Intrauterine Growth Restriction: Implications for Placental Metabolism and Transport. A Review

Intrauterine growth restriction (IUGR) correlates with a specific placental phenotype, associated with defects in placental transport functions, that lead to fetal undernutrition. Both placental metabolism and transport may be affected, thus modifying the normal supply of nutrients. Models to investigate placental function may either couple or separate metabolism and transport. In human pregnancies, nutrient concentrations can be measured at the time of delivery or at cordocentesis in the umbilical vessels connecting the fetus to the placenta. The kinetics of placental transport can be evaluated in vivo using stable isotopes, i.e. infusing ¹³C labelled nutrient in the mother by bolus or steady state techniques prior to cordocentesis or cesarean section. In vitro studies, using the model of the dually perfused human placenta or investigating the activity of transporters in the placental membranes have also significantly contributed to our understanding of placental function.In IUGR, the placental supply of amino acids is significantly reduced independently from the severity of growth restriction and from the presence of hypoxia. Moreover, maternal–fetal gradients of glucose are increased in severe IUGR fetuses, i.e. those with alterations of umbilical blood flows, and reduced conversion ratios of long chain-polyunsaturated fatty acids (LC-PUFA) from their parent fatty acids have been demonstrated.This review summarizes the current knowledge about placental metabolism and transport in IUGR pregnancies and the relationship with severity of the disease.     

Placental nutrient transfer capacity and fetal growth

The objective of this study was to determine whether the ability of the human placenta to transfer glucose and fatty acids is related to normal fetal growth. The intrinsic nutrient transport capacity of the placenta was measured under standardized conditions during in vitro perfusion of 30 human term placentas and related to birth weight (range 2640-4640g), birth weight centile (8th-99th), ponderal index (2.43-3.69), placental weight (418-1030g) and placental:fetal weight (0.14-0.31). There was no statistically significant change in the rate of nutrient transfer per placenta or per kg fetal weight, with birth weight, birth weight centile, ponderal index, placental weight and placental:fetal weight. There was a weak but significant relationship (P=0.020, r(2)=9 per cent) between the ratio of glucose to fatty acid transport and birth weight centile, largely due to the high ratio found in the lowest birth weight quartile where the babies are thinnest. This study provides no evidence that placental nutrient transport capacity limits fetal growth across a wide range of birth weights in normal pregnancies. It is proposed that the fetus itself may regulate placental nutrient transport in vivo via the fetal cardiac output and the rate of fetal nutrient utilization.     

Review: Adiponectin – The missing link between maternal adiposity,placental transport and fetal growth?

Adiponectin has well-established insulin-sensitizing effects in non-pregnant individuals. Pregnant women who are obese or have gestational diabetes typically have low circulating levels of adiponectin, which is associated with increased fetal growth. Lean women, on the other hand, have high circulating levels of adiponectin. As a result, maternal serum adiponectin is inversely correlated to fetal growth across the full range of birth weights, suggesting that maternal adiponectin may limit fetal growth. In the mother, adiponectin is predicted to promote insulin sensitivity and stimulate glucose uptake in maternal skeletal muscle thereby reducing nutrient availability for placental transfer. Adiponectin prevents insulin-stimulated amino acid uptake in cultured primary human trophoblast cells by modulating insulin receptor substrate phosphorylation. Furthermore, chronic administration of adiponectin to pregnant mice inhibits placental insulin and mammalian target of rapamycin complex 1 (mTORC1) signaling, down-regulates the activity and expression of key placental nutrient transporters and decreases fetal growth. Preliminary findings indicate that adiponectin binds to the adiponectin receptor-2 on the trophoblast cell and activates p38 MAPK and PPAR-α, which inhibits the insulin/IGF-1 signaling pathway. In contrast to maternal adiponectin, recent reports suggest that fetal adiponectin may promote expansion of adipose tissue and stimulate fetal growth. Regulation of placental function by adiponectin constitutes a novel physiological mechanism by which the endocrine functions of maternal adipose tissue influence fetal growth. These findings may help us better understand the factors determining birth weight in normal pregnancies and in pregnancy complications associated with altered maternal adiponectin levels such as obesity and gestational diabetes.     

Placental dysfunction and fetal programming: the importance of placental size, shape, histopathology, and molecular composition

Normal function of the placenta is pivotal for optimal fetal growth and development. Fetal programming commonly is associated with placental dysfunction that predisposes to obstetric complications and suboptimal fetal outcomes. We consider several clinical phenotypes for placental dysfunction that likely predispose to fetal programming. Some of these reflect abnormal development of the chorioallantoic placenta in size, shape, or histopathology. Others result when exogenous stressors in the maternal environment combine with maladaptation of the placental response to yield small placentas with limited reserve, as typical of early-onset intrauterine growth restriction and preeclampsia. Still others reflect epigenetic changes, including altered expression of imprinted genes, altered enzymatic activity, or altered efficiencies in nutrient transport. Although the human placenta is a transient organ that persists only 9 months, the effects of this organ on the offspring remain for a lifetime.     

