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Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.

Background and Aims: We investigated placental histopathology for lesions that are associated with maternal and fetal circulation abnormalities in obese pregnant women with and without metabolic alterations., Methods: 332 pregnant women were divided into three groups: Group 1 included 163 non-obese metabolically healthy (NOMH), Group 2 106 obese metabolically healthy (OMH), and Group 3 63 obese metabolically abnormal (OMA) subjects, respectively., Results: Fetal vascular supply (FVS) abnormalities and Willous maturation defect (WMD) rate were higher in obese subjects without metabolic abnormalities, compared to NOMH subjects (p < 0.021 and p < 0.018, respectively). In the logistic regression analysis, obesity emerged as a significant independent predictor of FVS abnormalities (OR 1.54, 95% CI 1.193-1.992, p = 0.001) and WMD (OR 2.004, 95% CI 1.173-3.422, p = 0.011). Although maternal vascular supply (MVS) abnormalities differed significantly across groups (31%, 38% and 54% respectively, p < 0.005), in the logistic regression analysis, obesity was not significantly associated with MVS abnormalities., Conclusions: We demonstrated that obesity, per se, is associated with an increased rate of placental vascular supply abnormalities and has a more adverse effect on fetal vascular circulation than on maternal vascular supply., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate outcome in the pregnancy following a stillbirth (SB) by a placental vascular disorders., Study Design: A prospective, observational, multicenter study was conducted in woman with a history of stillbirth (> 22 weeks) between 2005 and June 2013, in 3 Italian University Hospitals. Causes of SB were previously identified after extensive investigations. Pregnant women were enrolled within the first trimester. The main outcome was "adverse neonatal outcome", including perinatal death, fetal growth restriction, early preterm birth <33+6 weeks, hypoxic-ischemic encephalopathy, intracranial hemorrhage or respiratory distress., Results: Out of 364 index pregnancies, 320 women (87.9%) had a subsequent pregnancy during the study period. Forty-seven had an early pregnancy loss. Out of 273 babies, 67 (24.5%) had an adverse perinatal outcome, including 1 SB and 1 early neonatal death (3.7/1000). Women who had a SB related to placental vascular disorders (39.6%), were at higher risk of an adverse neonatal outcome compared with women whose SB was unexplained or resulted from other causes (Adj. OR = 2.1, 95%CI: 1.2-3.8). Moreover, also obesity independently predicts an adverse perinatal outcome (Adj OR = 2.1, 95%CI: 1.1-4.3)., Conclusion: When previous SB is related to placental vascular disorders there is a high risk for adverse neonatal outcomes in the subsequent pregnancy. Maternal obesity is an additional risk factor.

Abnormalities of placental development and function are known to underlie many pathologies of pregnancy, including spontaneous preterm birth, fetal growth restriction, and preeclampsia. A growing body of evidence also underscores the importance of placental dysfunction in the lifelong health of both mother and offspring. However, our knowledge regarding placental structure and function throughout pregnancy remains limited. Understanding the temporal growth and functionality of the human placenta throughout the entirety of gestation is important if we are to gain a better understanding of placental dysfunction. The utilization of new technologies and imaging techniques that could enable safe monitoring of placental growth and function in vivo has become a major focus area for the National Institutes of Child Health and Human Development, as evident by the establishment of the "Human Placenta Project." Many of the objectives of the Human Placenta Project will necessitate preclinical studies and testing in appropriately designed animal models that can be readily translated to the clinical setting. This review will describe the advantages and limitations of relevant animals such as the guinea pig, sheep, and nonhuman primate models that have been used to study the role of the placenta in fetal growth disorders, preeclampsia, or other maternal diseases during pregnancy., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

