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Preeclampsia (PE), the leading cause of maternal and fetal morbidity and mortality, is associated with poor fetal growth, intrauterine growth restriction (IUGR) and low birth weight (LBW). Offspring of women who had PE are at increased risk for cardiovascular (CV) disease later in life. However, the exact etiology of PE is unknown. Moreover, there are no effective interventions to treat PE or alleviate IUGR and the developmental origins of chronic disease in the offspring. The placenta is critical to fetal growth and development. Epigenetic regulatory processes such as histone modifications, microRNAs and DNA methylation play an important role in placental development including contributions to the regulation of trophoblast invasion and remodeling of the spiral arteries. Epigenetic processes that lead to changes in placental gene expression in PE mediate downstream effects that contribute to the development of placenta dysfunction, a critical mediator in the onset of PE, impaired fetal growth and IUGR. Therefore, this review will focus on epigenetic processes that contribute to the pathogenesis of PE and IUGR. Understanding the epigenetic mechanisms that contribute to normal placental development and the initiating events in PE may lead to novel therapeutic targets in PE that improve fetal growth and mitigate increased CV risk in the offspring., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR., (© 2021 The Author(s).)

Gestational diabetes mellitus (GDM) is a global health issue with significant short and long-term complications for both mother and baby. There is a strong need to identify an effective therapeutic that can prevent the development of GDM. A better understanding of the pathophysiology of GDM and the relationship between the adipose tissue, the placenta and fetal growth is required. The placenta regulates fetal growth by modulating nutrient transfer of glucose, amino acids and fatty acids. Various factors secreted by the adipose tissue, such as adipokines, adipocytokines and more recently identified extracellular vesicles, can influence inflammation and interact with placental nutrient transport. In this review, the role of the placental nutrient transporters and the adipose-derived factors that can influence their function will be discussed. A better understanding of these factors and their relationship may make a potential target for therapeutic interventions to prevent the development of GDM and its consequences., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Asthma is a highly prevalent co-morbidity during pregnancy that can worsen as gestation progresses and is associated with several adverse perinatal outcomes. These adverse outcomes often result from uncontrolled asthma during pregnancy and acute asthma exacerbations that are associated with alterations in placental function and fetal growth., Areas Covered: This paper will discuss how maternal asthma in pregnancy affects fetal growth and development which may alter future offspring health. Changes in placental function occur in a sex-specific manner in pregnancies complicated by asthma and result in differences in fetal growth and development which may influence child health. The follow up of children from mothers with asthma suggests they are at greater risk of developing asthma, have alterations in microvascular structure that may contribute to a future risk of cardiovascular disease and epigenetic modifications in immune cell function. The current evidence suggests that appropriately managed asthma during pregnancy results in normal fetal growth and development., Expert Opinion: Clinical management of asthma during pregnancy needs significant improvement to prevent adverse outcomes for the fetus. The key to improving maternal and fetal outcomes is through education of health professionals and parents about controlling asthma during pregnancy.

It is known that pig offspring born from pregnant pigs exposed to elevated ambient temperatures during gestation have altered phenotypes, possibly due to placental insufficiency and impaired fetal growth. Therefore, the objective of this study was to quantify the effect of maternal heat exposure during early-mid gestation, when pig placentae grow heavily, on placental and fetal development. Fifteen pregnant pigs were allocated to thermoneutral (TN; 20 °C; n = 7) or cyclic elevated temperature conditions (ET; 28 to 33 °C; n = 8) from d40 to d60 of gestation. Following euthanasia of the pigs on d60, placental and fetal morphometry and biochemistry were measured. Compared to TN fetuses, ET fetuses had increased (P = 0.041) placental weights and a lower (P = 0.013) placental efficiency (fetal/placental weight), although fetal weights were not significantly different. Fetuses from ET pigs had reduced (P = 0.032) M. longissimus fibre number density and a thicker (P = 0.017) placental epithelial layer compared to their TN counterparts. Elevated temperatures decreased (P = 0.026) placental mRNA expression of a glucose transporter (GLUT-3) and increased (P = 0.037) placental IGF-2 mRNA expression. In conclusion, controlled elevated temperatures between d40 to d60 of gestation reduced pig placental efficiency, resulting in compensatory growth of the placentae to maintain fetal development. Placental insufficiency during early-mid gestation may have implications for fetal development, possibly causing a long-term phenotypic change of the progeny.

