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.     

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.     

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.     

Placental system A amino acid transport is reduced in pregnancies with small for gestational age (SGA) infants but not in preeclampsia with SGA infants

Preeclampsia and intrauterine growth restriction (IUGR) are both associated with abnormal remodeling of maternal spiral arteries perfusing the placental site. This would be expected to be associated with reduced fetal growth, yet only one third of infants of mothers with preeclampsia are growth restricted. Infants with IUGR have decreased concentrations of amino acids in their blood and system A amino acid transporter activity is reduced in their placentas. Since infants of preeclamptic pregnancies have increased circulating amino acids, we tested system A amino acid transport activity of placental villous fragments from pregnancies with small for gestational age (SGA) infants with and without maternal preeclampsia and from uncomplicated and preeclamptic pregnancies with normal sized infants. We confirm the reduced uptake of amino acids in SGA pregnancies without preeclampsia but report that placental amino acid uptake of SGA infants with maternal preeclampsia is not reduced and is identical to uptake by normal and preeclamptic pregnancies with normal weight infants.     

Regulation of placental nutrient transport--a review

Fetal growth is primarily determined by nutrient availability, which is intimately related to placental nutrient transport. Detailed information on the regulation of placental nutrient transporters is therefore critical in order to understand the mechanisms underlying altered fetal growth and fetal programming. After briefly summarizing the cellular mechanisms for placental transport of glucose, amino acids and free fatty acids, we will discuss factors shown to regulate placental nutrient transporters and review the data describing how these factors are altered in pregnancy complications associated with abnormal fetal growth. We propose an integrated model of regulation of placental nutrient transport by maternal and placental factors in IUGR.     

Placental transport of amino acids in normal and growth-restricted pregnancies

In human pregnancies placental amino acid transport has been studied at the time of delivery and also by in utero fetal blood sampling (FBS). A significant reduction in amino acid fetal-maternal gradients and in umbilical veno-arterial differences has been demonstrated in intrauterine growth-restricted (IUGR) pregnancies. Fetal-maternal transfer rates have been further investigated in vivo by stable isotope methodologies. Following a maternal bolus infusion of [1-13C]-glycine and [1-13C]-leucine performed at fetal blood sampling, the transfer rate of the non-essential amino acid glycine is significantly lower than that for the essential amino acid leucine, suggesting that glycine can be newly synthesized in the feto-placental unit. Moreover, in growth-restricted pregnancies the fetal/maternal ratio of [1-13C]-leucine is significantly lower, and proportional to the degree of severity. In vitro studies have described a variety of transport systems for amino acids within the microvillous membrane (MVM) and the basal membrane (BM) of the placenta and significant differences have been reported in growth-restricted pregnancies for system A, system L, and taurine transporters. These changes are significantly associated to both biophysical and biochemical parameters of severity. Moreover, significant relationships can be found in arginine transport system and uterine oxygenation, suggesting a role in nitric oxide (NO) synthesis.     

Uterine blood flow--a determinant of fetal growth

An adequate increase of uterine blood flow throughout gestation is essential for uterine, placental and fetal growth. Maternal cardiovascular adaptation has to provide the uterine perfusion that is necessary to meet the requirements of the developing and growing fetus by providing transport of nutrients and oxygen to the placenta and the fetus. Thus, uterine blood flow is inextricably linked to fetal growth and survival. Reductions of uterine blood flow can occur under acute or chronic conditions or in a combination of both. Chronic reductions of uterine blood flow can be observed in pregnancy-induced hypertension (PIH), diabetes mellitus in pregnancy and intrauterine growth restriction (IUGR). Chronic restrictions in uterine blood flow will elicit a placental and fetal response in the form of growth adaptation to the reduced supply of oxygen and nutrients to the conceptus. If compensatory growth restriction reaches its limits intrauterine fetal distress can ensue. Among the great number of experimental models of intrauterine growth restriction, those involving a generalized reduction in the uteroplacental blood supply are of significance to questions relating to human pregnancy. Despite physiological differences, particularly with regard to maternal metabolism and placentation, the occlusion model in the pregnant sheep is suitable for investigating questions about fetal and placental growth.     

Uterine Doppler velocimetry and placental hypoxic-ischemic lesion in pregnancies with fetal intrauterine growth restriction.

