J Endocrinol Invest (2015) 38:31–38 DOI 10.1007/s40618-014-0168-4
SHORT REVIEW
Impact of maternal under nutrition on obstetric outcomes S. Triunfo · A. Lanzone
Received: 16 July 2014 / Accepted: 20 August 2014 / Published online: 7 September 2014 © Italian Society of Endocrinology (SIE) 2014
Abstract Maternal malnutrition, ranging from under nutrition to over dietary intake before and in the pregnant state, is worldwide problem with significant consequences, not only for survival and increased risk for acute and chronic diseases both in mother and child, but also for economic productivity of individuals in the societies and additional costs on health system. Inter alia, pre-pregnancy underweight and insufficient gestational weight gain are considered as individual risk factors for the occurrence of spontaneous interruption, preterm birth, fetal growth restriction, and hypertensive disorders, strongly associated with poorer perinatal outcome. In a portion of this population, major eating disorders (anorexia and bulimia nervosa), once thought to be rare, but nowadays enlarged due to cultural pressure on the drive for thinness, have been identified as the etiology of an abnormal nutritional condition in developed countries, in contrast to long standing food deprivation in developing countries. Actually, even if without a complete weight management guidance for these selected pregnant women, an appropriate weight gain is recommended during pregnancy. Mainly, therapeutic approach is prevention using specific programs of improving weight before pregnant status. In this article, a review of the literature on selected obstetrical risks associated with maternal
S. Triunfo (*) BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), University of Barcelona, Sabino de Arana, 1, 08028 Barcelona, Spain e-mail: [email protected] A. Lanzone Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
underweight has been performed and both the target prevention and management strategies have been described. Keywords Under nutrition · Pregnancy · Adverse perinatal outcome · Prevention
Introduction Maternal under nutrition, including stunting, wasting, and deficiencies of essential vitamins and minerals, represents a global problem with important consequences for survival, incidence of acute and chronic diseases, healthy development for mother and newborn, and the economic productivity of individuals and societies [1–4]. The impact of prepregnancy body mass index (BMI) on obstetric outcomes, as well as subsequent disease risk in the offspring, has attracted widespread attention due to the increased prevalence of its abnormal value in women childbearing age. In low-income and middle-income countries maternal malnutrition encompasses both under nutrition and a growing problem with overweight and obesity [3, 4]. Overall, low body mass index, indicative of maternal under nutrition, has declined somewhat in the past two decades, but continues to be prevalent in Asia and Africa [1]. In contrast, prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions [1, 5]. After the global alert for overweight and obesity, an opposite extreme on the same spectrum of malnutrition status has drawn attention in both developing and developed countries due to different reasons [6–13]. Considering the malnutrition as “under nutrition”, it can be linked to long standing food deprivation in the first case and eating disorders (anorexia and bulimia nervosa) in the second,
13
32
respectively [12]. Social, demographic, and obstetric factors, evaluated as independent variables, are identified as etiology of pre-pregnancy underweight [1, 5]. In these pregnancies, an increased risk of fetal loss, preterm birth, anemia, infections, fetal growth restriction (FGR), birth defects, low BW, brain damage, admission to neonatal intensive care unit, and a longer duration of hospital stay, signs of the metabolic syndrome accompanied the catch-up in body weight and central adiposity have been recognized [14–18]. In addition, under nutrition has profound effects on health throughout the human life course and is inextricably linked with cognitive and social development, especially in early childhood [16–19]. In settings with insufficient material and social resources, children are not able to achieve their full growth and developmental potential [19]. Consequences range broadly from raised rates of death from infectious diseases and decreased learning capacity in childhood to increased non-communicable diseases in adulthood, according to the ‘‘fetal origins’’ hypothesis that proposes that alterations in fetal nutrition results in developmental adaptations that permanently change the structure, physiology, and metabolism, thereby predisposing to overweight/obesity in adulthood [20]. As we know, the process whereby a stimulus or insult at a sensitive or critical period of development has long-term effects is termed ‘‘programming’’ [20]. Therefore, malnutrition in the mother has direct effects on the body size of the offspring, and may contribute to the health risks in childhood, persisting throughout life. Considering that one of the goals of prenatal care is the early identification of risk factors for unfavorable pregnancy outcomes, early prenatal care should focus greater attention on pregnant women with important nutritional deviations. An adequate referral may favor timely and pertinent measures for each case, thereby minimizing the effects of inadequate pre-gestational weight. The present review has a twofold purpose: firstly, to summarize the studies on the associations between maternal under nutrition and obstetric risks, and secondly, to identify potential strategies for preventing short- and longterm adverse outcomes.
