls aged 13-19 years demonstrated 3 mmHg higher systolic blood pressure in daughters of preeclamptic mothers in comparison to daughters of non-preeclamptic mothers (41). On the other hand, in the British cohort of subjects born in 1958, maternal preeclampsia was independently related to glycosylated hemoglobin =>6% at age 45 years with OR of 1.65 (95% CI: 1.02-2.69) (42). In our study of young adults aged 24-29 years, maternal preeclampsia (defined according to the standards of the 70-ties of the last century that included oedema) was significantly associated with insulin resistance index in men, and not significantly - in women. In male offspring of preeclamptic mothers HOMA-IR index adjusted for current body mass index was 2.6, and in male progeny of non-preeclamptic mothers - 2.1 (p=0.041). In female offspring it was - 1.8 and 1.5 (p=NS), respectively (43). Among the risk factors of preeclampsia there are: maternal obesity, diabetes, chronic hypertension, and also hypertriglyceridemia. It was found that hypertiglyceridemia in early pregnancy may predict preeclampsia in the later period of gestation. The risk of early onset preeclampsia (before 36th week of pregnancy) was five times higher in pregnant women with serum TG level exceeding 2.4 mmol/l in 18th week of pregnancy, than in those with serum TG level lower than 1.5 mmol/l (44). Enhancement of preeclampsia risk is probably mediated by pathology of placental vessels that may be induced by hypertriglyceridemia. The vascular changes include chronic inflammation, hypercoagulability, and endothelial dysfunction (45).
Maternal smoking during pregnancy
The possible influence of increased prooxidative stress during pregnancy on the risk of atherosclerosis in the offspring may be observed also in the case of maternal smoking during pregnancy. In the group of young male subjects we found that maternal smoking was related to higher value of CIMT in the offspring (46). The described effect remained significant after controlling for the current presence of metabolic syndrome (OR 3.71, 95% CI:1.49-9.26). This observation is in accordance with the study performed by Gunes et al. who had shown that the mean value of aortic IMT (intima media thickness) was significantly bigger in the neonates whose mothers smoked during pregnancy than in the control group (47).
Increased oxidative stress may be also induced by maternal hypercholesterolemia. This maternal condition was postulated to increase the risk of atherosclerosis in the offspring (45). Napoli et al. (48, 49) observed the accelerated progression of atherosclerosis in the progeny of hypercholesterolemic mothers. It concerned also the cases of normocholesterolemia in children. In animal models it was demonstrated that this consequence of maternal hypercholesterolemia may be prevented by both hypolipemic treatment or by supplementation with antioxidants during pregnancy (50). Hence, it was suggested that the detrimental effect of maternal hypercholesterolemia may be mediated by oxidative processes. In a human study Liguori et al (51) demonstrated a relationship between maternal inflammation, that is a common cause of enhanced oxidation, and the development of atherosclerosis lesions in the offspring. It was proposed that the increased susceptibility to atherogenesis in the progeny of hypercholesterolemic mothers, probably mediated by inflammation and oxidative stress, may be related to epigenetic regulation of activity of specific genes involved in immune responses and also in fatty acids metabolism. It seems that these changes may stimulate proatherogenic processes in the fetal arteries. It is assumed that the described alterations persist to adult life and may determine enhanced response to classic risk factors (50, 52).
Maternal inflammation processes are also a possible factor that may accelerate atherosclerosis processes in the offspring. High levels of cytokines circulating in maternal blood seem to affect the placenta. This in turn may influence cytokine expression in the fetus. It seems that maternal inflammatory stress may influence expression of fetal genes that are related to inflammatory processes. The epigenetic changes resulting in stimulation of proinflammation activity may probably persist to adult life (52). It was shown that maternal C-reactive protein (CRP) level during pregnancy may be related to the extent of aortic atherosclerosis in their offspring (51). Labayen et al. demonstrated that lower birthweight was related to chronic low-grade inflammation in childhood and adolescence measured by fibrinogen and C4 levels (35). These results suggest the potential role of inflammation processes in enhancing the risk of atherosclerosis in IUGR subjects.
