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.     

The Fascinating and Complex Role of the Placenta in Pregnancy and Fetal Well‐being

Existing evidence implicates the placenta as the origin of some common pregnancy complications. Moreover, some maternal conditions, such as inadequate nutrition, diabetes, and obesity, are known to adversely affect placental function, with subsequent negative impact on the fetus and newborn. The placenta may also contribute to fetal programming with health consequences into adulthood, such as cardiovascular, metabolic, and mental health disorders. There is evidence that altered placental development, specifically impaired trophoblast invasion and spiral artery remodeling in the first trimester, is the origin of preeclampsia. Prenatal care providers who understand the relationships between placental health and maternal‐newborn health can better inform and guide women to optimize health early in pregnancy and prior to conception. This article reviews the current understanding of placental function; placental contributions to normal fetal brain development and timing of birth; and impact of maternal nutrition, obesity, and diabetes on the placenta.     

Review: Placental derived biomarkers of pregnancy disorders

Pregnancy is one of the greatest physiological challenges that a women can experience. The physiological adaptations that accompany pregnancy may increase the risk of developing a number of disorders that can lead to both acute and chronic physiological outcomes. In addition, fetal development may be impaired and, if the fetus survives, the child may be at an increased risk of disease throughout life. Pregnancy disorders are poorly predicted by traditional risk factors and maternal history alone. The identification of biomarkers that can predict incidence and severity of disease would allow for improved and targeted prophylactic therapies to prevent adverse maternal and fetal outcomes. Many of these pregnancy disorders, including preeclampsia, intrauterine growth restriction, gestational diabetes mellitus and preterm birth are known to be regulated at least in part by poor trophoblast invasion and/or dysregulated placental function. Cellular stress within the placenta increases the release of a number of factors into the maternal circulation. While many of these factors minimally impact maternal biology, others affect key physiological systems and contribute to disease. Importantly, these factors may be detected in physiological fluids and have predictive capacity making them ideal candidates as biomarkers of pregnancy disorders. This review will discuss what is known about these placental derived biomarkers of pregnancy disorders and highlight potential clinical opportunities for disease prediction and diagnosis.     

Immunoregulation in normal pregnancy and pre-eclampsia: an overview

Pre-eclampsia is a major disorder of human pregnancy, which may have an immunological basis. It is a disease of two stages. The first stage concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The inadequate trophoblast invasion may result from decreased expression of human leukocyte antigen-G (HLA-G) leading to an abnormal interaction with decidual natural killer (NK) cells, which are believed to play a major role in these processes through the production of immunoregulatory cytokines and angiogenic factors. Recent evidence suggests that the interaction between trophoblast human leukocyte antigen-C (HLA-C) molecules and decidual NK cell receptors may be the point at which the apparent partner specificity of the disease originates. The second stage is the maternal syndrome, which is characterized by a generalized systemic inflammatory response involving both leukocytes and endothelium. The inflammatory stimulus is believed to come from the placenta. In pre-eclampsia, placental oxidative stress may lead to increased shedding of apoptotic and/or necrotic syncytiotrophoblast debris into the maternal circulation. There is evidence that such trophoblast debris interacts with maternal leukocytes and endothelial cells to stimulate the release of proinflammatory cytokines, which could then trigger the maternal disease.     

Implantationsst?rungen, Pr?eklampsie und intrauterine Wachstumsrestriktion

Preeclampsia and intrauterine growth restriction (IUGR) are major pregnancy pathologies and the leading causes of maternal and perinatal mortality and morbidity. Interestingly the etiologies of both syndromes are still unclear which is why a large number of hypotheses have been developed. The joint occurrence of both syndromes in a single pregnancy has deleterious effects on both mother and child. Studies dealing with such severe cases of preeclampsia with associated IUGR have led to the development of hypotheses attempting to explain all clinical and morphological alterations in a single hypothesis. This in turn has resulted in the general misconception that a failure in invasion of the placental trophoblast is directly linked with the etiology of preeclampsia. However, recent progress in the identification of new biomarkers to predict preeclampsia has changed views on the etiology of preeclampsia. It has become clear that a failure in trophoblast invasion is directly linked to IUGR while a defect of the villous trophoblast precedes preeclampsia.     