We tested the hypothesis that Doppler velocimetry of the ascending uterine arteries (Ut.DV) in cases of fetal intrauterine growth restriction (IUGR) can reflect the presence of hypoxic-ischaemic lesions of the placenta, and whether this prediction is affected by the maternal blood pressure status.Ut.DV was obtained within 7 days of delivery in 90 consecutive pregnancies with IUGR and in 37 uneventful control pregnancies. Abnormal Ut.DV was defined as an average of a (left and right systolic)/diastolic ratio >2.6 and diastolic notching. After delivery, pathological studies were performed with attention paid to macroscopic and microscopic evidence of hypoxic or ischaemic placental lesions related to uteroplacental vascular pathological features.In patients with IUGR, the total rate of placental lesions was significantly higher in the presence of abnormal Ut.DV compared to the presence of normal Ut.DV (relative risk, 6.35; 95 per cent confidence interval=5.2-7.3). The rate and the severity of these lesions was not significantly different between normotensive and hypertensive pregnancies (87 versus 93 per cent;P =0.2). When Ut.DV was normal, the rate of placental lesions was similar between IUGR cases and control pregnancies (14 versus 8 per cent;P =0.69). The perinatal outcome was not significantly different in any of the normotensive and the hypertensive pregnancies with growth-restricted fetuses and abnormal Ut.DV.The presence of abnormal Doppler velocimetry of the uterine arteries in pregnancies with fetal intrauterine growth restriction is may be in fact an important indicator of hypoxic or ischaemic placental lesions. This abnormal Doppler velocimetry is independent of the maternal blood pressure status.     

An animal model of placental insufficiency-induced intrauterine growth restriction

Intrauterine growth restriction (IUGR), often associated with functional placental insufficiency, results in increased perinatal mortality and morbidity. For obvious reasons, many questions regarding the progression of IUGR pregnancies cannot be addressed experimentally in humans, predicating the use of animal models. Although no animal model fully recapitulates human pregnancy, the pregnant sheep has been used extensively to investigate maternal-fetal interactions. In sheep, surgical placement of catheters in both the maternal and fetal vasculature allows repeated sampling from nonanesthetized pregnancies. Considerable insight has been gained on placental oxygen and nutrient transfer and utilization from use of pregnant sheep, often confirmed in the human once appropriate technologies became available. This review will focus on one sheep model, used to examine the impact of placental insufficiency-induced IUGR on oxygen and nutrient transport and utilization.     

Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) as seen in preeclampsia is associated with high levels of fetal DNA in maternal circulation, and whether fetal DNA is related to altered uterine and/or umbilical artery Doppler velocimetry. METHODS: Fetal DNA quantification was performed by real-time PCR on SRY sequences in 64 male-bearing pregnant women with IUGR and/or preeclampsia and 89 controls. RESULTS: Fetal DNA content was significantly elevated in IUGR pregnancies similar to preeclampsia and correlated with altered umbilical Doppler velocimetry, while no correlation was found with uterine Doppler status. CONCLUSION: Increased fetal DNA levels in maternal plasma may be a sign of placental or fetal pathology even in the presence of normal uterine Doppler velocimetry, allowing a more precise diagnostic evaluation. The finding that elevated fetal DNA in IUGR pregnancies correlates with abnormal umbilical Doppler velocimetry suggests that fetal DNA release is associated more with fetal chronic hypoxia than with fetal size.     

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.     

Evaluation of maternal and umbilical serum TNFα levels in preeclamptic pregnancies in the intrauterine normal and growth-restricted fetus

Objective.?The aim of this study was to carry out a comparative analysis of the maternal and umbilical cord TNFα serum levels in pregnancies complicated by severe preeclampsia with normal intrauterine fetal growth, in preeclamptic pregnancies with intrauterine growth restriction (IUGR), and in normotensive pregnant patients.

Patients and methods.?The study was carried out on eight patients with severe preeclampsia complicated by IUGR and 18 preeclamptic patients with normal intrauterine fetal growth. The control group consisted of 18 healthy normotensive patients with singleton uncomplicated pregnancies. Maternal and umbilical serum TNFα concentrations were estimated using a sandwich ELISA assay.

Results and conclusions.?Pregnant women with severe preeclampsia had significantly higher maternal and umbilical serum TNFα levels than those in the normotensive controls. Our findings and other reports indicate that TNFα may participate in the pathogenesis and sequelae of preeclampsia with and without IUGR. The results of excessive umbilical serum activity of tumor necrosis factor α (TNFα) in preeclamptic pregnancy complicated by intrauterine growth restriction (IUGR) may suggest additional changes and dysfunction of the placental–fetal unit and deterioration of placental function, leading to fetal hypotrophia in the course of preeclampsia.     

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.     

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.     