An increasing number of women of reproductive age are obese which affects the continuum of pregnancy and is associated with an increased incidence of adverse maternal and fetal outcomes, including preeclampsia, preterm birth, stillbirth, congenital anomalies, and macrosomia. Maternal obesity is associated with an increased incidence of metabolic and cardiovascular disease later in life in the mother and in the offspring who are developmentally programed by the obese pregnancy environment. The placenta transduces and mediates the effect of the adverse maternal environment to the fetus. The obese maternal environment is characterized by hyperlipidemia and an exaggerated state of inflammation and oxidative stress compared with normal pregnancy. Heightened inflammation and oxidative/nitrative stress are found in the placenta in association with placental dysfunction. We have described reduced mitochondrial respiration and ATP generation in trophoblast isolated from placentas of obese compared with lean women, again suggesting compromised placental function. In utero development exhibits sexual dimorphism with the male fetus at greater risk of poor outcome. We have shown dimorphism in inflammation-mediated regulation of trophoblast mitochondrial respiration. There is also increasing evidence that the obese in utero environment may cause epigenetic changes in placenta leading to altered function., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal and fetal tissues. The resulting intrauterine environment plays an important role in fetal programming and the future health of the fetus, and is impacted by multiple genetic and epigenetic factors. Abnormalities in placentation and spiral artery invasion can lead to ischemia, placental disease, and adverse obstetrical outcomes including preeclampsia, intrauterine growth restriction, and placental abruption. Although first trimester placentation is affected by multiple factors, preconception environmental influences such as mode of conception, including assisted reproductive technologies which result in fertilization in vitro and intrauterine influences due to sex differences, are emerging as potential significant factors impacting first trimester placentation., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Introduction: Magnesium (Mg(2+)) is essential for cellular growth and the maintenance of normal cellular processes. However, little is known about how maternal hypomagnesemia during pregnancy affects fetal growth and development. This study investigated the effects of maternal hypomagnesemia on the late gestation placenta and fetus, and postnatal outcomes until weaning., Methods: Female CD1 mice consumed a control (0.2% w/w Mg(2+)), moderately Mg(2+) deficient (MMD; 0.02% w/w Mg(2+)) or severely Mg(2+) deficient (SMD; 0.005% w/w Mg(2+)) diet for 4 weeks prior to mating and throughout pregnancy. Dams were killed at E18.5 for embryonic studies or allowed to litter naturally and the offspring studied up to postnatal day 21., Results: At E18.5, both Mg(2+) deficient diets decreased maternal plasma and bone Mg(2+) but only the SMD diet decreased fetal plasma Mg(2+). Maternal hypomagnesemia led to fetal loss and fetal growth restriction. Maternal Mg(2+) deficiency increased placental glycogen cell area and decreased spongiotrophoblast cell area while upregulating mRNA expression of the MagT1 Mg(2+) transporter in spongiotrophoblast cells. The SMD animals also displayed instances of gross placental abnormalities. After birth, pups in the SMD group had increased early postnatal mortality and failed to thrive. Pups in the MMD group underwent catch-up growth but remained shorter than controls at PN21 and were hypomagnesemic and hypoglycemic., Conclusions: These changes suggest that maternal Mg(2+) deficiency during pregnancy impairs placental development and fetal growth, which may have long-term health consequences for offspring. Collectively, these results have important implications for women who are Mg(2+) deficient during pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aim: To study the relation of retention of dead fetus resulting in its maceration and gestational age at delivery to placental diagnosis., Methods: Some 75 clinicoplacental phenotypes have been retrospectively analyzed in 520 consecutive stillbirths, 329 macerated and 191 nonmacerated, and at three gestational age interval cohorts (330 second trimester, 102 preterm third trimester, and 88 term). Chi-square and clustering methods (Ward dendrograms and multidimensional scaling) were used for statistical analysis., Results: Maternal diabetes mellitus, induction of labor, fetal growth restriction, various umbilical cord abnormalities, and placental clusters of sclerotic/hemosiderotic chorionic villi were more common in macerated stillbirths, while clinicoplacental signs and symptoms of ascending infection and placental abruption, i.e., retroplacental hematoma, premature rupture of membranes, and acute chorioamnionitis in nonmacerated stillbirths. Placental abnormalities were less common in the second trimester, other than the acute chorioamnionitis. Patterns of chronic hypoxic placental injury were common in preterm third trimester, while signs of in-utero hypoxia (abnormal cardiotocography, meconium, and histological erythroblastosis of fetal blood) in term pregnancy. In addition to classical statistics, the clustering analyses added new information to placental investigation of cause of stillbirth., Conclusions: Macerated third trimester stillbirths have multifactorial etiology more likely than the second trimester stillbirths and the likely stasis-induced fetal thrombotic vasculopathy secondary to occult umbilical cord compromise should be sought in placental investigation in such cases. Nonmacerated stillbirths are associated with ascending infection and placental abruption.