J Endocrinol Invest (2015) 38:31–38
Fig. 1 Weight gained in pregnancy, as the result of metabolic changes, although it varies across women
fluid, and the remaining 27 % consists of maternal fat stores (Fig. 1) [21]. In early- to mid-pregnancy, underweight and normal weight women deposit fat in their hips, back, and upper thighs, this is thought to be important as a caloric reserve for late pregnancy and lactation [22]. Insulin secretion and sensitivity rise, favoring increased lipogenesis and fat accumulation, in preparation for the increased energy needs of the growing fetus [22]. However, women entering pregnancy in a condition of under nutrition do not have this same rise in peripheral insulin sensitivity in early pregnancy and little or no additional fat is accrued [21, 22]. By late pregnancy, insulin resistance increases among all mothers and weight gain slows, a normal physiologic adaptation that shifts maternal energy metabolism from carbohydrate to lipid oxidation and thus spares glucose for the fetus [21, 22]. Hence, the pattern of gestational weight gain is most commonly described as sigmoidal, with the majority of weight gained in the second and early third trimesters of pregnancy [21, 22]. This complex of adjustments in carbohydrate and fat metabolism ensure that the fetus receives a continuous supply of fuel when its needs are maximal [22].
Effects of maternal under nutrition on placental development Biologic processes and metabolic changes in pregnancy The weight gained in pregnancy is the result of biologic processes and metabolic changes that promote the correct development of fetal programming [21]. Although the composition of weight gained during pregnancy varies across women, a general description can be assessed. Approximately 27 % resides in the fetus, 20 % includes the placenta, amniotic fluid and uterus, 3 % comprises breast weight, 23 % is made up of blood volume and extravascular
13
The placenta of mammals is a highly efficient multifunctional organ that integrates signals from both mother and fetus to match fetal demand with the maternal substrate supply of nutrients and gases, while ensuring that fetal waste products are transferred back to the mother. Altered placental structure and function (reflected by weight, morphology, vascular development, and transport function for amino acids, glucose, and fatty acids) may contribute to altered nutrient supply [23].
J Endocrinol Invest (2015) 38:31–38
Placental weight is correlated with dietary intake in mammalian pregnancies. Although the effect of global maternal under nutrition on placental weight is unequivocal, the timing, duration, and etiology of nutritional restriction can each differently affect placental mass [23, 24]. An important question is whether global maternal under nutrition or deprivation of a selected nutrient component is the insult that induces the change in growth trajectories of the placenta and fetus. Indeed, protein restriction with 9 vs. 18 % casein in the diet throughout pregnancy in the rat yielded heavier placentas and reduced fetal growth in late gestation [25]. The placental over growth compensates for the reduced protein availability in early gestation to maintain normal fetal weight in earlier gestation, but such compensation is insufficient to maintain fetal growth near parturition [25]. Consequently, the placenta compensates to minimize FGR, but placental function is not always improved with increases in weight because the histomorphology of the placenta ultimately determines placental function [26]. From a histological point of view, the placenta change throughout normal gestation and in response to maternal nutritional manipulations [27]. Indeed, in mammals, the placenta develops a large surface:volume ratio, forming highly branched structures with advancing pregnancy. Trophoblast provides the covering surface and is positioned to mediate critical steps in hormone production and immune protection of the fetus. Invasive trophoblasts also facilitate an increase in maternal vascular blood flow into the placenta [28]. Alterations of exchange surface area, barrier thickness, and cell composition of the different gestational ages of the placenta may all affect placental transport capacity [29]. The nutrient-deprived gestations exhibited placentas with surface area for exchange that were diminished by up to 70 % due to reduced development of the labyrinth, while barrier thickness was increased by 40 % in late gestation [30]. These histopathological changes predispose to reduced nutrient transfer to the fetus, and this insult compromises both placental vasculogenesis and angiogenesis, attributable to an impaired exchange between the maternal–fetal circulations, as ultimately described in FGR fetuses [31]. Vasculogenesis and angiogenesis processes are critical to the maternal–fetal exchange: vascular endothelial growth factor (VEGF) and angiopoietin proteins (placental growth factor, PlGF, and soluble fms-like tyrosine kinase-1, sFlt-1) play a pivotal role in this mechanism, although their impact on maternal under nutrition placentas is unknown to date [31, 32]. It is known that VEGF stimulates the release of endothelium-derived nitric oxide (NO) and upregulates the expression of NO synthetase [32, 33]. Animal models of FGR showed decreased placental arginine (a common substrate for NO), less NO synthesis, and reduced NO synthetase activity compared with normal protein diet
33
