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.     

Intrauterine growth retardation and diabetic pregnancy: two types of fetal malnutrition

Placental transfer of alpha-aminoisobutyric acid and methylglucose was studied near term in normal guinea pigs carrying growth-retarded fetuses and in streptozotocin-treated diabetic guinea pigs. Compared with their normal littermates, growth-retarded fetuses had lower placental weights and a diminished transfer of both nutrient analogues in proportion to the reduction in fetal weight. Fetuses from diabetic animals had normal fetal weight and placental methylglucose transfer but reduced litter size and a 40% reduction in placental alpha-aminoisobutyric acid transfer. These data suggest that intrauterine growth retardation in an otherwise normal pregnancy is associated with a small placenta and a reduced transfer of nutrients. Diabetic pregnancy may represent a different type of fetal malnutrition due to amino acid deprivation. It is speculated that birth weight does not necessarily reflect the degree of fetal malnutrition in diabetic pregnancy since fetal growth may be maintained by glucose and fat deposition.     

Origins of fetal growth restriction

Regulation of growth of the fetus and its placenta begins before pregnancy. Early in pregnancy the mother sets the rate of growth of the fetus on a trajectory, which may be modified by events later in pregnancy.Low maternal weight for height, history of previous small babies, maternal undernutrition, pregnancy disorders, e.g. pre-eclampsia, are associated with low birthweight. Maternal smoking is a major factor in developed countries; infections and undernutrition in developing countries.Recently, there has been emphasis on adverse long-term outcomes including ischaemic heart disease, hypertension and diabetes associated with poor fetal growth. Experimental studies in animals show that some of these outcomes can readily be induced by restriction of fetal growth.Progress in determining successful treatments to improve the growth of the fetus has lagged behind these epidemiological and experimental findings. However, nutrient supplements improve growth in undernourished women and smoking cessation also improves fetal size and outcome.     

Placental glycogen metabolism changes during walker tumour growth

The placenta provides all energy and nutrient requirements for healthy fetal development. The placenta in rats is capable of storing glycogen, although the placenta cells must therefore mobilize stored glycogen to its own glucose supply. Moreover, maternal glucose and/or placental lactate furnished the fetal growth. Adult female Wistar rats were divided into three groups: Control-C, tumour bearing-W; injected ascitic fluid-A. The rats were sacrificed on the 16th, 19th or 21st day of gestation, analysing the placenta and fetus weights and placental tissue samples was aliquoted for biochemical assays of glycogen and protein content and alkaline phosphatase activity. Placental sections were morphometrically analysed and glycogen positive cells were counted. The placental and fetal weight were significantly reduced in both W and A rats from 16th up to 21st day of gestation, which showed high levels of fetal reabsorption sites. Significant reduction in labyrinth zone at day 21 in both tumour bearing and ascitic fluid injected groups was shown, suggesting less substrate exchange at the maternal/fetal surface. The alkaline phosphatase activity as well total protein content were found to be reduced in W and A group. The total placental glycogen and glycogen cells decreased during tumour bearing and ascitic fluid injection, suggesting reduction in its own stored energy. Ascitic fluid injected group, representing an indirect tumour effect, presented similar reduction changes in the placenta to the tumour-bearing group. In conclusion, the tumour growth and, especially, ascitic fluid injection promoted irreversible placental tissue damage altering homeostasis and compromising fetal development.     

Relation between placental morphometry and fetal growth]

Forty-eight placentae of full term infants, 21 placentae from appropriate for gestational age infants (AGA) and 27 placentae from small for gestational age infants (SGA) were measured by morphometric technic using the automatic image analyzer, in order to find out the extent of fetomaternal exchange which determines the transfer of oxygen and nutrition from mother to fetus and fetal growth. The results of measurement correlated well both with infant birth weight and placental weight. They demonstrated striking quantitative differences when the placentae of SGA were compared with those of AGA. The placenta weights in the group of SGA were notably less than those in the group of AGA. It seems that low birth weight relates to low functional tissue mass of placenta. This reduction of functional tissue is accompanied by diminution of the area for exchange between mother and fetus, both at the villous surface area and at fetal capillary surface area. Thus, the ability of transferring oxygen and nutrition from mother to fetus is curtailed. The results show that the rate of fetal growth is limited by placental function as well as its weight.     