The Developmental Origins of Health and Disease (DOHaD) theory states that a sub-optimal prenatal and early postnatal environment during development leads to an increased risk of long-term development of adult chronic diseases. Developmental programming of disease has the potential to greatly impact the health of our population. Therefore, research has focused on the development of primary treatment strategies and/or therapeutic interventions for individuals who are at increased risk, with the objective to reverse or prevent later life onset of chronic disease in the offspring born from complicated pregnancies. Many studies have focused on systemic treatments and/or interventions in complicated pregnancies to improve offspring outcomes. However, there are limitations to systemic maternal/prenatal treatments, as most of the treatments are able to cross the placenta and have potential adverse off-target effects on the developing fetus. The placenta serves as the primary interface between mother and fetus, and placental dysfunction in complicated pregnancies has been associated with impaired fetal development and negative impact on offspring health. Therefore, recent research has focused on treatment strategies that specifically target the placenta to improve placental function and prevent passage of prenatal therapeutics and/or treatments into the fetal circulation, thus avoiding any potential adverse off-target effects on the fetus. This article reviews the currently available knowledge on treatment strategies and/or therapeutics that specifically target the placenta with the goal of improving pregnancy outcomes with a focus on long-term health of the offspring born of complicated pregnancies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Obesity and unhealthy nutrition are increasing and affect women of childbearing age and hence during pregnancy. Despite normal or even high birth weight, the offspring suffers from long-term metabolic risks. We hypothesized that fetal growth is disturbed during different intrauterine phases. Underlying molecular events remain elusive. Female mice were fed either a standard diet (SD) or a high-fat diet (HFD) after weaning until mating and during pregnancy. Pregnant mice were euthanized at gestational day (G)15.5 and G18.5, and fetuses and placentas were removed for analysis. HFD fetuses displayed intrauterine growth restriction (IUGR) at G15.5, which disappeared until G18.5, indicating intrauterine catch-up growth during that time period. Main placental findings indicate decreased canonical Wnt-GSK3β signaling and lower proliferation rates at G18.5, which goes along with a smaller placental transfer zone. On the other hand, glucose depots (glycogen cluster) in HFD placentas decreased more strongly between G15.5 and G18.5 compared with placentas from SD mothers, and the glucose transporter protein GLUT-1 was increased at G18.5 in the HFD group. Maternal diet-induced obesity causes an IUGR phenotype at the beginning of the third week (G15.5) in our mouse model. This phenotype is reversed by the end of the third week (G18.5) despite a smaller placental transfer zone, probably based on GSK3β-mediated increased glucose mobilization in the placenta and hence an increased glucose supply to the fetus.

Mitochondria respond to a range of stimuli and function in energy production and redox homeostasis. However, little is known about the developmental and environmental control of mitochondria in the placenta, an organ vital for fetal growth and pregnancy maintenance in eutherian mammals. Using respirometry and molecular analyses, the present study examined mitochondrial function in the distinct transport and endocrine zones of the mouse placenta during normal pregnancy and maternal inhalation hypoxia. The data show that mitochondria of the two zones adopt different strategies in modulating their respiration, substrate use, biogenesis, density, and efficiency to best support the growth and energy demands of fetoplacental tissues during late gestation in both normal and hypoxic conditions. The findings have important implications for environmentally induced adaptations in mitochondrial function in other tissues and for compromised human pregnancy in which hypoxia and alterations in placental mitochondrial function are associated with poor outcomes like fetal growth restriction., Competing Interests: The authors declare no conflict of interest.

The prevalence of obesity and type 2 (T2D) diabetes is a major health concern in the United States and around the world. T2D is a complex disease characterized by pancreatic β-cell failure in association with obesity and insulin resistance in peripheral tissues. Although several genes associated with T2D have been identified, it is speculated that genetic variants account for only <10% of the risk for this disease. A strong body of data from both human epidemiological and animal studies shows that fetal nutrient factors in utero confer significant susceptibility to T2D. Numerous studies done in animals have shown that suboptimal maternal environment or placental insufficiency causes intrauterine growth restriction (IUGR) in the fetus, a critical factor known to predispose offspring to obesity and T2D, in part by causing permanent consequences in total functional β-cell mass. This review will focus on the potential contribution of the placenta in fetal programming of obesity and TD and its likely impact on pancreatic β-cell development and growth.

Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.

Objective:: The aim of the present study was to compare the placental weight and birth weight/placental weight ratio for intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins., Methods:: This was a retrospective analysis of placentas from twin pregnancies. Placental weight and the birth weight/placental weight ratio were compared in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins. The association between cord insertion type and placental lesions in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins was also investigated., Results:: A total of 105 monochorionic (intrauterine growth restriction=40; non-intrauterine growth restriction=65) and 219 dichorionic (intrauterine growth restriction=57; non-intrauterine growth restriction=162) placentas were analyzed. A significantly lower placental weight was observed in intrauterine growth-restricted monochorionic (p=0.022) and dichorionic (p<0.001) twins compared to non-intrauterine growth-restricted twins. There was no difference in the birth weight/placental weight ratio between the intrauterine growth restriction and non-intrauterine growth restriction groups for either monochorionic (p=0.36) or dichorionic (p=0.68) twins. Placental weight and the birth weight/placental weight ratio were not associated with cord insertion type or with placental lesions., Conclusion:: Low placental weight, and consequently reduced functional mass, appears to be involved in fetal growth restriction in monochorionic and dichorionic twins. The mechanism by which low placental weight influences the birth weight/placental weight ratio in intrauterine growth-restricted monochorionic and dichorionic twins needs to be determined in larger prospective studies.