[33]. These changes are likely one mechanism for placental vascular dysfunction that results in reduced placental– fetal growth in the protein-deficient offspring. Collectively, these results underscore that typical features of nutrient restriction models include some level of placental vascular and angiogenesis dysfunction during pregnancy. Global maternal nutritional status affects transporters in the placenta, thereby influencing the rate of nutrient delivery through the placenta. The maternal–fetal glucose concentration gradient (which drives facilitative glucose diffusion across the placenta) is also reduced, and glucose transporter 3 [solute carrier family 2 (facilitated glucose transporter) member 3 (SLC2A3, previously called GLUT3)] expression is substantially decreased, suggesting a mechanism for placental glucose transport dysfunction [34]. Placental transport of amino acids is pivotal for fetal development and is affected by the activity and location of amino acid transporter systems. In humans, reduced circulating concentrations of essential amino acids (such as leucine and lysine) are observed in growth-restricted human fetuses, implying that there is a global alteration of placental amino acid transport activity in FGR [23, 34]. Similarly, adequate placental transport of fatty acids to the fetus is crucial for normal fetal development and growth because fatty acids have multiple roles as cell membrane components, energy sources, and precursors to cellular signaling molecules [34]. In FGR condition placentas showed disrupted lipid metabolism and altered microvillous plasma membrane lipidhydrolase activities; both affected the flux of essential fatty acids and preformed long-chain polyunsaturated fatty acids to the human fetus [35]. Undernourished women exhibited a relative placental deficiency of essential fatty acids, and this suggests a lower source of placental membrane fluidity and subnormal content of essential fatty acids in their offspring [36]. Placentas from pregnancies with FGR also have decreased levels of arachidonic acid and docosahexaenoic acid [37], and fetuses affected by FGR exhibit proportions of both these fatty acids that are lower than control proportions relative to their linoleic acid (LA) and LA precursors [38]. In conclusion, the combination of all these abnormal changes, responsible for the suboptimal placental growth, due to maternal under nutrition, provides insight into the main obstetric complication that is identified in the FGR.
Effect of maternal under nutrition on potential fetal growth Maternal diet affects fetal growth directly by determining the amount of nutrients available, indirectly by affecting the fetal endocrine system, and epigenetically by modulating gene activity [5]. Nutritional insults during critical
13
34
periods of gestation may thereby have a permanent effect on progeny throughout postnatal life and beyond [20]. In some conditions, such as short interpregnancy interval or in adolescence, a competition between mother and fetus or newborn for nutrients has been recorded, increasing the risk of adverse perinatal outcome [12]. Low intake of dietary nutrients due to a limited supply of food or because of severe nausea and vomiting that persists long after the usual first-trimester effects determines FGR in both humans and animal models [4]. In pregnant rat model, a 5 % protein reduction yielded offspring that were significantly smaller than pups born to 20 % proteinfed controls [36]. A decrease in placental amino acid, but not glucose transport, precedes FGR [36, 37], and this reduced amino acid supply likely contributes to the FGR, rather than being a consequence of the disorder. Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments. Secretion of these hormones, among them the most important are glucocorticoids, insulin-like growth factors and leptin, can be affected by maternal under nutrition and can in this manner affect fetal development. • Glucocorticoids are essential for maturation of fetal tissues [39, 40], but an excessive exposure to endogenous glucocorticoids in utero can reduce fetal growth and predispose to anxiety disorders, as demonstrated in adult rats [41]. Moreover, maternal global nutrient restriction during late gestation induced over exposure to glucocorticoids in the fetus and disturbed the hypothalamo-pituitary adrenal axis in the newborn [41]. In addition, in the newborn rat an increase in basal corticosterone levels accelerates the appearance of agerelated neural and cognitive deficits, including atrophy of dendritic processes and cell death [40, 41]. • Insulin-like growth factors (IGFs) are a family of hormones acting in autocrine, paracrine, and endocrine fashions to modulate growth [42]. The IGF ligands (IGF1 and IGF2) are regulated by a family of proteins known as the IGF-binding proteins (IGFBPs), and these interactions control fetal growth [42]. Although, maternal serum IGFs and IGFBP-1 and -3 levels increase during pregnancy, they do not cross the placenta in physiologically significant quantities and it therefore is suggested that IGFs may act locally on the placenta and/or modulate maternal physiology to regulate nutrient partitioning between the mother, placenta and fetus [43]. As modulators of IGFs actions, it has been postulated that IGFBPs influence the process of fetal growth: concentration of IGFBP1 is negatively correlated with BW and in fetal programming in contrast to fetal IGF-I and IGFBP-3 are likely to influence the growth of largefor-gestational age babies [42, 43].