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.     

Environmental toxicants and placental function

The placenta is a temporary endocrine organ that facilitates gas, nutrient, and waste exchange between maternal and fetal compartments, partially shielding the fetus from potentially hazardous environmental toxicants. However, rather than being “opaque”, the placenta is translucent or even transparent to some potential fetal developmental hazards, including toxic trace elements (TEs), perfluoroalkyl and polyfluoroalkyl substances (PFAS), and environmental phenols (EPs) to which women with pregnancy are frequently exposed. These agents are both passively and actively transferred to the fetal compartment, where endocrine disruption, oxidative stress, and epigenetic changes may occur. These pathologies may directly impact the fetus or deposit and accumulate in the placenta to indirectly impact fetal development. Thus, it is critical for clinicians to understand the potential placental toxicity and transfer of widely distributed environmental agents ubiquitous during pregnancy. With such knowledge, targeted interventions and clinical recommendations can be developed to limit those risks.     

Review: The Placenta is a Programming Agent for Cardiovascular Disease

Cardiovascular disease remains the number one killer in western nations in spite of declines in death rates following improvements in clinical care. It has been 20 years since David Barker and colleagues showed that slow rates of prenatal growth predict mortality from ischemic heart disease. Thus, fetal undergrowth and its associated cardiovascular diseases must be due, in part, to placental inadequacies. This conclusion is supported by a number of studies linking placental characteristics with various adult diseases. A “U” shaped relationship between placental-to-fetal weight ratio and heart disease provides powerful evidence that placental growth-regulating processes initiate vulnerabilities for later heart disease in offspring. Recent evidence from Finland indicates that placental morphological characteristics predict risks for coronary artery disease, heart failure, hypertension and several cancers. The level of risk imparted by placental shape is sex dependent. Further, maternal diet and body composition strongly influence placental growth, levels of inflammation, nutrient transport capacity and oxidative stress, with subsequent effects on offspring health. Several animal models have demonstrated the placental roots of vulnerability for heart disease. These include findings that abnormal endothelial development in the placenta is associated with undergrown myocardial walls in the embryo, and that placental insufficiency leads to depressed maturation and proliferation of working cardiomyocytes in the fetal heart. Together these models suggest that the ultimate fitness of the heart is determined by hemodynamic, growth factor, and oxygen/nutrient cues before birth, all of which are influenced, if not regulated by the placenta.     

Glycemic control in the diabetic pregnancy: is tighter always better?

Glucose is the principal nutrient that the mother supplies to the fetus through the placenta by way of concentration-dependent mechanisms. In the presence of maternal hypoglycemia, with limited glucose supply, fetal hypoglycemia and hypoinsulinism ensue. This may be viewed as an adaptive mechanism to increase the chances of fetal survival in the face of limited maternal supply, albeit of a growth-restricted fetus. Fetal nutrient deprivation and the resulting hypoinsulinism may have both short- and long-term consequences. Intrauterine growth failure is associated with higher rates of gestational age-specific neonatal mortality and with long-term cognitive deficits. Furthermore, epidemiologic data suggest that diabetes, coronary artery disease, and hypertension are more common among adults who were small for gestational age at birth. Thus, pancreatic failure in adulthood may be either a response to excessive exposure to glucose as a result of maternal hyperglycemia, or as a result of hypoglycemia where nutrient deprivation leads to fetal growth restriction and reduced islet cell proliferation. Because low mean concentrations of maternal glucose in gestational diabetes are associated with an increased risk of fetal growth restriction, overzealous glycemic control during pregnancy may raise concerns regarding the possible effects on the infant. In the mother with Type 1 diabetes, strict glycemic control is often associated with an increased incidence of severe hypoglycemia. Up to 40% of women report at least one episode of severe hypoglycemia during pregnancy, requiring assistance by another person or professional intervention. It is quite possible that in some patients striving to optimize pregnancy outcome by maintaining the best possible glycemic control jeopardizes the well-being of the mother and the fetus. Thus, with respect to tight glycemic control of pregnant women with diabetes, the question arises: How tight is too tight? Is there a threshold below which the trade-off in terms of maternal morbidity as well as fetal growth restriction and its consequences outweighs the benefits of preventing the effects of maternal hyperglycemia?     