Preterm labor (PTL) accounts for almost 11% of deliveries, and is a major cause of neonatal morbidity and mortality. T regulatory (Treg) cells may prevent fetal rejection by the maternal immune system under the influence of progesterone. Case control study was conducted to determine Treg cells, IL-10, TGF-β, and membrane progesterone receptorα (mPRα) in the maternal-fetal interface (placenta), including eight pregnant women with threatened PTL (study group) and 16 normal-delivery women (control group). Comparing study group versus control, mean gestational age of delivery differed significantly (p = 0.02), as did endothelial hyperplasia in the upper half (p = 0.035) and the lower half (p = 0.005) of the placenta. Besides, there was higher expression of mPRα and IL-10 in all layers, while Foxp3 expression occurred equally and only in the decidua. TGF-β expression was similar in both groups. Preterm group placentas showed higher endothelial hyperplasia in both upper and lower halves of the placenta.

Obesity has reached epidemic proportions, and pregnancies in obese mothers have increased risk for complications including gestational diabetes, hypertensive disorders, pre-term birth and caesarian section. Children born to obese mothers are at increased risk of obesity and metabolic disease and are susceptible to develop neuropsychiatric and cognitive disorders. Changes in placental function not only play a critical role in the development of pregnancy complications but may also be involved in linking maternal obesity to long-term health risks in the infant. Maternal adipokines, i.e., interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), leptin and adiponectin link maternal nutritional status and adipose tissue metabolism to placental function. Adipokines and metabolic hormones have direct impact on placental function by modulating placental nutrient transport. Nutrient delivery to the fetus is regulated by a complex interaction including insulin signaling, cytokine profile and insulin responsiveness, which is modulated by adiponectin and IL-1β. In addition, obese pregnant women are at risk for hypertension and preeclampsia with reduced placental vascularity and blood flow, which would restrict placental nutrient delivery to the developing fetus. These sometimes opposing signals regulating placental function may contribute to the diversity of short and long-term outcomes observed in pregnant obese women. This review focuses on the changes in adipokines and obesity-related metabolic hormones, how these factors influence placental function and fetal development to contribute to long-term metabolic and behavioral consequences of children born to obese mothers., (© 2017 Society for Reproduction and Fertility.)

Introduction: Offspring exposed to preeclampsia (PE) show an increased risk of cardiovascular disease in adulthood. We hypothesize that this is mediated by a disturbed vascular development of the placenta, umbilical cord and fetus. Therefore, we investigated associations between early-onset PE (EOPE), late-onset PE (LOPE) and features of placental and newborn vascular health., Methods: We performed a nested case-control study in The Rotterdam Periconceptional Cohort, including 30 PE pregnancies (15 EOPE, 15 LOPE) and 218 control pregnancies (164 uncomplicated controls, 54 complicated controls including 28 fetal growth restriction, 26 preterm birth) and assessed macroscopic and histomorphometric outcomes of the placenta and umbilical cord., Results: A significant association was observed between PE and a smaller umbilical vein area and wall thickness, independent of gestational age and birth weight. In EOPE we observed significant associations with a lower weight, length and width of the placenta, length of the umbilical cord, and thickness and wall area of the umbilical vein and artery. These associations attenuated after gestational age and birth weight adjustment. In LOPE a significant association with a larger placental width and smaller umbilical vein wall thickness was shown, independent of gestational age and birth weight., Discussion: Our study suggests that PE is associated with a smaller umbilical cord vein area and wall thickness, independent of gestational age and birth weight, which may serve as a proxy of disturbed cardiovascular development in the newborn. Follow-up studies are needed to ultimately predict and lower the risk of cardiovascular disease in offspring exposed to PE., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Congenital heart defects (CHDs) have been associated with placental anomalies. The nature and the consequences of this association remain poorly understood. We aimed to estimate the associations between all major subtypes of CHD and placental weight at birth, and the association between placental weight and measures of both overall and cerebral growth in fetuses with CHD, as well., Methods: We included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 7569. We compared mean differences in placental weight z score between newborns with CHD and newborns without CHD by multivariable linear regression adjusted for potential confounders., Results: CHD was associated with a mean z score difference of -0.04 (95% confidence interval, -0.07 to -0.02). Some subtypes were associated with smaller placental size at birth: tetralogy of Fallot, -0.45 (95% confidence interval, -0.58 to -0.31); double-outlet right ventricle, -0.48 (95% confidence interval, -0.87 to -0.10); major ventricular septal defects, -0.41 (95% confidence interval, -0.52 to -0.29). Placental weight z score was associated with birth weight and head circumference z scores in all subtypes. In the 3 mentioned subtypes, the mean deviations from the population mean head circumference and birth weight z scores were reduced by up to 66% with adjustment for placental weight z score., Conclusions: Three subtypes of CHD were associated with lower placental weight, and placental weight was associated with measures of both overall growth and cerebral growth in fetuses with all subtypes of CHD. In certain subtypes, the described deviations in fetal growth were reduced by up to two-thirds after adjustment for placental weight z score., (© 2016 American Heart Association, Inc.)