Placental chorioangioma is the most common benign non-trophoblastic tumor of the placenta. It is derived from primitive chorionic mesenchyme and is typically vascular. Placenta chorioangiomas occur in approximately 1% of pregnancies. Most placental chorioangiomas are small and are not clinically important. However, those measuring more than 4-5 cm in diameter may be associated with maternal and fetal complications. Early diagnosis, close prenatal surveillance and appropriate intervention may prevent severe complications and perinatal mortality caused by chorioangioma. Here we review the incidence, prenatal diagnosis, complications, the pathophysiological mechanisms of maternal and fetal complications, and the therapeutic possibilities in pregnancies complicated by placental chorioangiomas.

Objective: As the patterns and frequency of maternal and clinical conditions and outcomes and gross and histological placental features and lesions vary with gestational age at delivery, we aimed to study the impact of these changes on the placental diagnosis, hoping to uncover potential novel clusters of gestational age-associated clinical and pathological diagnoses., Design: Retrospective statistical analysis of clinicoplacental database., Population: We analyzed 28 clinical (maternal and fetal) and 49 gross and microscopic placental variables from 3294 consecutively signed placentas received between 2001 and 2012, divided into three gestational age groups: 16-27 weeks, 697 cases; 28-36 weeks, 1365 cases; and 37+ weeks, in all 1232 cases., Methods: Classical statistics by chi-squared and Fischer's tests, and the Ward agglomerative hierarchical clustering and multidimensional scaling techniques, were used., Results: The placental phenotypes clustered statistically significantly with severe preeclampsia in the second trimester; preterm premature rupture of membranes, placental abruption, and fetal growth restriction in the whole third trimester; and abnormally invasive placenta, thick meconium, maternal diabetes mellitus, and substance abuse in term pregnancies., Conclusions: The applied statistical analyses made it possible to simultaneously compare the strength of clinicoplacental associations separately in three pregnancy intervals. Placental clinicopathological associations are strongest for the second trimester, i.e. severe preeclampsia and preterm ascending infection-related conditions, but were not significant for other pregnancy complications such as mild preeclampsia, chronic hypertension, diabetes mellitus, or umbilical cord compromise., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Pregnancy induces a number of alterations to maternal physiology to accommodate the increased demands made by the developing fetus and placenta. These alterations appear at least in part to be driven by products derived from the feto-placental unit, including microchimeric cells, as well as placental exosomes and microparticles, inducing changes to maternal physiology both during pregnancy and beyond. Further, increasing evidence suggests that some of these alterations are dependent on the sex of the fetus. Pre-eclampsia and asthma represent two common pregnancy complications that have provided valuable insight into how the feto-placental unit influences maternal physiology in a sex-specific manner. Pregnancy-induced alterations in maternal physiology may expose pre-existing subclinical pathologies and provide insight into future maternal health and disease. While most pregnancy-induced alterations to the maternal system are reversed following delivery, some can persist after parturition leading to cardiovascular, metabolic and autoimmune disease and increased risk of early mortality., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