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.     

Apoptosis in the placenta of pregnancies complicated with IUGR.

OBJECTIVE: In this study we have investigated the presence of apoptosis in the placental tissue of pregnancies complicated with intra-uterine growth restriction (IUGR). METHOD: Placental samples were obtained from 22 normal third trimester pregnancies and 20 pregnancies complicated with IUGR. The criteria for fetal growth impairment were clinical evidence of sub-optimal growth, ultrasonographic demonstration of deviation from normal percentiles of growth and birth weight under 10th percentile. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL) staining was used to demonstrate the apoptotic cells in all samples. Student-t, Mann-Withney U-test, Fisher exact test and Spearman correlation were used for statistical analysis. RESULTS: We detected apoptosis in 10 placentas in the study group vs. none in the control group. Placentas from pregnancies complicated with IUGR demonstrated 0.12% (0.1%-0.4%) apoptotic cells. The rate of apoptotic cells in the placenta was significantly higher in pregnancies complicated with IUGR than normal uncomplicated pregnancy (P=0.0019). Apoptosis were more abundant in the trophoblasts, especially cytotrophoblasts, in the placenta. We could not find a correlation between the apoptosis in the placenta of pregnancies complicated with IUGR and birth weight, multi-parity, gestational age, birth weight percentile and mode of delivery (C/S vs. vaginal delivery). CONCLUSION: We believe that the increased number of apoptosis in the placenta of pregnancies complicated with IUGR may have an important compensatory role to transmit nutrition and gas exchange easily to the fetus.     

Undernutrition during the first half of gestation increases the predominance of fetal tissue in late-gestation ovine placentomes

OBJECTIVE: To investigate, in sheep, the effects of maternal undernutrition during the first half of pregnancy on placental growth and development and fetal growth. STUDY DESIGN: Six ewes (R) were subjected to a 15% reduction in nutrient intake for the first 70 days of gestation and thereafter received the recommended daily intake. Another group of six ewes (C) received the recommended daily intake throughout pregnancy. At 130 days gestation the ewes were killed and morphological and morphometrical measurements were carried out on the placenta and fetus. RESULTS: Undernutrition resulted in a significant alteration in placental morphology, which was seen as increased growth of the fetal side of the placenta in R animals. However, fetal size in late gestation was not affected by the undernutrition, suggesting that placental adaptation was successful in maintaining fetal growth. CONCLUSION: Placental adaptations, including changes in gross morphology, may preserve fetal growth if maternal undernutrition is not severe. The mechanisms remain to be elucidated.     

Maternal food restriction reduces the exchange surface area and increases the barrier thickness of the placenta in the guinea-pig