Pregnancy is characterized by an altered inflammatory profile, compared to the non-pregnant state with an adequate balance between pro-and anti-inflammatory cytokines needed for normal development. Cytokines are small secreted proteins expressed mainly in immunocompetent cells in the reproductive system. From early developmental stages onward, the secretory activity of placenta cells clearly contributes to increase local as well as systemic levels of cytokines. The placental production of cytokines may affect mother and fetus independently. In turn because of this unique position at the maternal fetal interface, the placenta is also exposed to the regulatory influence of cytokines from maternal and fetal circulations, and hence, may be affected by changes in any of these. Gestational diabetes mellitus (GDM) is associated with an overall alteration of the cytokine network. This review discusses the changes that occur in cytokines post GDM and their negative effects on maternal insulin and placental-fetal development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Excessive fetal and placental growth are very common in diabetic pregnancy. We aimed to analyze in women with gestational diabetes mellitus (GDM) the association with birth weight (BW), placental weight (PW) and placental-to-birth weight (PWBW) ratio of acknowledged BW predictors., Material and Methods: We performed a retrospective analysis of a prospective cohort database from a tertiary hospital. Inclusion criteria were singleton pregnancy, diagnosis of GDM, delivery between 1982 and 2011 and gestational age at birth ≥23 weeks. Multiple regression analysis was performed using as dependent variables BW, PW and PWBW ratio and as independent ones maternal characteristics at baseline, metabolic characteristics (GDM diagnosis, treatment, control), pregnancy-induced hypertension, gestational age at delivery and fetal sex. Two sensitivity analyses were performed., Results: We evaluated 2547 women, PW being available in 85.3%. BW was 3260g (2976, 3575), PW 620g (540, 720) and PWBW ratio 19.27 (17.20, 21.47). Among the 24 analyzed variables, there was an important overlap among those associated with BW, PW and PWBW ratio. For most characteristics associated with both BW and PW, the magnitude of the association was greater for the latter, both when promoting growth (i.e. prepregnancy body mass index, 3h plasma glucose at diagnosis) and when restricting it (insulin treatment)., Conclusion: We conclude that in women with GDM and singleton pregnancies, variables associated with BW, PW and PWBW ratio overlap. The latter is the result of disproportionate associations with BW and PW, usually larger with PW., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In Islamic religion, daytime fasting during the month called Ramadan is an annual practice. In this study, we aimed to investigate the effect of Ramadan fasting and maternal hypoalbuminaemia on neonatal growth parameters. A prospective case-control study was conducted in Diyarbakir and Istanbul, Turkey. The sample size of fasting group was 168 and that of non-fasting group was 170. Demographic characteristics, obstetrics ultrasonographic findings and laboratory parameters of the participants were recorded. Neonatal anthropometric parameters and placental weight were noted. The mean placental weight was significantly higher in the fasting group (p = 0.037). Also, in the fasting group, pregnant women with hypoalbuminaemia had significantly higher placental weight (p = 0.009). In conclusion, the mean placental weight in the fasting group was significantly higher. Also a significant correlation between placental weight and maternal serum albumin level was observed in the fasting group.

The maternal endocrine stress system is profoundly altered during the course of human pregnancy. The human placenta expresses the genes for CRH as early as the seventh week of gestation and it is the expotential increase in placental CRH (pCRH) over the course of human gestation that is responsible for the greatest modification in the maternal stress system. The bi-directional placental release of hormones into the maternal and fetal compartments has profound influences for both. The influential Fetal Programming model predicted that early or fetal exposures to maternal signals of threat or adverse conditions have lifelong consequences for health outcomes. A basic assumption of this model was that developing organisms play a dynamic role in their own construction. Data are reviewed and new data are presented that elevated pCRH over the course of human gestation plays a fundamental role in the organization of the fetal nervous system, modifies birth phenotype (the timing of the onset of spontaneous labor and delivery), and influences developmental, temperamental and metabolic trajectories. Evidence for sex differences and conserved function across species is presented. Finally, a model is presented that proposes several pathways that pCRH can program risk for health and disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: Fetal growth restriction (FGR) affects up to 5 % of pregnancies worldwide, and trophoblast function plays a significant role on the outcome. An epidemiological study has linked vitamin D deficiency to adverse perinatal outcomes, which include decreased birth weight. The placenta as an important source of vitamin D regulates its metabolism through the vitamin D receptor (VDR), but the mechanism by which VDR regulates trophoblast function is poorly understood. Our study aimed at determining placental VDR expression in FGR and gestation-matched control (GMC) pregnancies and identifying the actions of VDR in trophoblast differentiation and apoptosis. Placentae were collected from a well-defined cohort of idiopathic FGR and GMC pregnancies. VDR mRNA and protein expressions were determined by PCR, immunohistochemistry and immunoblotting, while functional consequences of VDR inactivation in vitro were determined on BeWo cells by determining changes in differentiation, attachment and apoptosis. Significant decreases in VDR mRNA expression (p = 0.0005) and protein expression (p = 0.0003) were observed in the FGR samples, while VDR inactivation, which showed markers for differentiation, cell attachment and apoptosis, was significantly increased. Thus, decreased placental VDR may contribute to uncontrolled premature differentiation and apoptosis of trophoblasts that are characteristics of idiopathic FGR pregnancies., Key Message: Fetal growth restriction (FGR) affects up to 5 % of all pregnancies worldwide. FGR is the second highest cause of perinatal mortality and morbidity. The placenta plays a pivotal role in vitamin D metabolism during pregnancy. Vitamin D deficiency is associated with adverse pregnancy outcomes. Placental vitamin D receptor expression is decreased in FGR.