In Vivo Characteristics of Placental Amino Acid Transport and Metabolism in Ovine Pregnancy—A Review

The placental transport of amino acids which is nutritionally important is the net entry rate into the fetal circulation (the umbilical uptake). This entry rate is a function of transport across cell membranes, the effect of competition among amino acids for transport, particularly across the fetal surface of the trophoblast, and their metabolism and interconversion within the placenta. The result of these different interactive fluxes is that the relationship between maternal concentration and fetal supply of an amino acid differs for each amino acid. For some amino acids there are relatively large bidirectional fluxes at both the fetal and maternal surfaces of the placenta. These fluxes can be measured in vivo utilizing stable isotope methodology. There is an important interorgan exchange of amino acids between the placenta and fetal liver. This exchange is, at least in part, a function of the absence of gluconeogenesis in the fetal liver. Both glutamate and serine, which are released from the fetal liver, are taken up by the placenta from the fetal circulation and metabolized within the placenta.     

Evaluation of maternal and umbilical serum TNFalpha levels in preeclamptic pregnancies in the intrauterine normal and growth-restricted fetus.

OBJECTIVE: The aim of this study was to carry out a comparative analysis of the maternal and umbilical cord TNFalpha serum levels in pregnancies complicated by severe preeclampsia with normal intrauterine fetal growth, in preeclamptic pregnancies with intrauterine growth restriction (IUGR), and in normotensive pregnant patients. PATIENTS AND METHODS: The study was carried out on eight patients with severe preeclampsia complicated by IUGR and 18 preeclamptic patients with normal intrauterine fetal growth. The control group consisted of 18 healthy normotensive patients with singleton uncomplicated pregnancies. Maternal and umbilical serum TNFalpha concentrations were estimated using a sandwich ELISA assay. RESULTS AND CONCLUSIONS: Pregnant women with severe preeclampsia had significantly higher maternal and umbilical serum TNFalpha levels than those in the normotensive controls. Our findings and other reports indicate that TNFalpha may participate in the pathogenesis and sequelae of preeclampsia with and without IUGR. The results of excessive umbilical serum activity of tumor necrosis factor alpha (TNFalpha) in preeclamptic pregnancy complicated by intrauterine growth restriction (IUGR) may suggest additional changes and dysfunction of the placental-fetal unit and deterioration of placental function, leading to fetal hypotrophia in the course of preeclampsia.     

Discordant clinical presentations of preeclampsia and intrauterine fetal growth restriction with similar pro- and anti-angiogenic profiles

Abstract

Objective: To evaluate the plasma levels of angiogenic factors in preeclampsia (PE) and intrauterine fetal growth restriction (IUGR) and their potential as biomarkers to distinguish normal from pathologic pregnancies.

Methods: Case control study included singleton pregnancies in four categories: (i) normal (n?=?29), (ii) PE (n?=?15), (iii) PE and IUGR (n?=?16) and (iv) IUGR (n?=?24). The classification of IUGR included umbilical artery Doppler resistance. Maternal plasma placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble kinase domain receptor (sKDR) and soluble endoglin (sEng) as well as fetal umbilical artery sFlt-1 levels were determined. Each individual marker and their ratios were assessed for their potential to distinguish normal pregnancy from pregnancies affected by PE and/or IUGR.

Results: We found (i) elevated plasma sFlt-1, sEng and reduced PlGF, sKDR in PE and IUGR; (ii) similar angiogenic profiles in PE and IUGR and (iii) sEng and sFlt-1*sEng/PlGF performed best as biomarkers in identifying pathologic pregnancies.

Conclusions: PE and IUGR have similar angiogenic profiles, suggesting that angiogenic marker profiles lack specificity in identifying PE and that other factors are required for the development of PE instead of IUGR. sEng should be included in a biomarker profile for predicting PE or IUGR.     

Maternal and fetal plasma endothelin levels in intrauterine growth restriction: relation to umbilical artery Doppler flow velocimetry

The objective of this study was to examine maternal and fetal endothelin-1 (ET-1) in pregnancies complicated with intrauterine growth restriction (IUGR) and to correlate these data with umbilical artery Doppler flow velocity waveforms (FVW). Higher mean maternal (13.8 +/- 6.4 vs 9.2 +/- 3.4 pmol/L, p < 0.05) and fetal (18.5 +/- 9.6 vs 11.7 +/- 6.9 pmol/L, p < 0.05) ET-1 levels were found in pregnancies complicated with IUGR than in controls. Fetal ET-1 level was related to birth weight percentile for gestational week. Maternal and fetal ET-1 concentrations were not related to umbilical artery Doppler flow S/D ratio, PI and RI. Maternal or fetal ET-1 concentrations were also not related to umbilical artery pH, PO2 and PCO2. Pregnancy-induced hypertension was significantly associated with an elevated fetal and maternal ET-1 concentration. In conclusion, increased production and secretion of ET-1 may play a role in the pathophysiology of idiopathic IUGR. Over-production of ET-1 in IUGR is not associated with increased placental resistance as reflected in abnormal umbilical artery Doppler FVW.     