Fetal growth restriction: a workshop report

Intrauterine growth restriction (IUGR) is associated with significantly increased perinatal morbidity and mortality as well as cardiovascular disease and glucose intolerance in adult life. A number of disorders from genetic to metabolic, vascular, coagulative, autoimmune, as well as infectious, can influence fetal growth by damaging the placenta, leading to IUGR as a result of many possible fetal, placental and maternal disorders. Strict definitions of IUGR and of its severity are needed in order to eventually distinguish among different phenotypes, such as gestational age at onset, degree of growth restriction and presence of hypoxia. This report explores and reviews some of the most recent developments in both clinical and basic research on intrauterine growth restriction, by seeking mechanisms that involve genetic factors, utero-placental nutrient availability and vascular growth factors. New exciting findings on the genomic imprinting defects potentially associated with IUGR, and the placental anomalies associated with the decreased nutrient transport are summarized. Moreover, recent data on angiogenic growth factors as well as new information arising from application of gene chip technologies are discussed.     

Maternal cocaine use and cigarette smoking in pregnancy in relation to amino acid transport and fetal growth.

This review covers the weight of evidence that shows the association of cocaine and cigarette smoking in pregnancy with the impaired transplacental amino acid transport which might give rise to fetal growth restriction (IUGR). Vasoconstrictive effects of both cocaine and nicotine on the placental vasculature are clearly not the only cause for inhibition of placental amino acid uptake and transfer. In vitro studies strongly suggest that cocaine decreases the activity of placental amino acid transport system A and system N, and possibly system l and system y(+), while nicotine decreases the activity of system A. These findings are supported by cordocentesis studies in human IUGR pregnancies not resulting from drug abuse. More work is needed to be done in order to understand the potential additive or synergistic effect of cocaine and cigarette smoking on fetal growth and to determine the underlying cellular mechanisms of interaction with placental amino acid transporters.     

Leptin Affects System A Amino Acid Transport Activity in the Human Placenta: Evidence for STAT3 Dependent Mechanisms

BackgroundAmino acids are important nutrients during fetal development, and the activity of placental amino acid transporters is crucial in the regulation of fetal growth. Leptin, an adipocyte- and placenta-derived hormone, has been proposed to act as a peripheral signal in reproduction in humans. Leptin is elevated during pregnancy and elevated further in pathologic pregnancies such as preeclampsia. However, the role of leptin in placental function has not been fully elucidated. We hypothesize that leptin plays a role in the regulation of placental amino acid transport by activation of the JAK–STAT pathway.MethodsPlacental amino acid transport, specifically system A transport was studied in placental villous fragments using the amino acid analog, methylaminoisobutyric acid (MeAIB). Specific inhibitors of the JAK–STAT signal transduction pathway were used to further elucidate their role in leptin-mediated effects on amino acid transport activity. Western blotting was performed to identify STAT3 phosphorylation as a measure of leptin receptor activation.ResultsLeptin significantly increased system A amino acid transporter activity by 22–42% after 1 h of incubation. Leptin activated JAK–STAT signaling pathway as evidenced by STAT3 phosphorylation, and inhibition of STAT3 or JAK2 resulted in 36–45% reduction in system A amino acid transporter activity. Furthermore, blocking endogenously produced leptin also decreased system A transport by 45% comparable to STAT3 inhibition.ConclusionsThese data demonstrate that leptin stimulates system A by JAK–STAT dependent pathway in placental villous fragments. Our findings support the autocrine/paracrine role of leptin in regulating amino acid transport in the human placenta.     

Nutrient transport across the intrauterine growth-restricted placenta

This chapter is a brief review of the current literature on nutrient transport across the intrauterine growth restricted placenta in human pregnancies in vivo. These studies, performed at the time of fetal blood sampling or elective cesarean section, show that the placenta plays a very important role in the pathophysiology of intrauterine growth restriction, clarifying the mechanisms of impaired nutrient placental transport. Further studies are needed though to open new perspectives in the clinical management and in the prevention of the disease.     