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., (© 2015 by the American College of Nurse-Midwives.)

Preeclampsia (PE) affects 5-8% of pregnancies and is responsible for 18% of maternal deaths in the US, and for long-term complications in mother and child. PE is an inflammatory state and may influence placental function in a sex-specific manner. We determined if there is a sexual dimorphism in the placental inflammatory and apoptotic responses in preeclamptic pregnancies. Placentas were collected from normotensive and preeclamptic pregnancies with either male or female fetuses (MPE and FPE respectively) after c-section at term with no labor. Expression patterns of markers of inflammation measured by ELISA, as well as hypoxia, apoptosis and angiogenesis markers measured by Western blotting were determined in the placenta. Consistent with previous studies, an increase in inflammation, hypoxia, and apoptotic cell death was observed in PE compared to normotensive pregnancies. Levels of TNFα, IL-6 and IL-8, and HIF-1α were significantly greater, whereas the angiogenic marker VEGF was significantly reduced in MPE vs. FPE. Sexual dimorphism was also observed in the activation of cell death: the number of TUNEL-positive cells, and the expression pro-apoptotic markers PUMA and Bax being higher in MPE vs. FPE. We also found an increase in the levels of protein and DNA-binding activity of NFκB p65 in MPE vs. FPE. In summary, we show here that in preeclamptic pregnancies the placentas of males were associated with significantly higher expression of inflammatory, hypoxia and apoptotic molecules but reduced expression of a pro-angiogenic marker compared to placentas of female fetuses. We propose that the transcription factor NFκB p65 might, at least partially, be involved in sexual dimorphism during PE., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development., Methods and Results: This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (P values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (P values<0.05). These associations were not explained by birth weight. Stronger associations tended to be present among girls as compared with boys., Conclusions: Higher third trimester feto-placental vascular resistance, but not utero-placental vascular resistance, was associated with slower fetal growth rates and cardiovascular adaptations in childhood.

Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells are most susceptible to environmental influences during cellular specification and differentiation stages. Because biochemical differentiation precedes morphological outcome often by days, the period of susceptibility to environmental chemicals expectedly precedes visible morphogenic effects. The cellular mechanisms by which drugs and other environmental factors disrupt embryonic development and induce cardiac abnormalities have remained undefined., (Copyright © 2013. Published by Elsevier Ltd.)

Altered maternal nutrition and metabolism, restricted utero-placental blood flow, and other perturbations in the maternal compartment may disturb critical periods of fetal development resulting in increased susceptibility to develop disease in childhood and adult life. In response to these perturbations, changes in placental structure and function occur, which influence the supply of nutrients, oxygen, and methyl donors and alter the secretion of hormones and other signaling molecules into the fetal circulation. Thus, the placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.

Pregnancy-related complications not only represent a risk for maternal and fetal morbidity and mortality, but are also a risk for several diseases later in life. Many epidemiological studies have shown clear associations between an adverse intrauterine environment and an increased risk of diabetes, hypertension, cardiovascular disease, depression, obesity, and other chronic diseases in the adult. Some of these syndromes could be prevented by avoiding adverse stimuli or insults including psychological stress during pregnancy, intake of drugs, insufficient diet and substandard working conditions. Hence, all of these stimuli have the potential to alter health later in life. The placenta plays a key role in regulating the nutrient supply to the fetus and producing hormones that control the fetal as well as the maternal metabolism. Thus, any factor or stimulus that alters the function of the hormone producing placental trophoblast will provoke critical alterations of placental function and hence could induce programming of the fetus. The factors that change placental development may interfere with nutrient and oxygen supply to the fetus. This may be achieved by a direct disturbance of the placental barrier or more indirectly by, e. g., disturbing trophoblast invasion. For both path-ways, the respective pathologies are known: while preeclampsia is caused by alterations of the villous trophoblast, intra-uterine growth restriction is caused by insufficient invasion of the extravillous trophoblast. In both cases the effect can be undernutrition and/or fetal hypoxia, both of which adversely affect organ development, especially of brain and heart. However, the mechanisms responsible for disturbances of trophoblast differentiation and function remain elusive., (© Georg Thieme Verlag KG Stuttgart · New York.)