Maternal stress and enhanced glucocorticoid secretion
Some authors also discuss the possible role of maternal stress and enhanced glucocorticoid secretion in the development of insulin resistance, glucose intolerance, hypertension, and atherosclerosis in the offspring (53). Prenatal exposure to glucocorticoids or stress may result in impaired intrauterine growth that in turn may be associated with impaired glucose metabolism, raised cardiovascular risk, and increased activity of HPA axis. Maternal glucocorticoids mediate the effect of maternal stress or dietary protein restriction on the risk of hypertension in the progeny. Elevated levels of these hormones in late pregnancy may permanently dysregulate expression of glucocorticoid-sensitive genes in peripheral tissues. In rats intrauterine exposure to glucocorticoids or undernutrition may upregulate the hepatic glucocorticoid receptor (GR) which in turn is probably responsible for the increase of the activity of phosphoenolypyruvate carboxykinase (PEPCK), the key enzyme that takes part in gluconeogenesis. Increased activity of GR may contribute to programming of insulin resistance and glucose intolerance. It is suggested that a reduction in hippocampal GR may affect glucocorticoid negative feedback and lead to HPA axis hyperactivity (53, 54). Physiologically, the fetus is protected against elevated maternal cortisol levels due to its inactivation by the placental enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). The decline of its activity may result in the increased cortisol transplacental passage which in turn may reduce fetal growth. It was shown that inhibition of 11ß-HSD2 may cause the decrease in birthweight and subsequent hypertension, impaired glucose tolerance, and HPA hyperactivity in later life. Maternal stress, low protein diet, proinflammatory cytokines, and hypoxia may decrease 11ß-HSD2 activity (54). Reduced 11ß-HSD2 expression and activity has been observed in preeclampsia as well (55). Human placenta produces also corticotropin-releasing hormone (CRH). Increased CRH levels may contribute to IUGR and prematurity. Placental CRH secretion is stimulated by glucocorticoids. Thus maternal stress is characterized by enhancement of both, cortisol and CRH levels, what in turn may lead to fetal growth retardation (54). It was shown in animal models that prenatal treatment with glucocorticoids may result in permanent decrease of nephron number, enhanced sensitivity to vasoconstrictors, elevated GR expression in the kidney and subsequent hypertension (54, 56).
Human observations are in accordance with animal studies. Maternal stress was shown to be associated with impaired intrauterine development, prematurity, disturbances in neurodevelopment, and increased salivary cortisol concentrations in the progeny, what suggests upregulation of HPA axis (54).
Maternal malnutrition, measured both by prepregnancy underweight and inadequate body mass gain during pregnancy, is related to IUGR (56). In our study (58), we found that women who were underweight before pregnancy (BMI<19.8 kg/m2) gave birth to significantly smaller babies (mean birthweight 3163ą410 g) than those with normal body mass before pregnancy (BMI 19.8-26.0 kg/m2, mean birthweight 3480ą435 g, p=0.001) or those who were overweight (BMI>26.0 kg/m2, mean birthweight 3781ą330 g, p<0.01). This relationship persisted after excluding smokers. In the same group of subjects we also analysed the relationship between weight gain during pregnancy and birthweights of the offspring. The mean birthweight of newborns of women whose weight gains during pregnancy did not meet IOM recommendations was significantly lower (3144ą494 g) than in those whose mothers weight gains were normal (3505ą340 g, p<0.01) or excessive (3469ą488 g, p<0.01). Similar relationship was observed after exclusion of smokers. Energy intake during pregnancy tended to increase with the raise in the pregnancy weight gain. There is accumulating evidence that restricted maternal diet may result not only in lower birthweight in the offspring but also in their enhanced susceptibility to atherosclerosis. It was shown that subjects who experienced famine during their fetal life in the time of the Dutch Hunger Winter (1944-45) had more atherogenic lipid profile, increased prevalence of glucose intolerance, hypertension, obesity, and ischemic heart disease than those whose mothers were not exposed to energy restrictions during pregnancy (59, 60, 61). In nine-years old children