The value of ultrasonic placental grading: no correlation with intrauterine growth retardation or with maternal smoking

In a prospective study the usefulness of placental grading in detecting IUGR has been evaluated. Those who were echoscopically examined within one week before delivery were taken into the study (n = 137). Changes in placental tissue increased clearly as pregnancy progressed and in 42% (57/137) the placentae reached Grade III. Increasing placental grading is associated with normal maturation of the placenta. Post partum examination of the placenta correlated well with the echoscopic picture (accuracy = 80.5%). No relationship was found in an unselected group between Grade III and IUGR at term. When a Grade III placenta was first seen before 36 weeks, in three out of five cases a growth retarded neonate was born. The effects of maternal smoking habits during pregnancy on birth weight and placenta were examined. There were no significant differences in mean placental weight, placental ratio and placental grading as the amount of cigarettes increased. The mean birth weight and birth weight percentile decreased significantly when the mother smoked more than 10 cigarettes per day.     

Defective implantation and placentation: laying the blueprint for pregnancy complications

Normal implantation and placentation is critical for pregnancy success. Many pregnancy-related complications that present late in gestation (such as pre-eclampsia and preterm labour) appear to have their origins early in pregnancy with abnormalities in implantation and placental development. Implantation is characterized by invasion of the maternal tissues of the uterus by fetal trophoblast, and the degree to which trophoblast invades these tissues appears to be a major determinant of pregnancy outcome. Excessive invasion can lead to abnormally firm attachment of the placenta to the myometrium (placenta accreta) with increased maternal and perinatal morbidity. Inadequate invasion, specifically restricted endovascular invasion, has been implicated in the pathophysiology of such conditions as pre-eclampsia (gestational proteinuric hypertension), preterm premature rupture of membranes, preterm labour, and intrauterine growth restriction. The molecular and cellular mechanisms responsible for implantation remain enigmatic. This review will include an overview of implantation followed by a discussion of a number of molecular mechanisms implicated in defective implantation and placentation including the role of decidual prostaglandins and haemorrhage in regulating trophoblast invasion. An improved understanding of the molecular mechanisms responsible for abnormal implantation and placentation will likely improve clinicians' abilities to treat disorders that occur along this continuum, including infertility, recurrent pregnancy loss, pre-eclampsia, and preterm birth.     

The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations

The 'Fetal origins hypothesis' states that individuals born small because of malnutrition are predisposed to adult diseases. Fetal malnutrition has two main causes, poor maternal nutrition and placental insufficiency. A distinction between these causes is important because it is likely that maternal nutrition has been sufficient in the majority of populations in which the fetal origins hypothesis has been tested. Thus, placental insufficiency is a more reasonable cause of reduced fetal growth in adequately nourished populations. Placental insufficiency is mainly due to inadequate vascular adaptation at the uteroplacental interface ('poor placentation'). Among women with placental insufficiency syndromes such as pre-eclampsia and 'idiopathic' intrauterine growth retardation, there is an increased prevalence of risk factors for cardiovascular diseases. Maternal cardiovascular risk factors may therefore increase the risk of adult diseases in the offspring both through direct inheritance and by interfering with uteroplacental vascular adaptation. The latter may result in placental insufficiency and fetal growth retardation that by itself could cause adult disease (as the Fetal origins hypothesis states). Alternatively, the association between low birth weight for gestational and adult disease could be an epiphenomenon, leaving inheritance as the main explanation for the fetal origins hypothesis, in adequately nourished populations.     