As the primary interface between maternal and fetal circulations, the placenta is subject to a myriad of environmental exposures with the capacity to alter placental function and fetal development. Many of these effects are likely to be mediated by epigenetic ('above DNA') change, which is also in turn regulated by maternal and fetal genetic factors. Linking specific environmental exposures, genetic, and epigenetic variation to maternal and fetal outcomes may provide valuable mechanistic insights into the role of placental dysfunction in pregnancy-associated disease and later health. The complexities are manifold but are rapidly being overcome by technological advances and emerging analytical approaches. Although focussing on recent genome-scale and gene-specific DNA methylation studies in the human placenta, this review also discusses the potential of a future broader exploration of combined environmental, genetic and epigenomic approaches, encompassing higher order epigenetic modifications, for unravelling the molecular mechanisms underlying gene-environment interaction at the fetomaternal interface., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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.)

The placenta evolved to support development of the fetus, and so potentially plays a key role in the aetiology of developmental programming through its impact on nutrient transfer. Placental transport efficiency depends on a variety of parameters, including surface area for exchange, thickness of the interhaemal membrane and density of transporter proteins inserted into the trophoblast membranes. Here, we review recent studies that tested whether adaptations of placental efficiency are induced in the mouse placenta when maternal nutrient supply and fetal demand are manipulated experimentally. Naturally small placentas, and those exposed to maternal undernutrition, displayed structural changes indicative of accelerated maturation at E16, with enlargement of the labyrinth exchange zone at the expense of the endocrine junctional zone. These changes were associated with increased transport of a non-metabolisable amino acid analogue per gram of placenta, and expression of genes encoding specific System A transporters. Up-regulation of transporters was also observed when a mismatch between placental size and fetal demand was generated through genetic manipulation of the Igf2/H19 axis. Conversely, overgrowth of the placenta induced by deletion of H19 resulted in reduced transport capacity and expression of transporter genes. We conclude that under conditions when the maternal nutrient supply or placental size may be limiting for normal fetal growth, the placenta adapts so as to increase its transport capacity. Hence, it ameliorates the effects of environmental cues that would otherwise lead to more extensive developmental programming. The P0 transcript of Igf2 appears to be a strong candidate as a mediator of these adaptations in the mouse., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

While utero-placental insufficiency is associated with adverse outcomes for both mother and fetus, many of the maternal-fetal adaptations during pregnancy in models of fetal compromise remain unclear. The purpose of this study was to determine if chronically reduced uterine perfusion pressure (RUPP) during days 14-19 of gestation alters feto-placental growth differentially from the cervical to ovarian ends of the uterus and generates metabolic adaptations such as increased blood lactate (BLa) concentrations and lactate transporter expression in the placenta. Fetal growth restriction was evident, placental efficiency (fetal weight/placental weight) decreased (4.7 ± 0.35 vs. 5.9 ± 0.30; P < 0.05) and fetal growth pattern within the uterus was altered in the RUPP compared to the normal pregnant (NP) rats. Blood lactate concentrations were increased (3.3 ± 0.3 vs. 2.1 ± 0.4 mmol/l; P < 0.05) in NP compared to virgin rats, and in RUPP compared to NP (5.0 ± 0.6 vs. 3.3 ± 0.3 mmol/l; P < 0.05). Lactate concentration was increased (10.0 ± 0.6 vs. 7.1 ± 0.8 mmol/l; P < 0.05) in the media from hypoxic compared to normoxic BeWo cells. No changes in expression of placental MCT1, 2, or 4 were observed between RUPP and NP rats. RUPP resulted in decreased plasma leptin (2.0 ± 0.3 vs. 3.1 ± 0.4; P < 0.05) but no change in IGF-1 compared to NP. The present data indicate chronic placental ischemia results in numerous endocrine and metabolic changes during late pregnancy in the rat and that the RUPP model has differential effects on fetal growth depending on uterine position., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

There is currently considerable uncertainty regarding prescribing practices for pregnant women with severe and persistent psychiatric disorders. The physician and the mother have to balance the risks of untreated psychiatric illness against the potential fetal toxicity associated with pharmacological exposure. This is especially true for women taking atypical antipsychotics. Although these drugs have limited evidence for teratological risk, there are reports of altered fetal growth, both increased and decreased, with maternal atypical antipsychotic use. These effects may be mediated through changes in the maternal metabolism which in turn impacts placental function. However, the presence of receptors targeted by atypical antipsychotics in cell lineages present in the placenta suggests that these drugs can also have direct effects on placental function and development. The signaling pathways involved in linking the effects of atypical antipsychotics to placental dysfunction, ultimately resulting in altered fetal growth, remain elusive. This paper focuses on some possible pathways which may link atypical antipsychotics to placental dysfunction.