it was shown that lower maternal energy intake during pregnancy may increase their risk of atherosclerosis development measured by carotid IMT value (62). It was demonstrated by many authors that maternal protein restriction may contribute to intrauterine growth retardation and later obesity and type 2 diabetes (63). In undernourished populations, such as that of India, neonates are often born with low birthweight, but their visceral fat mass is relatively increased. They are also characterized by hyperinsulinemia. These subjects are particularly prone to develop obesity and type 2 diabetes in adult life (64). Supplementation with well balanced protein-energy preparations in pregnant women with nutritional deficiencies may result in prevention of IUGR in the offspring (65, 66). In animal studies severe energy restriction during pregnancy resulted in reduced birthweights in the offspring, their enhanced food intake during early development, and also obesity and hypoactivity in the later life (63). Energy- or protein restricted maternal diet may lead to decreased insulin secretion, increased insulin resistance, endothelial dysfunction, hypertension, and reduced nephron number in the progeny (2, 62, 67). Prenatally undernourished animals are prone do develop hyperleptinemia and hyperphagia in their adult life (63). It was demonstrated in mechanistic studies that maternal protein restriction may be followed by disturbed pancreatic development, decreased beta cell mass, and reduction of insulin secretory response to glucose and amino acids in the offspring. There is a growing body of evidence that it may also affect structure and function of the fetal liver, increase phosphoenolpyruvate carboxykinase (PEPCK) activity, a key enzyme in gluconeogenesis, and decrease glycolytic glucokinase level. These changes persist into postnatal life. The altered metabolic response to insulin was also reported to be caused by disturbed insulin suppression of hepatic glucose output. Similar metabolic aberrations were reported in human type 2 diabetic subjects (53). Protein restriction during fetal development may be also followed by the decline of skeletal muscle mass and decreased insulin-stimulated muscle glucose uptake in the later life. This effect is probably mediated by the decreased activity of zetaisoform of protein kinase C (PKC) in muscle cells (53). Maternal low protein diet may also influence adipose tissue metabolism in the offspring. It was shown in animals that anti-lipolytic action of insulin was reduced in epididymal and intra-abdominal adipocytes (53). Prenatal exposure to protein restricted diet may also influence activity of HPA axis (56) and may impair kidney development in the fetus (54). It was suggested that the last effect may be mediated by enhanced glucocorticoid exposure, resulting from raised passage of maternal glucocorticoids through placenta. This in turn is probably caused by decreased activity of 11â-HSD2 under condition of malnutrition (54). Exposure to undernutrition during fetal life seems to programme later hypertension risk through increased adiposity, enhanced sympatho-adrenal response and the renin-angiotensin system (RAS) activity (68). In animal models maternal protein restriction produced increase of ANG II receptors expression in the offspring brain regions responsible for cardiovascular regulation. ANG II receptors seem to play a key role in the programming of hypertension. The central activation of RAS results in the rise of renal sympathetic activity that increases sodium reabsorption that in turn leads to elevation of blood pressure (69). Reduced vasodilation was also proposed as a potential mechanism responsible for hypertension programming by protein deprivation during intrauterine life (70). Maternal protein restriction may also result in reduced glycine generation that seems to contribute to hypertension development in the offspring (68). RDA (Recommended Dietary Allowance) for protein during pregnancy is 1.1 g per kilogram of body mass daily and is 37.5% higher than before conception (71). In contemporary developed populations the problem of protein deficiency during pregnancy seems to be marginal, as it was shown in our study of Polish pregnant women, whose average daily consumption of protein was 74,1ą23,5 g/d in women underweight before pregnancy, 89,2ą34,0 g/d in women with normal body mass and 73,1ą33,2 g/d in overweight women (58). However, there is a concern about possible inadequate protein