Obstetric conduct in IUGR

Purpose of the study is to identify the correct attitude that the obstetrician must engage in the management of pregnancy and birth in case of IUGR. Different methods of diagnosis and therapy of IUGR and the formalities of assistance to the birth have been examined and compared. Accurate clinical examinations of the mother, the study of fetal kariotype and ultrasonography, are essential for the diagnosis of IUGR. The genetic study could be performed by collecting chorionic villi, amniocentesis, cordocentesis or placenta biopsy. Ultrasonography identifies the cases of IUGR, and distinguishes early IUGR from late IUGR. Color Doppler identifies the pathology of the flow in the umbilical artery, in the abdominal aorta and in the middle cerebral artery. After the 26th week, the follow-up of the fetus with IUGR is done with cardiotocography with or without acoustic stimulation or oxytocin. The amelioration of maternal conditions is obtained by avoiding the cigarette smoking, preferring to rest in bed and a balanced feeding; the hyperoxygenation doesn't find unanimous consent. The treatment off IUGR can consist of abdominal decompression, intra-abdominal infusion of amniotic liquid, or use of aspirin. The birth is carried out in the hospital, when the fetus has reached a sufficient maturity. The management of IUGR requires an accurate follow-up and an adequate antepartum therapy. The goal is a birth with less risk.     

The cytotrophoblastic shell and complications of pregnancy

Many complications of pregnancy have their pathophysiological roots in the early stages of placentation. Impaired trophoblast invasion and deficient remodelling of the maternal spiral arteries are a common feature. While malperfusion of the placenta may underpin cases of fetal growth restriction and early-onset pre-eclampsia, the mechanistic links to spontaneous miscarriage, pre-term labour and premature rupture of the membranes are less obvious. Here, we speculate that formation of a well-developed cytotrophoblastic shell at the maternal-fetal interface is crucial for pregnancy success. Initially, extravillous trophoblast cells differentiate from the outer layer of the shell in contact with the endometrium. Impaired development may thus contribute to reduced invasion and deficient remodelling. In addition, the extent of the shell influences the timing and spatial configuration of onset of the maternal arterial circulation. A thin and fragmentary shell results in premature and disorganised onset, leading to spontaneous miscarriage. In less severe cases it may predispose to haemorrhage at the interface and formation of intrauterine haematomas. If pregnancy continues, these haematomas may act as a source of oxidative stress, promoting senescence and weakening of the membranes, and stimulating inflammation in the uterine wall and premature contractions. Formation of the shell is dependent on proliferation of cytotrophoblast progenitor cells during the first weeks after implantation, when the developing placenta is supported by histotrophic nutrition from endometrial glands. Hence, we propose the fitness of the endometrium prior to conception, and the peri-conceptional dialogue between the endometrium and the trophoblast is critical for avoidance of later complications of pregnancy.     

滋养细胞凋亡的二阶段与子痫前期二阶段发病机制关系的探讨

子痫前期是产科的严重并发症,不仅影响孕产妇健康,而且影响后代远期预后,发病原因至今不清。该病是胎盘源性疾病,其发生发展可分为两个阶段：第1阶段为病理生理变化形成过程,以滋养细胞浸润异常,螺旋动脉重铸不良,胎盘血流灌注减少为特点;第2阶段为器官受损阶段,导致各种临床征象发生。滋养细胞凋亡在子痫前期发病中起重要作用,细胞凋亡失衡可导致其侵袭能力异常。在子痫前期发病的不同阶段,滋养细胞凋亡的机制也不同。总结相关文献发现,第1阶段为蜕膜自然杀伤细胞及诱导绒毛外滋养细胞凋亡引起螺旋动脉重铸不足的阶段,第2阶段为螺旋动脉重铸不足引起胎盘缺血缺氧导致合体滋养细胞凋亡的阶段。其相关的机制有待进一步研究。     

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.     