The limits of placental plasticity, i.e., the ability of the placenta to adapt and alter its growth trajectory in response to altered fetal requirements, are not known. We report fetal and placental hemodynamic adaptations in a novel non-human primate model in which the fetal inter-placental bridging vessels were surgically ligated. Doppler ultrasound studies showed that the rhesus placenta compensates for an approximate 40% reduction in functional capacity by increased growth and maintenance of umbilical volume blood flow. This unique experimental animal model has applications for mechanistic studies of placental plasticity and the impact on fetal development., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Maternal asthma is a common disease to complicate human pregnancy. Epidemiological studies have identified that asthma during pregnancy increases the risk of a number of poor outcomes for the neonate including growth restriction, lower birthweight, preterm delivery, neonatal resuscitation, and stillbirth. Asthma therefore represents a significant health burden to society and could have an impact on the lifelong health of the children of women with asthma. Our research has identified that maternal asthma in pregnancy induces placental dysfunction and developmental perturbation in the fetus in a sex specific manner. These alterations in development could increase the risk of metabolic disease in adulthood of children of asthmatic mothers, especially females. In this paper, we will discuss the evidence currently available that supports the hypothesis that children of mothers with asthma may be at risk of lifelong health complications which include diabetes and hypertension.

Background: Chronic maternal asthma is associated with reduced growth of the female fetus and normal growth of the male fetus. The mechanisms that control the differential effects of maternal asthma on the fetus have not been fully elucidated but alterations in placental function may play a role. In the current study we have used microarray platform to examine fetal sex-specific global changes in placental gene expression in pregnancies complicated by asthma as compared to non-asthmatic subjects., Methods: Placental RNA was extracted from 11 control subjects and 38 asthmatic subjects. Labeled cDNA was hybridized to an oligonucleotide chip with 1700 double spotted well-characterized human genes. Global gene expression data analysis and visualization were performed using the Binary Tree-Structured Vector Quantization (BTSVQ) software. Functional relationships of differentially expressed genes were assessed using protein-protein interaction database I2D, network analysis and visualization software NAViGaTOR and Ingenuity Pathway Analysis software., Results: Overall, 65 genes were found to be altered in placentae of pregnancies complicated by asthma. Of these, only 6 genes were altered in male placentae. There were 59 gene changes in female placentae of asthmatic mothers relative to control placentae. Some of the sex-specific genes were associated with growth, inflammation and immune pathways., Conclusion: There are sex-specific alterations in placental gene expression in the presence of maternal asthma. Given that many of the identified genes in the female placentae were associated with or involved in cellular growth and tissue development, these may contribute to the sexually dimorphic difference in fetal growth in response to maternal asthma., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (© Thieme Medical Publishers.)

Susceptibility to disease begins during fetal life, and adverse events in utero are a critical factor in determining quality of life and overall health. In fact, up to 50% of metabolic syndrome diseases can be attributed to an adverse in utero environment. However, the mechanisms linking impaired fetal development to augmented cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, remain elusive. This review discusses the latest research in the fetal programming of cholesterol homeostasis from both clinical studies and animal models. It also underscores the role of the placenta as an important mediator in cholesterol homeostasis during pregnancy and uncovers some of the molecular mechanisms underlying how the homeostatic mechanisms in liver may be impaired in fetal and postnatal life due to undernutrition and/or hypoxia., (© Thieme Medical Publishers.)

Intrauterine growth restriction (IUGR) is observed in conditions with limitations in uterine space (e.g., uterine anomalies and multifetal gestations). IUGR is associated with reduced fetal weight, organ growth, and a spectrum of adult-onset diseases. To examine the interaction of uterine anomalies and multifetal gestations, we developed a surgical uterine space restriction model with a unilateral uterine horn ligation before breeding (unilateral surgery). Placentas and fetuses were studied on Gestational Day (GD) 120 and GD 130 (term = 147 days). Unilateral surgery decreased placentome numbers in singleton and twin pregnancies (25% and 50%, respectively) but not unilateral triplets. Unilateral surgery decreased total placentome weight in twin pregnancies (decreased 24%). Fetuses categorized as uterine space restricted (unilateral twin and both groups of triplets) had 51% fewer placentomes per fetus and a 31% reduction in placentomal weight per fetus compared to the nonrestricted group (control singleton, unilateral singleton, and control twin). By GD 130, uterine space-restricted fetuses exhibited decreased weight, smaller crown-rump, abdominal girth, and thoracic girth as well as decreased fetal heart, kidney, liver, spleen, and thymus weights. Lung and brain weights were unaffected, demonstrating asymmetric IUGR. At GD 130, placental efficiency (fetal weight per total placentomal weight) was elevated in uterine space-restricted fetuses. However, fetal arterial creatinine, blood urea nitrogen, and cholesterol were elevated, suggesting insufficient placental clearance. Maternal-to-fetal glucose and triglycerides ratios were elevated in the uterine space-restricted pregnancies, suggesting placental nutrient transport insufficiency. This model allows for examination of interactive effects of uterine space restriction-induced IUGR on placental adaptation and fetal organ growth.