intake in vegans. Although a properly composed vegan diet may cover RDA for protein, also during pregnancy, some vegan women may have insufficient knowledge about meal planning. Proper polyunsaturated fatty acids intake also seems to be of importance for normal development of the fetus. It is suggested that n-3 fatty acids deficiency may contribute to fetal growth retardation (72). This effect may be explained by the beneficial influence of these fatty acids on placental blood flow (73). It is also proposed that proper perinatal intake of long chain n-3 fatty acids may protect against the development of insulin resistance and hypertension in later life. The last is explained by the aberration of function of neurons that take part in the osmo/sodium sensor activity that may be observed under condition of inadequate supply of n-3 fatty acids (74). On the other hand, excessive intake of trans fatty acids (TFA), that interfere with n-3 fatty acids metabolism, may also enhance the risk of IUGR (75, 76). It was shown by means of fetal ultrasonography (Pinto et al., personal communication) that fetuses of mothers that were at the top intake of total fat, saturated fatty acids, trans fatty acids, and n-6 fatty acids gained less weekly weights since the 18th gestational week onwards. It seems that also some micronutrient deficiencies during pregnancy may contribute to IUGR. It concerns, among others, folate that is a coenzyme that takes part in transport of monocarbon groups in metabolic pathways important for synthesis of nucleic acids. As the enhanced production of these acids during pregnancy is essential for intensive cellular division, low folate intake may result in the intrauterine growth retardation (77). Low vitamin B12 status seems also to contribute to IUGR (78). In human infants adequate maternal folate intake paired with vitamin B12 insufficiency was related to higher adiposity and insulin resistance. Progeny of mothers who had the lowest vitamin B12 status and the highest folate levels were the most insulin resistant. The described pattern of maternal micronutrient status was related both to vegetarian diet and folic acid supplementation (78). These results support the concept that methyl groups metabolism plays a crucial role in fetal programming. It also seems that maternal inadequate folate intake may contribute to enhanced propensity to hypertensive disorder in the offspring through the reduced glycine generation. Fetal requirement for glycine is covered by placental transamination of serine. The serine-glycine pathway efficiency is influenced by folate. Changes in folate availability and resulting changes in glycine production seems to be related to hypertension risk in the progeny (68). Results of other studies suggest that also deficiency of other micronutrients may contribute to low birthweight. It concerns vitamin A, thiamine, iron, zinc and magnesium (79, 80). Iron deficiency may result in maternal anaemia and this in turn, especially if it occurs in the first trimester, may increase, even threefold, the risk of low birthweight (80). In animal models maternal iron restriction may programme hypertension in the offspring (56). Zinc, similarly to folate, takes part in the synthesis of nucleic acids and cellular divisions. The role of these nutrients in fetal programming of cardiovascular risk is not clear.
Prematurity and cardiovascular risk in adult life
Birthweight reflects both maturity of the fetus and his/her intensity of growth during intrauterine life. The positive results of studies on developmental mechanisms leading to cardiovascular risk factors in adult life relate consistently to impaired fetal growth and not to shortened gestational age. However, there is emerging evidence that also prematurity may contribute to cardiovascular risk. We have shown that prematurity may increase the risk of atherosclerosis development measured by CIMT value (46). Other investigators demonstrated increased insulin resistance and glucose intolerance in subjects born preterm (17). It was demonstrated in the sample of middle-aged Danes that prematurity may increase the risk of type 2 diabetes. This effect was related to decreased insulin sensitivity (81). In our study, higher insulin resistance index in preterm than in term babies was observed in females only (82). The relationship between prematurity and cardiovascular risk should be treated with caution, since it is possible that majority of premature babies are growth restricted (83).