Placental 11beta-hydroxysteroid dehydrogenase type 2 is reduced in pregnancies complicated with idiopathic intrauterine growth Restriction: evidence that this is associated with an attenuated ratio of cortisone to cortisol in the umbilical artery

The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) serves as a functional barrier to protect the fetus from excessive exposure to high levels of maternal cortisol. There is evidence that placental 11beta-HSD2 is reduced in pregnancies complicated with intrauterine growth restriction (IUGR), but the relationship between the two is uncertain owing to other maternal complications often associated with this pathological condition of pregnancy. To gain insight into the role of placental 11beta-HSD2 in the pathogenesis of IUGR, we studied variations in the activity and expression of this important enzyme as well as its functional indicator, the ratio of cortisone to cortisol in umbilical cord blood, in a cohort of 12 term deliveries complicated with idiopathic IUGR and 12 term controls. We showed that both placental 11beta-HSD2 activity and mRNA were reduced in IUGR. This was accompanied by a decrease in the ratio of cortisone to cortisol in the umbilical artery, suggesting that not only placental but also fetal 11beta-HSD2 activity may be compromised in idiopathic IUGR. Given that we previously identified the nuclear receptor PPARdelta as a potent suppressor of placental 11beta-HSD2, we also tested but found no evidence to support the hypothesis that placental PPARdelta expression is increased in IUGR thereby contributing to the molecular mechanisms that underlie the attenuated placental 11beta-HSD2. Taken together, our present findings provide evidence suggesting a role for an attenuated placental as well as fetal 11beta-HSD2 in the pathogenesis of IUGR.     

Reduced l-Arginine Transport and Nitric Oxide Synthesis in Human Umbilical Vein Endothelial Cells from Intrauterine Growth Restriction Pregnancies is Not Further Altered by Hypoxia

Intrauterine growth restriction (IUGR) is associated with chronic fetal hypoxia, altered placental vasodilatation and reduced endothelial nitric oxide synthase (eNOS) activity. In human umbilical vein endothelial cells (HUVEC) from pregnancies complicated with IUGR (IUGR cells) and in HUVEC from normal pregnancies (normal cells) cultured under hypoxia l-arginine transport is reduced; however, the mechanisms leading to this dysfunction are unknown. We studied hypoxia effect on l-arginine transport and human cationic amino acid transporters 1 (hCAT-1) expression, and the potential NO and protein kinase C α (PKCα) involvement. Normal or IUGR HUVEC monolayers were exposed (0–24 h) to 5% O₂ (normoxia), and 1 or 2% O₂ (hypoxia). l-Arginine transport and hCAT-1 expression, phosphorylated and total PKCα or eNOS protein and mRNA expression were quantified. eNOS involvement was tested using a siRNA against eNOS (eNOS-siRNA) adenovirus. IUGR cells in normoxia or hypoxia, and normal cells in hypoxia exhibited reduced l-arginine transport, hCAT-1 expression, NO synthesis and eNOS phosphorylation at Serine¹¹⁷⁷, effects reversed by calphostin C (PKC inhibitor) and S-nitroso-N-acetyl-l,d-penicillamine (SNAP, NO donor). However, N^G-nitro-l-arginine methyl ester (l-NAME, NOS inhibitor) reduced hCAT-1 expression only in normal cells in normoxia. Increased Thr⁶³⁸-phosphorylated PKCα was exhibited by IUGR cells in normoxia or hypoxia and normal cells in hypoxia. The effects of hypoxia in normal cells were mimicked in eNOS-siRNA transduced cells; however, IUGR phenotype was unaltered by eNOS knockdown. Thus, IUGR- and hypoxia-reduced l-arginine transport could result from increased PKCα, but reduced eNOS activity leading to a lower hCAT-1 expression in HUVEC. In addition, IUGR endothelial cells are either not responsive or maximally affected by hypoxia. These mechanisms could be responsible for placental dysfunction in diseases where fetal endothelium is chronically exposed to hypoxia, such as IUGR.