Intraplacental choriocarcinoma metastasizing to the maternal lung

BACKGROUND: Although normal pregnancy is the precursor of 25% of cases of maternal choriocarcinoma, intraplacental choriocarcinoma in an otherwise normal placenta associated with viable pregnancy has rarely been reported. CASE: Examination of the placenta after delivery of a pale and small-for-date infant at term revealed intraplacental choriocarcinoma. There was no evidence of metastatic disease in the mother or child, but the mother exhibited postpartum rising levels of beta-HCG. The mother refused chemotherapy and disappeared from follow-up. Nine months later, she presented with metastatic choriocarcinoma of the lung. Eleven courses of the multi-drug EMA CO regimen effected a decrease of beta-HCG to normal and disappearance of lung metastases. To date, 28 months after the end of chemotherapy, the patient is alive and without evidence of gestational trophoblastic disease. Moreover, since then she has given birth to an additional two children. CONCLUSIONS: This case is an example of natural disease progression of intraplacental choriocarcinoma metastasizing to the mother. Furthermore, it supports common knowledge that the multi-drug EMA CO regimen is effective treatment in poor prognosis metastatic choriocarcinoma.     

Interest in preeclampsia for researchers in reproduction.

Gestational hypertension/preeclampsia, is a major disease of human reproduction, with 10% of human births being affected. It is due to the failure of extravillous cytotrophoblast to invade the maternal uterine spiral arteries to a sufficient depth at the second physiological invasion around the 14-16th week of gestation, inducing poor vascular exchanges between the mother and the placenta. The rise of blood pressure in the human mother is then a compensatory mechanism to increase the exchanges and try to save the fetus from poor supplies. Indeed, it is only in the late 1970s that a puzzling phenomenon has been described: in human pregnancy, in contrast with other mammals, implantation of the embryo occurs by two physiological invasions of the cytotrophoblast inside the uterine wall: (a) at the beginning of pregnancy after fecundation (like all mammals); (b) then follows an apparent long pause (6-8 weeks) and (c) late at the end of first trimester (14-16th week) of gestation, a second very deep (1/3 of the uterine wall) invasion. This two-wave physiological endovascular trophoblast invasion represents a remarkable immunological placental-maternal interaction. Moreover, preeclampsia which has been considered as 'the disease of primigravidae' during all the XXth century may be in fact associated with new paternity especially in couples conceiving very shortly after the beginning of their sexual relationship. 'Primipaternity', rather than primigravidity, is probably the leading cause of preeclampsia. Comprehension in the near future of the physiological immunological tolerance in normal pregnancies and immunological rejection (preeclampsia) of the second trophoblastic invasion will give the biological clue of this puzzling disease, real plague of human reproduction.     

Endocrine regulation in asymmetric intrauterine fetal growth retardation.

OBJECTIVE: The ponderal index (PI) is a widely accepted measure of disproportionate growth or asymmetrical growth retardation by pediatricians worldwide. Identification of disproportionately grown small for gestational age (SGA) neonates by using the ponderal index as a measure of the nutritional status at birth, is important because they constitute a high-risk group among SGA neonates. Poor nutritional status of the mother could have a direct effect on the organs of the developing fetus and/or affect the endocrine milieu in the maternal feto-placental unit resulting in an increased incidence of intrauterine growth-retarded (IUGR)/SGA births. IUGR is a significant risk factor for adult disease. In this study, we have investigated the endocrine adaptation by the fetus to overcome the growth disadvantage caused due to poor nutritional status of the mother. MATERIALS AND METHODS: We examined the quantitative variations in hormonal and growth factor profiles in paired maternal and cord blood samples obtained from mothers and their neonates who were classified based on their growth status into SGA and appropriate for gestational age (AGA). RESULTS: (1) A total of 24.7% neonates had a PI < 2, indicating a high incidence of asymmetric IUGR in the population studied. (2) Anthropometric parameters measured in the mothers indicate that the mothers giving birth to neonates with a PI < 2 had poor nutritional status, both prior to and during pregnancy. (3) We observed increased levels of placental lactogen and prolactin and decreased levels of insulin in the cord blood of neonates with PI < 2, while lower levels of insulin-like growth factor 1 (IGF-1) and higher levels of epidermal growth factor (EGF) were observed in their mothers. CONCLUSION: Poor maternal nutritional status results in fetal adaptation to a growth restricted environment via the modulation of the pituitary-thyroid axis thereby altering the endocrine milieu, thus affecting fetal growth.     