Pregnancy complications such as pre-eclampsia, placental abruption and growth restriction were once thought to represent end-of-pregnancy issues. Currently, the cause of such complications are being increasingly recognised as defective implantation and placentation. The molecular mechanisms responsible for normal and abnormal implantation are an area of active investigation. Screening tests, such as Doppler ultrasound of the maternal uterine arteries and evaluation of markers in the maternal serum, are being assessed to determine if such tests might allow for better recognition and, perhaps, prevention of many pregnancy complications related to abnormal placentation. Many techniques during pregnancy have been used to prevent pregnancy complications such as pre-eclampsia. Most have been unsuccessful. Ultimately, the solution may reside in pre-pregnancy approaches to improve implantation and placentation. Such approaches are actively being investigated and have promise., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Defective deep placentation has been associated with a spectrum of complications of pregnancy including preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. The disease of the placental vascular bed that underpins these complications is commonly investigated with targeted biopsies. In this review, we critically evaluate the biopsy technique to summarize the salient types of defective deep placentation, and propose criteria for the classification of defective deep placentation into 3 types based on the degree of restriction of remodeling and the presence of obstructive lesions in the myometrial segment of the spiral arteries., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Purpose of Review: To evaluate the impact of early pregnancy complications involving placentation and early placental development on adverse obstetric outcome in ongoing and subsequent pregnancies., Recent Findings: We found an increased risk of adverse outcome (odds ratio >2.0) in ongoing pregnancies of preterm delivery (PTD), very preterm delivery (VPTD), placental abruption, small for gestational age (SGA), low birth weight (LBW) and very LBW (VLBW) after a threatened miscarriage episode; pregnancy-induced hypertension, preeclampsia, placental abruption, PTD, SGA and low 5-min Apgar score following the detection of an intrauterine haematoma; and VPTD, VLBW and perinatal death after a vanishing twin phenomenon. In subsequent pregnancies, the risk of perinatal death was increased (odds ratio >2.0) after a single miscarriage, the risk of VPTD after two or more miscarriages, the risk of placenta previa, premature preterm rupture of membranes, PTD, VPTD and LBW after recurrent miscarriage and the risk of VPTD after two or more terminations of pregnancy., Summary: Our analysis of the literature review indicates a link between early pregnancy complications involving the placenta and subsequent adverse obstetric and perinatal outcomes. Some of these associations are based on limited or small uncontrolled studies. Larger population-based prospective controlled studies have recently been published confirming most of these findings. This suggests that the early detection of these risk factors could improve the screening of women at high risk of specific obstetric complications in ongoing and subsequent pregnancies.

The placenta not only "records" and reflects the intrauterine environment, it also provides valuable information on the cause and timing of many adverse events and conditions. The placenta may be useful in several ways. It may be the cause of injury due to an inherent abnormality, it may "malfunction" because of disease processes that are not primarily placental in origin, or it may merely reflect an abnormal intrauterine environment. Not only may the etiology of the injury be ascertained from placental examination, but also a time frame during which the abnormal condition has been operating. Acute lesions may be associated with sudden catastrophic events, whereas other, more chronic lesions lead to decreased placental reserves. Markedly depleted reserves will render the infant susceptible to other, sometimes more acute, events and thus are also associated with significant injury or even death.

Miscarriage and pre-eclampsia are the most common disorders of human pregnancy. Both are placental-related and exceptional in other mammalian species. Ultrasound imaging has enabled events during early pregnancy to be visualized in vivo for the first time. As a result, a new understanding of the early materno-fetal relationship has emerged and, with it, new insight into the pathogenesis of these disorders. Unifying the two is the concept of placental oxidative stress, with associated necrosis and apoptosis of the trophoblastic epithelium of the placental villous tree. In normal pregnancies, the earliest stages of development take place in a low oxygen (O2) environment. This physiological hypoxia of the early gestational sac protects the developing fetus against the deleterious and teratogenic effects of O2 free radicals (OFRs). In miscarriage, development of the placento-decidual interface is severely impaired leading to early and widespread onset of maternal blood flow and major oxidative degeneration. This mechanism is common to all miscarriages, with the time at which it occurs in the first trimester depending on the aetiology. In contrast, in pre-eclampsia the trophoblastic invasion is sufficient to allow early pregnancy phases of placentation but too shallow for complete transformation of the arterial utero-placental circulation, predisposing to a repetitive ischaemia-reperfusion (I/R) phenomenon. We suggest that pre-eclampsia is a three-stage disorder with the primary pathology being an excessive or atypical maternal immune response. This would impair the placentation process leading to chronic oxidative stress in the placenta and finally to diffuse maternal endothelial cell dysfunction.