13
J Endocrinol Invest (2015) 38:31–38
• Leptin is a satiety factor that has a key role in the regulation of energy homeostasis; in fetus and growthrestricted newborn plasma leptin concentrations are low, but these concentrations increased in infants by age 1 year with weight gain and an increase in subcutaneous tissue [44]. Whether this increase in plasma leptin is related to changes in leptin transport, metabolism, or clearance is unknown to date. The low levels of leptin in the growth-restricted fetuses enhanced development of appetite stimulatory pathways and suppressed development of anorexigenic inhibitory pathways [44]. Overall, the findings among humans and in animal models indicate that undernutrition in utero programs leptin dysregulation to yield subsequent obesity [23, 44]. Collectively, these studies suggest that alteration in fetal hormones following maternal under nutrition emerges as a major contributor to restricted fetal growth and suboptimal development. Programmed changes induced by altered fetal hormone activity in utero can thus affect newborns and eventually yield disordered responses in adults. In addition, this maternal condition can program adult disease susceptibility through epigenetic changes of the fetal genome that affect the adult genotype and phenotype [20, 23, 26]. Indeed, epigenetic changes result from mechanisms unrelated to the DNA sequence: availability of amino acids and micronutrients may alter DNA methylation or modify histones, determining hypomethylation of the nuclear receptor peroxisome proliferator-activated receptor alpha (Ppara) and the glucocorticoid receptor (Nr3c1, previously called Gr) in the liver of offspring [45], linked to adultonset hypertension and to impaired fat and carbohydrate metabolism. Therefore, epigenetic modifications represent a molecular mechanism by which maternal nutrition influences fetal programming, postnatal disease susceptibility, and genomic imprinting [20, 45]. Unquestionably, low BW is a major consequence of maternal under nutrition in both humans and animals [1, 3, 5, 7, 19, 23–26]. Human newborns with low BW are more likely than newborns with average BW to develop insulin resistance, type 2 diabetes mellitus, and hypertension in adult life [2]. In addition, infants exposed to FGR are at high risk for physical and mental impairments in later life [46]. Maternal under nutrition results in precocious maturation of the fetal hypothalamic pituitary axis, and these effects are associated with a delay, if not a permanent deficit, in cognitive processes [47] and school performance of affected children [3, 12, 19]. Moreover, FGR newborns exhibited altered thermogenesis, glucose levels, and cholesterol homeostasis at birth, while insulin action was adversely affected later in life [14, 16]. In animal models exposed to 50 % maternal under nutrition in the last half of pregnancy had reduced fetal and newborn weights [14,
J Endocrinol Invest (2015) 38:31–38
47], with poor remodeling of vasculature, a contributing factor to subsequent hypertension [3, 15]. The liver of FGR rat offspring increased expression of peroxisome proliferator-activated receptor gamma coactivator 1, a regulator of mRNA expression for glucose-6-phosphatase and other gluconeogenic enzymes, suggesting that the alteration in hepatic glucose production resulted from changes in intracellular signaling [48]. As a result, a suboptimal maternal nutrition not only affects fetal growth, but also influences long-term outcomes of the affected offspring.