The Role of the Placenta in Fetal Programming—A Review

The fetal origins hypothesis proposes that adult cardiovascular and metabolic disease originate through developmental plasticity and fetal adaptations arising from failure of the materno-placental supply of nutrients to match fetal requirements. The hypothesis is supported by experimental data in animals indicating that maternal nutrition can programme long term effects on the offspring without necessarily affecting size at birth. There is now evidence linking body composition in pregnant women and the balance of nutrient intake during pregnancy with raised levels of cardiovascular risk factors in the offspring. Maternal body composition and diet are thought to affect fetal development and programming as a result of both direct effects on substrate availability to the fetus and indirectly through changes in placental function and structure. Alterations in placental growth and vascular resistance, altered nutrient and hormone metabolism in the placenta, and changes in nutrient transfer and partitioning between mother, placenta and fetus all have important effects on the fetal adaptations thought to be central to programming. Future interventions to improve placental function are likely to have lifelong health benefits for the offspring.     

Intrauterine growth restriction and genetic determinants - existing findings,problems, and further direction

Fetal growth is determined largely by the nutrient supply, placental transport function, and growth hormones. Recently, gene mutation and expression, especially of those genes associated with the proteins that are related to the fetal growth, have been reported to play an important role in the development of intrauterine growth restriction (IUGR). Fetal growth epigenetics, a new concept in fetal growth, has resulted from studies on fetal programing. This paper outlines the findings of our serial studies on IUGR, and summarizes data on IUGR animal models, placental function in transferring nutrients, cell proliferation dynamics in IUGR, and experimental treatment of IUGR. We review genetic approaches to IUGR, especially those relating to growth factor genes, angiotensinogen genes and other gene mutations. We also discuss the epigenetics of fetal growth and future study directions on fetal growth restriction. These should be valuable in elucidating the mechanisms employed by the fetus and in helping to develop interventional strategies that might prevent the development of IUGR.     

Placental transport and metabolism of amino acids

This review examines the placental transport and metabolism of amino acids, with a special emphasis on unifying and interpreting in-vivo and in-vitro data. For a variety of technical reasons, in-vivo studies, which quantify placental amino-acid fluxes and metabolism, have been relatively limited, in comparison to in-vitro studies using various placental preparations. Following an introduction to placental amino-acid uptake and transfer to the fetus, the review attempts to reconcile in-vitro placental transport data with in-vivo placental data. Data are discussed with reference to the measured delivery rates of amino acids into the fetal circulation and the contribution of placental metabolism to this rate for many amino acids. The importance of exchange transporters in determining efflux from the placenta into the fetal circulation is presented with special reference to in-vivo studies of non-metabolizable and essential amino acids. The data which illustrate the interconversion and nitrogen exchange of three groups of amino acids, glutamine-glutamate, BCAAs and serine-glycine, within the placenta are discussed in terms of the potential role such pathways may serve for other placenta functions. The review also presents comparisons of the sheep and human placentae in terms of their in-vivo amino-acid transport rates.     

Moderate maternal nutrient restriction, but not glucocorticoid administration, leads to placental morphological changes in the baboon (Papio sp.)

The aims of the present study were to describe the ontogeny of spatial relationships between placental components in baboons and to investigate alterations in these indices following (1) moderate maternal nutrient restriction and (2) administration of glucocorticoids to pregnant baboons. We investigated the effects of glucocorticoids since they have been shown to play a role in the altered fetal growth that accompanies maternal nutrient restriction. Glucocorticoids are also given to pregnant women who threaten premature labor to accelerate fetal lung maturation. A third aim was to compare our findings to those in similar conditions in human pregnancy. Volumetric placental development in the baboon was similar to that in the human, although growth of fetal capillaries was slower over the second half of gestation in baboon than in human placentas. Intervillous space (IVS) and villous star volumes were halved at the end of gestation compared to the middle of gestation, as described in the human placenta. When mothers were fed 70% of feed eaten by controls fed ad libitum, placental volumetric structure was unchanged at mid-gestation but was altered by the end of gestation when placental weight, but not fetal weight or length, was decreased. At the end of gestation villous volume and surface area, capillary surface area, and the villous isomorphic coefficient were all decreased, In contrast, IVS hydraulic diameter was increased. All parameters were similar in pregnancies with male and female fetuses, with the exception of fetal capillary volume, which was unchanged in pooled samples and those from male fetuses, but decreased in pregnancies with female fetuses. Glucocorticoid administration during the second half of gestation did not produce any changes in the measured indices of placental composition. In summary, these changes in placental structure, associated with maternal nutrient restriction, would all act to decrease placental transport of nutrients. The influence of MNR on villous capillarization depends on fetal gender.     