The extent to which maternal nutrition influences fetal growth through effects on placental functional development is unclear. Poor maternal nutrition is a major cause of poor fetal growth which increases neonatal morbidity and mortality, and may also increase the risk of several adult-onset diseases. We have therefore characterized the ontogeny of structural determinants of function in the placenta in guinea-pigs fed ad libitum or food restricted from before and during pregnancy. Guinea-pigs were killed at days 30 and 60 (term=67 days) of pregnancy. In ad libitum fed animals, the surface density (surface area/g placental labyrinth), which is a measure of the convolution of the exchange surface, doubled, while total surface area increased 18-fold between mid and late gestation. Concomitantly, the arithmetic mean barrier thickness to diffusion across trophoblast decreased by 68 per cent. Late in gestation, food restriction reduced the proportion of the placenta devoted to exchange (labyrinth) by 70 per cent (P< 0.04) and the weight of the placental labyrinth by 45 per cent (P=0.001). Maternal food restriction also reduced the total placental surface area for exchange by 36 per cent at day 30 (P=0.02) and 60 per cent at day 60 (P< 0.0005) of gestation, and the surface density of trophoblast by 36 per cent at day 30 (P=0.01) and 29 per cent at day 60 (P=0.005) of gestation. The arithmetic mean barrier thickness for diffusion was increased by maternal food restriction at both gestational ages (day 30, +37 per cent, P=0.008, and day 60, +40 per cent, P=0.01). These findings suggest that maternal food restriction not only reduces fetal and placental weights, but also induces structural alterations in the placenta that indicate functional impairment beyond what would be expected for the reduction in its weight.     

Effect of placenta previa on fetal growth restriction and stillbirth

Aim

To examine the association between placenta previa and adverse perinatal outcomes such as low birth weight, preterm delivery, stillbirth and fetal growth restriction (FGR).

Methods

This retrospective cohort study includes 12,034 delivered pregnant women who were recruited for the study between 2004 and 2010 in Ege University Hospital. Data were collected by browsing the clinic??s archives. The association between placenta previa and adverse perinatal outcomes was determined via Chi-square tests and Student??s t test. Logistic regression analysis was used to adjust for confounding factors in evaluating the association between placenta previa and the adverse perinatal outcomes.

Results

There was no significant relationship between placenta previa and FGR or stillbirth. Low birth weight and preterm delivery were significantly higher in the placenta previa group. According to logistic regression analysis, low birth weight was associated with an OR of 3.01 (95?% CI 2.05?C4.52) and preterm delivery was associated with an OR of 8.14 (95?% CI 5.60?C11.83); while, placenta previa did not affect FGR and stillbirth significantly.

Conclusion

Although there is no consensus on the association between placenta previa and FGR in previous studies, we suggest that placenta previa is not a reason for placental insufficiency. Management of placenta previa especially depends on maternal hemodynamic parameters such as heavy hemorrhage and hypotensive shock rather than fetal well-being protocols based on serial growth ultrasound and fetal Doppler investigation.     

Histologic chorioamnionitis is associated with fetal growth restriction in term and preterm infants

OBJECTIVE: Our aim was to evaluate associations between chorioamnionitis and fetal growth restriction in infants enrolled in the Collaborative Perinatal Project. STUDY DESIGN: A total of 2579 nonanomalous, singleton infants delivered at 28 to 44 weeks' gestation with chorioamnionitis were matched 1:3 for ethnicity, gestational age, parity, and maternal cigarette use (all of which were correlated with both chorioamnionitis and markers of fetal growth restriction) with 7732 control infants. Moderate or marked leukocytic infiltrates of the placenta defined chorioamnionitis. Birth weight, length, head circumference, weight/length ratio, ponderal index, and birth weight/head circumference ratio in the lowest 5th percentile were markers of fetal growth restriction. Placental weight and the birth weight/placental weight ratio were also evaluated. RESULTS: Compared with data on matched control infants, histologic chorioamnionitis was associated with all markers of fetal growth restriction and with low birth weight/placental weight ratios (odds ratios, 1.3-1.7). The strongest associations were found at 28 to 32 weeks' gestation (odds ratios, 2.2-11). Attributable risks for several markers of fetal growth restriction exceeded 50% in infants born at <33 weeks' gestation. CONCLUSION: Histologic chorioamnionitis is associated with multiple markers of fetal growth restriction, with stronger associations noted in prematurity.     