Objective: To investigate the value of second-trimester uterine artery Doppler in the prediction of complications resulting from uteroplacental insufficiency in low- and high-risk multiparous women., Methods: Color flow pulsed Doppler imaging of both uterine arteries at 20 weeks' gestation was performed on 628 multiparous women; 458 of them had no known risk factors and 170 had clinically identifiable high-risk factors at booking. An abnormal result was defined as bilateral notches and a mean resistance index (RI) >/= 0.55 (50th centile) or unilateral notches and a mean RI >/= 0.65 (80th centile). The main outcome measure was adverse pregnancy outcome defined as any case of pre-eclampsia, small-for-gestational age birth weight (< 5th centile), placental abruption, stillbirth or early neonatal death., Results: There was an adverse outcome in 30 women (6.6%) in the low-risk group and 48 (28.2%) women in the high-risk group. In the high-risk group the sensitivity to predict adverse pregnancy outcome in screen-positive women was 81.4% for a specificity of 89.0%, a positive predictive value of 71.4% and a negative predictive value of 93.4%. Normal Doppler studies in the high-risk group conferred a risk of adverse perinatal outcome of 6.6%, similar to the risk of adverse outcome in the low-risk population (6.6%). In the low-risk group the sensitivity for an adverse outcome in screen-positive women was 33.3% for a specificity of 92.8% and a positive predictive value of 24.4%., Conclusion: In high-risk multiparous women, persistent bilateral notches with mean RI >/= 0.55 and unilateral notches with mean RI >/= 0.65 at 20 weeks' gestation identifies the vast majority of women who will subsequently develop complications secondary to uteroplacental insufficiency. Normal uterine artery Doppler studies in these women confers a risk of adverse outcome similar to that of women with an uncomplicated obstetric history. In low-risk women, the screening efficacy of uterine artery Doppler for adverse perinatal outcome is poor and does not justify routine screening., (Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd.)

The authors studied uterine Doppler findings in four cases of retroplacental hematoma at 26, 30.5, 31 and 37 weeks of amenorrhea. In all cases, the diastolic index was low, and a diastolic notch was present. In three cases, the hematoma was visualised under ultrasound. The literature on the subject confirms that the velocity of the uterine circulation is always abnormal in retroplacental hematoma. This test is therefore fundamental for the detection of clinically incomplete retroplacental hematomas and for determining the pregnancy prognosis in women with a history of vascular problems. Two of our patients received treatment with acetylsalicylic acid at an early stage of a subsequent pregnancy. The uterine Doppler scans carried out during this pregnancy at the same date as during the pregnancy with retroplacental hematoma revealed normal bloodflow velocity. The infants were born at term with normal weight. Uterine Doppler ultrasound is, therefore, an essential prognosis factor for these high-risk patients. In addition, routine performance of a uterine Doppler scan at about 22 weeks of amenorrhea in women in their first pregnancy could be useful, as any abnormal finding might be the indication for preventive treatment with acetylsalicylic acid.

Examination of the uteroplacental hemodynamics was performed on 109 occasions in women admitted to the hospital in the third trimester because of various complications of pregnancy. The radioactive tracer 113m In was injected intravenously and the build-up and equilibrium times were measured over the placenta, myometrium and heart. The placental build-up times were most informative, with prolonged values being recorded in about one quarter of these cases. When those extending beyond three minutes were further studied, they were usually found to be associated with severe complications of pregnancy. This did not obtain in cases with shorter placental build-up times.