Macrosomia of a newborn, maternal diabetes, maternal obesity and cardiovascular risk in adult life
Not only IUGR, but also macrosomia is a risk factor of diabetes and cardiovascular diseases in adult life. Subjects born with macrosomia have a tendency to develop overweight and obesity, glucose intolerance, insulin resistance, and impaired insulin secretion. Opposite to low birthweight, macrosomia seems to be related to maternal overweight and obesity, and probably also to excessive body mass gain during pregnancy. Fetal overgrowth is often a consequence of maternal diabetes. The mechanism of the influence of maternal adiposity and/ or diabetes on fetal growth is not clear, but it seems that the most important factor is maternal hyperglycemia. Maternal high glucose levels in the third trimester result in fetal hyperglycemia which in turn stimulates fetal beta-cells to produce insulin. As insulin is a fetal growth factor, it stimulates excessive intrauterine growth. Moreover, maternal diabetic condition is often accompanied by increased concentrations of maternal, placental and fetal insulin-like growth factors (IGF). As IGF-I, similarly to insulin, stimulates fetal growth, its raised levels may also contribute to macrosomia. Also increased transport of amino acids through placenta is one of the discussed mechanisms of fetal overgrowth in diabetic pregnancy. This may be observed even in cases of proper metabolic control (84, 85, 86, 87, 88). However, some diabetic mothers give birth to IUGR progeny. It is proposed that this may result from insulin resistance that develops in the fetus. This in turn may decrease the trophic effect of insulin and result in growth retardation (89). It was demonstrated that the increased risk of overweight and obesity in the offspring of diabetic mothers may be related to the malprogramming of neuroendocrine regulatory systems of food intake (87). It is probably mediated by the increased insulin concentrations in the fetal hypothalamus resulting in dysplasia of the central nervous nuclei, in particular the ventromedial hypothalamic nucleus (VMN), that regulate metabolism and body mass. This is followed by the permanent hypothalamic resistance to the peripheral signals of insulin and leptin. Increased activity of neurons that secrete orexigenic peptides, such as galanin and neuropeptide Y, was also shown. This in turn results in hyperphagia, increased adiposity, and disturbances of carbohydrate metabolism (87). It seems that also fetal hyperleptinemia may be involved in programming of mechanisms that influence energy homeostasis in the central nervous system. The excess of leptin may originate from the placenta that produces its increased amounts under circumstances of maternal insulin treatment. It is also possible that increased amounts of leptin produced by the obese mother may cross the placenta and raise its fetal level (63). It was reported that maternal diabetes may be related to increased aortic IMT in macrosomic newborns (86). It is probable that this effect may be mediated by increased levels of IGF-I, fetal dyslipidemia, and enhanced chronic inflammation related to the increased levels of intracellular adhesion molecule 1 (ICAM1) and IL-6 (52, 86). Another problem, related to maternal diabetes, is transgenerational, independent of genetic heritage, transmission risk of diabetes. As the offspring of diabetic mothers are often macrosomic, they are characterized by enhanced propensity to overweight, obesity, and carbohydrate metabolism disorders. The similar problem concerns the IUGR offspring of diabetic mothers. As it was discussed above, IUGR may be also related to impaired glucose tolerance and diabetes in adult life. Daughters of diabetic mothers, both born as micro- or macrosomic neonates, are prone to develop pre- or gestational diabetes. Hence, their progeny is also at the increased risk of diabetes development. Hence, diabetes risk may be transmitted over subsequent female generations (53). The risk of macrosomia in the offspring may result not only from maternal diabetes, but also from maternal overnutrition, and the resulting overweight or obesity (84). Maternal overweight is often complicated with hyperglycemia, gestational diabetes, hypertension and/or preeclampsia. As described above, diabetes often results in macrosomia and sometimes, in particularly severe cases, in microsomia. Preeclampsia is often complicated with microsomia. Both, micro- and macrosomia are risk factors for metabolic syndrome and atherosclerosis in the offspring. Hypertriglyceridemia, that increases the risk of early onset preeclampsia, is one of complications of obesity and may result from the high intake of energy and particularly of sucrose and fructose (45). High maternal fat intake seems to be particularly important in fetal programming. In animal models it was shown that maternal high fat diet during pregnancy may increase the risk of obesity, endothelial dysfunction, hypertension, hyperleptinemia, hypertriglyceridemia, glucose stimulated insulin secretory deficiency, insulin resistance, and metabolic syndrome in the progeny (20, 90, 91). It seems that maternal high intake of n-6 fatty acids may contribute to obesity, increased hepatic lipid content and hepatic insulin resistance in the offspring (63). It was suggested that imbalance between n-6 and n-3 PUFA i.e. linoleic acid (LA) and alfa-linolenic acid (ALA), precursors of long-chain fatty acids, in maternal diet is of importance. Excess of LA may result in increased arachidonic acid (AA) production. As AA is adipogenic, its elevated levels may promote development of obesity (20). It was demonstrated in rats that maternal junk food diet (rich in fat, sugar and salt) during pregnancy and lactation may contribute to obesity in the offspring. Their increased adiposity was accompanied by elevated glucose, insulin, triglyceride and/or cholesterol levels when compared to controls (92). It seems that exposure to junk food during fetal life predisposes to exacerbated taste for junk food and obesity (93) and also to the accumulation of lipids in skeletal muscles, what probably is an early sign of metabolic disturbances (94). In another study plasma insulin levels and insulin secretory response were significantly increased in fetuses of mothers characterized by chronic consumption of high-fat diet. The male offspring weaned into a standard chow diet had increased body mass. In adulthood they were significantly heavier than controls. They also had elevated plasma concentrations of insulin, glucose, and triglycerides. These features of metabolic profile were even worse in the case of weaning to a high sucrose diet (95). As it was described above, it is proposed that insulin may be a modulator of the brain development. High levels of this hormone probably contribute to malprogramming of the central regulators of metabolism and body mass in the nervous system. Progeny of the dams fed high fat diet demonstrated increased activity of orexigenic peptides, galanin, enkephalin, and dynorphin in the paraventricular nucleus and also orexin, and melanin-concentrating hormone in the perifornical lateral hypothalamus (96). It was observed in humans that maternal high protein and low carbohydrate diet may result in reduced birthweight and increase the risk of hypertension in the offspring. Intrauterine exposure to this sort of diet was associated with increased fasting plasma cortisol levels and also amplified HPA responses (97). This observation is of importance as high protein and low carbohydrate diets became popular in the last decades.