Tissue transglutaminase expression and activity in placenta

Tissue transglutaminase (tTG) expression, distribution and activity were examined in human placenta and derived cells. Immunochemical techniques and RT-PCR were used to demonstrate tTG protein and mRNA in stromal cells and trophoblast in first trimester and at term, with higher levels later in pregnancy. Decidual cells also produce tTG. The data were confirmed using primary cultures of trophoblast, fibroblasts and decidual stromal cells. Substrate incorporation studies indicated tTG activity in association with fibroblast extracellular matrix and the syncytial microvillous membrane (MVM), where several target polypeptides could be observed. tTG is a major autoantigen in Coeliac disease (CoD) which is associated with poor pregnancy outcome. tTG at the placental MVM is a plausible target of maternal autoantibody action.     

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.     

抗心磷脂抗体阳性产妇胎盘的病理观察

目的 探讨抗心磷脂抗体阳性产妇与不良妊娠的关系。方法 选ＡＣＡ阳性产妇胎盘１６例（不良妊娠及正常妊娠结果各８例）为研究组。ＡＣＡ阴性产妇产胎盘８例为对照组,用免疫荧光法标记。     

Taurine and taurine-deficiency in the perinatal period

Taurine, a non-protein sulfur amino-acid, is the most abundant free amino-acid in the body and plays an important role in several essential biological processes. Apart from its role in cholesterol degradation, it acts as neurotransmitter, and has a function as osmoregulator and antioxidant in most body tissues. During pregnancy, taurine accumulates in the maternal tissues, to be released in the perinatal period to the fetus via the placenta and to the newborn via the maternal milk. It is accumulated especially in the fetal and neonatal brain. Low maternal taurine levels result in low fetal taurine levels. Taurine-deficiency in the mother leads to growth retardation of the offspring, and to impaired perinatal development of the central nervous system and of the endocrine pancreas. The adult offspring of taurine-deficient mothers display signs of impaired neurological function, impaired glucose tolerance and vascular dysfunction; they may develop gestational diabetes and transmit the effects to the next generation. This transgeneration effect of taurine-deficiency in the perinatal period fits into the concept of fetal origin of adult disease.     

Maternal serum soluble HLA-G in complicated pregnancies

Abstract

Preeclampsia, intrauterine growth retardation (IUGR), oligohydramnios, abortus, preterm birth and premature rupture of the membranes (PROM) are significant complications of pregnancy. Insufficient trophoblastic invasion plays an important role in the pathophysiology of pregnancy complications. Soluble human leukocyte antigen-gestation (HLA-G)1/G5 is a molecule associated with trophoblast invasion. When pregnancy complications are predicted early, strategies to prevent these complications can be implemented. The aim of this study was to investigate the relationship between first trimester maternal serum soluble HLA-G1/G5 levels and high-risk pregnancies. A total of 232 pregnant women were followed prospectively. Maternal blood samples were collected for determination of soluble HLA-G1/G5 levels at 11–14 weeks, during which routine serum free beta human chorionic gonadotropin (βhCG) and pregnancy associated plasma protein-A (PAPP-A) level determinations in addition to nuchal translucency (NT) measurements for Down’s syndrome screening were done during 20–22 weeks gestation. The subjects were classified into normal pregnancy, preeclampsia, oligohydramnios, IUGR, preterm birth and PROM groups. First trimester maternal serum soluble HLA-G1/G5 levels were not significantly different between the groups. First trimester soluble HLA-G1/G5 did not predict high-risk pregnancies. Studies with larger number of cases are need to confirm our findings.