Additional effects of maternal under nutrition on obstetric outcome • Anemia (hemoglobin
SHORT REVIEW
Impact of maternal under nutrition on obstetric outcomes S. Triunfo · A. Lanzone
Received: 16 July 2014 / Accepted: 20 August 2014 / Published online: 7 September 2014 © Italian Society of Endocrinology (SIE) 2014
Abstract Maternal malnutrition, ranging from under nutrition to over dietary intake before and in the pregnant state, is worldwide problem with significant consequences, not only for survival and increased risk for acute and chronic diseases both in mother and child, but also for economic productivity of individuals in the societies and additional costs on health system. Inter alia, pre-pregnancy underweight and insufficient gestational weight gain are considered as individual risk factors for the occurrence of spontaneous interruption, preterm birth, fetal growth restriction, and hypertensive disorders, strongly associated with poorer perinatal outcome. In a portion of this population, major eating disorders (anorexia and bulimia nervosa), once thought to be rare, but nowadays enlarged due to cultural pressure on the drive for thinness, have been identified as the etiology of an abnormal nutritional condition in developed countries, in contrast to long standing food deprivation in developing countries. Actually, even if without a complete weight management guidance for these selected pregnant women, an appropriate weight gain is recommended during pregnancy. Mainly, therapeutic approach is prevention using specific programs of improving weight before pregnant status. In this article, a review of the literature on selected obstetrical risks associated with maternal
S. Triunfo (*) BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), University of Barcelona, Sabino de Arana, 1, 08028 Barcelona, Spain e-mail: [email protected] A. Lanzone Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy
underweight has been performed and both the target prevention and management strategies have been described. Keywords Under nutrition · Pregnancy · Adverse perinatal outcome · Prevention
Introduction Maternal under nutrition, including stunting, wasting, and deficiencies of essential vitamins and minerals, represents a global problem with important consequences for survival, incidence of acute and chronic diseases, healthy development for mother and newborn, and the economic productivity of individuals and societies [1–4]. The impact of prepregnancy body mass index (BMI) on obstetric outcomes, as well as subsequent disease risk in the offspring, has attracted widespread attention due to the increased prevalence of its abnormal value in women childbearing age. In low-income and middle-income countries maternal malnutrition encompasses both under nutrition and a growing problem with overweight and obesity [3, 4]. Overall, low body mass index, indicative of maternal under nutrition, has declined somewhat in the past two decades, but continues to be prevalent in Asia and Africa [1]. In contrast, prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions [1, 5]. After the global alert for overweight and obesity, an opposite extreme on the same spectrum of malnutrition status has drawn attention in both developing and developed countries due to different reasons [6–13]. Considering the malnutrition as “under nutrition”, it can be linked to long standing food deprivation in the first case and eating disorders (anorexia and bulimia nervosa) in the second,
13
32
respectively [12]. Social, demographic, and obstetric factors, evaluated as independent variables, are identified as etiology of pre-pregnancy underweight [1, 5]. In these pregnancies, an increased risk of fetal loss, preterm birth, anemia, infections, fetal growth restriction (FGR), birth defects, low BW, brain damage, admission to neonatal intensive care unit, and a longer duration of hospital stay, signs of the metabolic syndrome accompanied the catch-up in body weight and central adiposity have been recognized [14–18]. In addition, under nutrition has profound effects on health throughout the human life course and is inextricably linked with cognitive and social development, especially in early childhood [16–19]. In settings with insufficient material and social resources, children are not able to achieve their full growth and developmental potential [19]. Consequences range broadly from raised rates of death from infectious diseases and decreased learning capacity in childhood to increased non-communicable diseases in adulthood, according to the ‘‘fetal origins’’ hypothesis that proposes that alterations in fetal nutrition results in developmental adaptations that permanently change the structure, physiology, and metabolism, thereby predisposing to overweight/obesity in adulthood [20]. As we know, the process whereby a stimulus or insult at a sensitive or critical period of development has long-term effects is termed ‘‘programming’’ [20]. Therefore, malnutrition in the mother has direct effects on the body size of the offspring, and may contribute to the health risks in childhood, persisting throughout life. Considering that one of the goals of prenatal care is the early identification of risk factors for unfavorable pregnancy outcomes, early prenatal care should focus greater attention on pregnant women with important nutritional deviations. An adequate referral may favor timely and pertinent measures for each case, thereby minimizing the effects of inadequate pre-gestational weight. The present review has a twofold purpose: firstly, to summarize the studies on the associations between maternal under nutrition and obstetric risks, and secondly, to identify potential strategies for preventing short- and longterm adverse outcomes.