Review: Placenta,evolution and lifelong health

The intrauterine environment has an important influence on lifelong health, and babies who grew poorly in the womb are more likely to develop chronic diseases in later life. Placental function is a major determinant of fetal growth and is therefore also a key influence on lifelong health. The capacity of the placenta to transport nutrients to the fetus and regulate fetal growth is determined by both maternal and fetal signals. The way in which the placenta responds to these signals will have been subject to evolutionary selective pressures. The responses selected are those which increase Darwinian fitness, i.e. reproductive success. This review asks whether in addition to responding to short-term signals, such as a rise in maternal nutrient levels, the placenta also responds to longer-term signals representing the mother’s phenotype as a measure of environmental influences across her life course. Understanding how the placenta responds to maternal signals is therefore not only important for promoting optimal fetal growth but can also give insights into how human evolution affected developmental history with long-term effects on health and disease.     

Fetoplacental growth in sheep administered progesterone during the first three days of pregnancy

We have previously shown that administration of progesterone during early pregnancy in sheep enhances fetal weight and crown-rump length. The present study examined the effect of this treatment on individual fetal organ weights and on placental growth and structure. Embryos that had been exposed to either a normal or a high concentration of progesterone on days 1-3 in initial recipient ewes were transferred at random to final recipient ewes that had or had not been treated with progesterone on days 1-3. Embryos in an additional group of ewes were exposed to progesterone on days 1-3 with oviducts of the ewes ligated.An increase in fetal weight was observed in the final recipient group that had been treated with progesterone (P< 0.01) but not in the initial group treated with progesterone. Fetal weight was increased (P< 0.05) in the initial recipients treated with progesterone plus ligation. Placental weight did not differ between any of the treatments in either initial or final recipients, while placental volumes of chorionic membrane and maternal crypts were increased by progesterone, with and without ligation, in initial recipients (P< 0.05). The responses of fetal weight in final recipients were associated with increases in the weight and linear dimensions of specific fetal components (e.g. brain, kidney, heart, spleen, total gut, head width, thorax circumference). Proportionate increases were observed for most parameters with the exception of brain, heart and M tibialis anterior weight; adjusted least squares means indicated disproportionate increases in these of 5 per cent, 32 per cent and 26 per cent respectively. Enhanced fetal weight in the progesterone plus ligation group was associated with increased (P< 0.05) heart weight; a disproportionate increase of 39 per cent was recorded. Increased fetal weight and fetal heart, skeletal muscle and brain weight were correlated with increased volumes and surface area of the fetal trophectoderm and maternal fetomaternal syncytium in the final recipients treated with progesterone. It is concluded that alteration of the embryo's environment during the first few days of development enhances fetal growth disproportionately, in close association with increased abundance of the exchange epithelia in the placenta.     

The evolutionary significance of placental interdigitation in mammalian reproduction: Contributions from comparative studies

The placenta is fundamental to mammalian reproduction and is surprisingly diverse in gross morphology among species. Whether and how this diversity affects maternal investment and fetal growth is still poorly understood. Contrary to suggestions that highly invasive hemochorial placentation is beneficial to fetal development, recent comparative studies have revealed that interdigitation - the degree of contact between maternal and fetal tissues at the area of exchange - strongly influences fetal growth rates. Species with labyrinthine placentae give birth to neonates of similar size to those of species with villous or trabecular placentae but in less than half the time. These findings suggest that there might be tradeoffs between fetal growth rates (higher with greater interdigitation) and gestation time (shorter with greater interdigitation), in association with type of interdigitation. Such tradeoffs might be the results of maternal-offspring conflict over the allocation of maternal resources, with paternal genes favouring greater interdigitation and so higher fetal growth, and maternal genes responding by reducing gestation time. These results emphasize the role of interdigitation as a means to increase the surface area for exchange, and are consistent with within species studies demonstrating that a higher surface area for exchange is associated with heavier neonates. Further studies could investigate the role of other traits in the evolution of placental diversity and their impact on fetal development.