Placental glucose transport in gestational diabetes mellitus

OBJECTIVE: We have previously reported that type 1 diabetes mellitus with hyperglycemia during the first trimester is associated with an up-regulation of placental glucose transport at term. We speculated that glucose concentrations regulate placental glucose transporters only during early pregnancy. To test this hypothesis we studied placental glucose transport in gestational diabetes mellitus, which is associated with hyperglycemia mainly during the second half of pregnancy. STUDY DESIGN: Syncytiotrophoblast microvillous membrane vesicles and basal membrane vesicles were isolated from uneventful pregnancies (control group, n = 32) and pregnancies complicated by gestational diabetes mellitus (n = 18). Glucose uptake and glucose transporter 1 expression were studied by means of radiolabeled tracers and Western blotting, respectively. RESULTS: Gestational diabetes mellitus was not associated with alterations in placental glucose transport. Separate analysis of 6 patients in the gestational diabetes mellitus group with large-for-gestational-age babies did not affect these results. CONCLUSION: These findings are consistent with the hypothesis that the sensitivity of placental glucose transporters to regulation by nutrient availability is limited to early pregnancy.     

Large chloride channel from pre-eclamptic human placenta

Chloride transport involving conductive pathways participates in numerous epithelial functions, such as membrane voltage maintenance, solute transport and cell volume regulation. Evidence points to involvement of transepithelial chloride transport in such functions in placental syncytiotrophoblast. A molecular candidate for physiologic conductive chloride transport in apical syncytiotrophoblast membrane is a Maxi-chloride channel with distinct biophysical properties: conductance over 200 pS, multiple substates, voltage dependent open probability, and permeation to anionic amino acids. Pre-eclampsia, a high incidence pathology of pregnancy, exerts great impact on fetal morbi-mortality. This relies, among others, on intrauterine growth restriction (IUGR), thought to be mediated by diminished blood flow to the placenta, with growing knowledge regarding contribution of other factors. The Maxi-chloride channel's properties suggest it could be altered in this pathology. We have characterized the apical chloride channels from pre-eclamptic placentae, reconstituted in giant liposomes suitable for patch-clamp electrophysiological studies. In n=33 experiments from n=6 pre-eclamptic placentae we observed a chloride-permeable channel with similar biophysical properties to the channel from normal tissue (n=29 experiments from n=15 placentae). However, the main conductance state showed diminished magnitude (<150 pS), and the open probability versus voltage relationship exhibited a flattened curve instead of the bell-shaped curve of normal placentae. These results are the first evidence of a functionally altered ionic channel from placental syncytiotrophoblast in pre-eclampsia. Considering the abundance of chloride-conducting channel activity in human apical membrane and their relevance in epithelial function in general, these alterations could greatly disturb numerous placental functions that rely on syncytiotrophoblast integrity.     

Review: Alterations in placental glycogen deposition in complicated pregnancies: Current preclinical and clinical evidence

Normal placental function is essential for optimal fetal growth. Transport of glucose from mother to fetus is critical for fetal nutrient demands and can be stored in the placenta as glycogen. However, the function of this glycogen deposition remains a matter of debate: It could be a source of fuel for the placenta itself or a storage reservoir for later use by the fetus in times of need. While the significance of placental glycogen remains elusive, mounting evidence indicates that altered glycogen metabolism and/or deposition accompanies many pregnancy complications that adversely affect fetal development. This review will summarize histological, biochemical and molecular evidence that glycogen accumulates in a) placentas from a variety of experimental rodent models of perturbed pregnancy, including maternal alcohol exposure, glucocorticoid exposure, dietary deficiencies and hypoxia and b) placentas from human pregnancies with complications including preeclampsia, gestational diabetes mellitus and intrauterine growth restriction (IUGR). These pregnancies typically result in altered fetal growth, developmental abnormalities and/or disease outcomes in offspring. Collectively, this evidence suggests that changes in placental glycogen deposition is a common feature of pregnancy complications, particularly those associated with altered fetal growth.     

Pathophysiology of fetal growth restriction: implications for diagnosis and surveillance

Normal fetal growth depends on the genetically predetermined growth potential and is modulated by fetal, placental, maternal, and external factors. Fetuses with intrauterine growth restriction (IUGR) are at high risk for poor short- and long-term outcome. Although there are many underlying etiologies, IUGR resulting from placental insufficiency is most relevant clinically because outcome could be altered by appropriate diagnosis and timely delivery. A diagnostic approach that aims to separate IUGR resulting from placental disease from constitutionally small fetuses and those with other underlying etiologies (e.g., aneuploidy, viral infection, nonaneuploid syndromes) needs to integrate multiple imaging modalities. In placental-based IUGR, cardiovascular and behavioral responses are interrelated with the disease severity. Ultrasound assessment of fetal anatomy, amniotic fluid volume, and growth is complementary to the Doppler investigation of fetoplacental blood flow dynamics. A diagnostic approach to IUGR combining these modalities is presented in this review. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to describe the development of the placental interface, to outline the mechanisms of placental insufficiency, and to list the manifestations of placental insufficiency and the tests that can be used to diagnose fetal growth restriction.