J Endocrinol Invest (2015) 38:31–38
Fig. 1 Weight gained in pregnancy, as the result of metabolic changes, although it varies across women
fluid, and the remaining 27 % consists of maternal fat stores (Fig. 1) [21]. In early- to mid-pregnancy, underweight and normal weight women deposit fat in their hips, back, and upper thighs, this is thought to be important as a caloric reserve for late pregnancy and lactation [22]. Insulin secretion and sensitivity rise, favoring increased lipogenesis and fat accumulation, in preparation for the increased energy needs of the growing fetus [22]. However, women entering pregnancy in a condition of under nutrition do not have this same rise in peripheral insulin sensitivity in early pregnancy and little or no additional fat is accrued [21, 22]. By late pregnancy, insulin resistance increases among all mothers and weight gain slows, a normal physiologic adaptation that shifts maternal energy metabolism from carbohydrate to lipid oxidation and thus spares glucose for the fetus [21, 22]. Hence, the pattern of gestational weight gain is most commonly described as sigmoidal, with the majority of weight gained in the second and early third trimesters of pregnancy [21, 22]. This complex of adjustments in carbohydrate and fat metabolism ensure that the fetus receives a continuous supply of fuel when its needs are maximal [22].
Effects of maternal under nutrition on placental development Biologic processes and metabolic changes in pregnancy The weight gained in pregnancy is the result of biologic processes and metabolic changes that promote the correct development of fetal programming [21]. Although the composition of weight gained during pregnancy varies across women, a general description can be assessed. Approximately 27 % resides in the fetus, 20 % includes the placenta, amniotic fluid and uterus, 3 % comprises breast weight, 23 % is made up of blood volume and extravascular
13
The placenta of mammals is a highly efficient multifunctional organ that integrates signals from both mother and fetus to match fetal demand with the maternal substrate supply of nutrients and gases, while ensuring that fetal waste products are transferred back to the mother. Altered placental structure and function (reflected by weight, morphology, vascular development, and transport function for amino acids, glucose, and fatty acids) may contribute to altered nutrient supply [23].
J Endocrinol Invest (2015) 38:31–38
Placental weight is correlated with dietary intake in mammalian pregnancies. Although the effect of global maternal under nutrition on placental weight is unequivocal, the timing, duration, and etiology of nutritional restriction can each differently affect placental mass [23, 24]. An important question is whether global maternal under nutrition or deprivation of a selected nutrient component is the insult that induces the change in growth trajectories of the placenta and fetus. Indeed, protein restriction with 9 vs. 18 % casein in the diet throughout pregnancy in the rat yielded heavier placentas and reduced fetal growth in late gestation [25]. The placental over growth compensates for the reduced protein availability in early gestation to maintain normal fetal weight in earlier gestation, but such compensation is insufficient to maintain fetal growth near parturition [25]. Consequently, the placenta compensates to minimize FGR, but placental function is not always improved with increases in weight because the histomorphology of the placenta ultimately determines placental function [26]. From a histological point of view, the placenta change throughout normal gestation and in response to maternal nutritional manipulations [27]. Indeed, in mammals, the placenta develops a large surface:volume ratio, forming highly branched structures with advancing pregnancy. Trophoblast provides the covering surface and is positioned to mediate critical steps in hormone production and immune protection of the fetus. Invasive trophoblasts also facilitate an increase in maternal vascular blood flow into the placenta [28]. Alterations of exchange surface area, barrier thickness, and cell composition of the different gestational ages of the placenta may all affect placental transport capacity [29]. The nutrient-deprived gestations exhibited placentas with surface area for exchange that were diminished by up to 70 % due to reduced development of the labyrinth, while barrier thickness was increased by 40 % in late gestation [30]. These histopathological changes predispose to reduced nutrient transfer to the fetus, and this insult compromises both placental vasculogenesis and angiogenesis, attributable to an impaired exchange between the maternal–fetal circulations, as ultimately described in FGR fetuses [31]. Vasculogenesis and angiogenesis processes are critical to the maternal–fetal exchange: vascular endothelial growth factor (VEGF) and angiopoietin proteins (placental growth factor, PlGF, and soluble fms-like tyrosine kinase-1, sFlt-1) play a pivotal role in this mechanism, although their impact on maternal under nutrition placentas is unknown to date [31, 32]. It is known that VEGF stimulates the release of endothelium-derived nitric oxide (NO) and upregulates the expression of NO synthetase [32, 33]. Animal models of FGR showed decreased placental arginine (a common substrate for NO), less NO synthesis, and reduced NO synthetase activity compared with normal protein diet
33