The described above conditions that may be present during fetal development seem to programme the risk of atherosclerosis in adult life through epigenetic imprinting. This does not mean change in nucleotide sequence in DNA, but is associated with alteration of gene expression. The possible mechanisms are: DNA methylation, histone acetylation/ methylation/ phosphorylation or sumoylation and also chromatin remodeling. Epigenetic patterns determine availability of chromatin to transcription factors what may result in up-regulation or silencing of specific genes. These changes may persist into adult life. Epigenetic changes may be transmitted mitotically, and even meiotically. The last may be associated with inheritance of a regulatory pattern (98). It seems possible that changed environmental conditions present during life time of several generations may activate specific silent allele, or suppress others. These imprinting patterns, if not erased after fertilization, may become stable and persist to the subsequent generation. Such transgeneration adaptations to changed life circumstances may be reversed in future generations (98). It was observed in animal models that maternal protein restricted diets during pregnancy may result in hypomethylation of peroxisome proliferator-activated receptor alpha and also hepatic glucocorticoid receptor promoters in the progeny. It is proposed that this effect may be mediated by the reduction of activity of the DNA methyltransferase 1. It is also supposed that these changes may correspond to the inadequate supply of one-carbon groups (52). Intrauterine exposure to lowprotein diet may increase the risk of hypertension also by the increased corticosteroid levels (52). Binding glucocorticoid-receptor complex to DNA may result in its demethylation and chromatin remodeling what in turn may enhance glucocorticoid response (99). DNA methylation reactions depend on dietary availabily of methyl donors, such as methionine and choline. Their cofactors, i.e. folate, vitamin B12 and pyridoxal phosphate, are also of importance. Inadequate intake of these vitamins and protein, a source of amino acids, may adversely affect the pattern of DNA methylation and histone modifications. Also alfa-threonine has been proposed to be a factor that takes part in epigenetic changes. Its deficiency seems to result in aberrations of methionine metabolic pathways, that in turn implicates increase in homocysteine production and hypermethylation of fetal DNA. The embryo at the preimplantation stage of development is particularly vulnerable to epigenetic programming (53). Waterland and coworkers (100) have shown in a mouse models that maternal obesity may be related to a successive generation-to generation aggravation of adiposity. This phenomenon is probably mediated by DNA methylation as supplementation with methyl donors prevented this effect.
Intrauterine environment influences fetal growth and cardiovascular risk in adult life. Both micro- and macrosomia, and also prematurity, may contribute to type 2 diabetes, obesity, hypertension, metabolic syndrome, and atherosclerosis development. There is compelling evidence that maternal health status and life-style, including both under- and overnutrition, smoking, and response to stress, play a key role in programming metabolic risk in the offspring. Epigenetic imprinting underlies the described associations.
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Adres do korespondencji / Address for correspondence::
Department of Preventive Medicine and Hygiene,
Medical University of Warsaw
ul. Oczki 3, 02-007 Warszawa