[33]. These changes are likely one mechanism for placental vascular dysfunction that results in reduced placental– fetal growth in the protein-deficient offspring. Collectively, these results underscore that typical features of nutrient restriction models include some level of placental vascular and angiogenesis dysfunction during pregnancy. Global maternal nutritional status affects transporters in the placenta, thereby influencing the rate of nutrient delivery through the placenta. The maternal–fetal glucose concentration gradient (which drives facilitative glucose diffusion across the placenta) is also reduced, and glucose transporter 3 [solute carrier family 2 (facilitated glucose transporter) member 3 (SLC2A3, previously called GLUT3)] expression is substantially decreased, suggesting a mechanism for placental glucose transport dysfunction [34]. Placental transport of amino acids is pivotal for fetal development and is affected by the activity and location of amino acid transporter systems. In humans, reduced circulating concentrations of essential amino acids (such as leucine and lysine) are observed in growth-restricted human fetuses, implying that there is a global alteration of placental amino acid transport activity in FGR [23, 34]. Similarly, adequate placental transport of fatty acids to the fetus is crucial for normal fetal development and growth because fatty acids have multiple roles as cell membrane components, energy sources, and precursors to cellular signaling molecules [34]. In FGR condition placentas showed disrupted lipid metabolism and altered microvillous plasma membrane lipidhydrolase activities; both affected the flux of essential fatty acids and preformed long-chain polyunsaturated fatty acids to the human fetus [35]. Undernourished women exhibited a relative placental deficiency of essential fatty acids, and this suggests a lower source of placental membrane fluidity and subnormal content of essential fatty acids in their offspring [36]. Placentas from pregnancies with FGR also have decreased levels of arachidonic acid and docosahexaenoic acid [37], and fetuses affected by FGR exhibit proportions of both these fatty acids that are lower than control proportions relative to their linoleic acid (LA) and LA precursors [38]. In conclusion, the combination of all these abnormal changes, responsible for the suboptimal placental growth, due to maternal under nutrition, provides insight into the main obstetric complication that is identified in the FGR.
Effect of maternal under nutrition on potential fetal growth Maternal diet affects fetal growth directly by determining the amount of nutrients available, indirectly by affecting the fetal endocrine system, and epigenetically by modulating gene activity [5]. Nutritional insults during critical
13
34
periods of gestation may thereby have a permanent effect on progeny throughout postnatal life and beyond [20]. In some conditions, such as short interpregnancy interval or in adolescence, a competition between mother and fetus or newborn for nutrients has been recorded, increasing the risk of adverse perinatal outcome [12]. Low intake of dietary nutrients due to a limited supply of food or because of severe nausea and vomiting that persists long after the usual first-trimester effects determines FGR in both humans and animal models [4]. In pregnant rat model, a 5 % protein reduction yielded offspring that were significantly smaller than pups born to 20 % proteinfed controls [36]. A decrease in placental amino acid, but not glucose transport, precedes FGR [36, 37], and this reduced amino acid supply likely contributes to the FGR, rather than being a consequence of the disorder. Normal pregnancy entails substantial production of hormones in the maternal, placental, and fetal compartments. Secretion of these hormones, among them the most important are glucocorticoids, insulin-like growth factors and leptin, can be affected by maternal under nutrition and can in this manner affect fetal development. • Glucocorticoids are essential for maturation of fetal tissues [39, 40], but an excessive exposure to endogenous glucocorticoids in utero can reduce fetal growth and predispose to anxiety disorders, as demonstrated in adult rats [41]. Moreover, maternal global nutrient restriction during late gestation induced over exposure to glucocorticoids in the fetus and disturbed the hypothalamo-pituitary adrenal axis in the newborn [41]. In addition, in the newborn rat an increase in basal corticosterone levels accelerates the appearance of agerelated neural and cognitive deficits, including atrophy of dendritic processes and cell death [40, 41]. • Insulin-like growth factors (IGFs) are a family of hormones acting in autocrine, paracrine, and endocrine fashions to modulate growth [42]. The IGF ligands (IGF1 and IGF2) are regulated by a family of proteins known as the IGF-binding proteins (IGFBPs), and these interactions control fetal growth [42]. Although, maternal serum IGFs and IGFBP-1 and -3 levels increase during pregnancy, they do not cross the placenta in physiologically significant quantities and it therefore is suggested that IGFs may act locally on the placenta and/or modulate maternal physiology to regulate nutrient partitioning between the mother, placenta and fetus [43]. As modulators of IGFs actions, it has been postulated that IGFBPs influence the process of fetal growth: concentration of IGFBP1 is negatively correlated with BW and in fetal programming in contrast to fetal IGF-I and IGFBP-3 are likely to influence the growth of largefor-gestational age babies [42, 43].
13
J Endocrinol Invest (2015) 38:31–38
• Leptin is a satiety factor that has a key role in the regulation of energy homeostasis; in fetus and growthrestricted newborn plasma leptin concentrations are low, but these concentrations increased in infants by age 1 year with weight gain and an increase in subcutaneous tissue [44]. Whether this increase in plasma leptin is related to changes in leptin transport, metabolism, or clearance is unknown to date. The low levels of leptin in the growth-restricted fetuses enhanced development of appetite stimulatory pathways and suppressed development of anorexigenic inhibitory pathways [44]. Overall, the findings among humans and in animal models indicate that undernutrition in utero programs leptin dysregulation to yield subsequent obesity [23, 44]. Collectively, these studies suggest that alteration in fetal hormones following maternal under nutrition emerges as a major contributor to restricted fetal growth and suboptimal development. Programmed changes induced by altered fetal hormone activity in utero can thus affect newborns and eventually yield disordered responses in adults. In addition, this maternal condition can program adult disease susceptibility through epigenetic changes of the fetal genome that affect the adult genotype and phenotype [20, 23, 26]. Indeed, epigenetic changes result from mechanisms unrelated to the DNA sequence: availability of amino acids and micronutrients may alter DNA methylation or modify histones, determining hypomethylation of the nuclear receptor peroxisome proliferator-activated receptor alpha (Ppara) and the glucocorticoid receptor (Nr3c1, previously called Gr) in the liver of offspring [45], linked to adultonset hypertension and to impaired fat and carbohydrate metabolism. Therefore, epigenetic modifications represent a molecular mechanism by which maternal nutrition influences fetal programming, postnatal disease susceptibility, and genomic imprinting [20, 45]. Unquestionably, low BW is a major consequence of maternal under nutrition in both humans and animals [1, 3, 5, 7, 19, 23–26]. Human newborns with low BW are more likely than newborns with average BW to develop insulin resistance, type 2 diabetes mellitus, and hypertension in adult life [2]. In addition, infants exposed to FGR are at high risk for physical and mental impairments in later life [46]. Maternal under nutrition results in precocious maturation of the fetal hypothalamic pituitary axis, and these effects are associated with a delay, if not a permanent deficit, in cognitive processes [47] and school performance of affected children [3, 12, 19]. Moreover, FGR newborns exhibited altered thermogenesis, glucose levels, and cholesterol homeostasis at birth, while insulin action was adversely affected later in life [14, 16]. In animal models exposed to 50 % maternal under nutrition in the last half of pregnancy had reduced fetal and newborn weights [14,
J Endocrinol Invest (2015) 38:31–38
47], with poor remodeling of vasculature, a contributing factor to subsequent hypertension [3, 15]. The liver of FGR rat offspring increased expression of peroxisome proliferator-activated receptor gamma coactivator 1, a regulator of mRNA expression for glucose-6-phosphatase and other gluconeogenic enzymes, suggesting that the alteration in hepatic glucose production resulted from changes in intracellular signaling [48]. As a result, a suboptimal maternal nutrition not only affects fetal growth, but also influences long-term outcomes of the affected offspring.
Additional effects of maternal under nutrition on obstetric outcome • Anemia (hemoglobin