The placenta is the organ that transports nutrients, respiratory gases, and wastes between the maternal and fetal systems. Consequently, placental blood flow and vascular development are essential components of normal placental function and are critical to fetal growth and development. Normal fetal growth and development are important to ensure optimum health of offspring throughout their subsequent life course. In numerous sheep models of compromised pregnancy, in which fetal or placental growth, or both, are impaired, utero-placental blood flows are reduced. In the models that have been evaluated, placental vascular development also is altered. Recent studies found that treatments designed to increase placental blood flow can 'rescue' fetal growth that was reduced due to low maternal dietary intake. Placental blood flow and vascular development are thus potential therapeutic targets in compromised pregnancies.

Objective: To evaluate if maternal glucose level and growth of the fetus were related to placental vascular impedance in pregnancy complicated by gestational diabetes mellitus., Material and Methods: A retrospective study of 146 gestational diabetic women of which 117 needed insulin therapy. Glycosylated hemoglobin (HbA1c) was evaluated as well as umbilical and uterine artery Doppler velocimetry. The results were related to adverse outcome of pregnancy including newborn birthweight., Results: Abnormal umbilical artery blood flow velocity was seen in 5% of the cases and abnormal uterine artery flow in 16%. Uterine and umbilical artery vascular impedance was significantly lower in macrosomic newborns. There was a poor correlation between HbA1c, vascular impedance and birthweight. There were 11 cases that developed preeclampsia, all having abnormal uterine artery Doppler and two abnormal umbilical artery Doppler., Conclusion: Uterine and umbilical artery vascular impedance in pregnancies complicated by gestational diabetes is related to birthweight and placental weight, but not to maternal HbA1c levels. Placental Doppler ultrasound does not seem to be of clinical value for fetal surveillance in these pregnancies unless the pregnancy is complicated by preeclampsia and/or intrauterine fetal growth restriction.

The maternal diabetic environment alters the embryo and the feto-placental development. The results of these alterations are: increased embryo resorption and malformation rates, placental dysfunction, fetal alterations that lead to increased neonatal morbidity and mortality rates, and also diseases that will be evident later in the adult life of the newborn. The etiology of these many maternal diabetes-induced complications are not yet understood in full. In this review the role of maternal diabetes as an inductor of a pro-inflammatory environment that impairs embryo and placental development is discussed. An overproduction of pro-inflammatory agents is found in the uterus during implantation and the developing embryo and placenta from experimental models of diabetes, as well as in placenta from diabetic women. In these tissues there are increases in reactive oxygen species, pro-inflammatory cytokines and prostaglandins, nitric oxide and peroxynitrites. These pro-inflammatory agents lead to the intrauterine activation of matrix metalloproteinases, proteases involved in remodeling the extracellular matrix during implantation and feto-placental development. Many of these pro-inflammatory agents have overlapping mechanisms of action and cross regulatory pathways that propagate the inflammatory processes. Antioxidants, PPARgamma activators, and NF-kappaB inhibitors are able to reduce the concentrations of these agents in intrauterine gestational tissues. This article reviews the current understanding of maternal diabetes-induced changes in pro-inflammatory and anti-inflammatory pathways that affect the embryo and placental development in maternal diabetes, and stresses the need of a strict maternal control of the pathology to prevent deleterious consequences in the offspring.

Individual differences in psychoneuroendocrine function play an important role in health and disease. Developmental models postulate that these individual differences evolve through a progressive series of dynamic time-, place- and context-dependent interactions between genes and environments in fetal, infant and adult life. The effects of early experience have longer-lasting and more permanent consequences than those later in life. Experimental studies in animals have provided convincing evidence to support a causal role for stress-related psychoneuroendocrine processes in negatively influencing critical developmental and health outcomes over the life span, and have also offered valuable insights into putative physiological mechanisms. However, the generalizability of these findings from animals to humans may be limited by the existence of large inter-species differences in physiology and the developmental time-line. We have initiated a program of research in behavioral perinatology and conducted studies over the past several years to examine the effects of stress-related psychoneuroendocrine processes in human pregnancy on fetal developmental and health outcomes. Our findings support a significant and independent role for maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis, and specifically by placental corticotropin-releasing hormone. Our findings also suggest that the use of a fetal challenge paradigm offers a novel way to quantify fetal neurobehavioral maturity in utero, and that the maternal environment exerts a significant influence on the fetal neurodevelopmental processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first few years of postnatal life. A description of this body of work is followed by the elucidation of questions for further research and a discussion of implications for life-span development and health.

Recent studies in humans suggest that alterations in the activity of the neuroendocrine system mediate the effects of psychosocial stress on fetal development and birth outcome. Chronic maternal distress compromises the normal regulation of hormonal activity during pregnancy and elevates free circulating corticotrophin-releasing hormone (CRH), probably of placental origin, before the normal increase occurs at term. Excess CRH, and other hormones like cortisol and met-enkephalin that pass through the placenta, could precipitate preterm labor, reduce birth weight and slow growth rate in prenatally stressed infants. CRH and/or cortisol have also been associated with impaired fetal habituation to stimuli and temperamental difficulties in infants. These changes may result from actions of the hormones on their receptors in the fetal limbic system. In the rat, gestational stress and excess maternal and fetal plasma corticosterone cause downregulation of fetal glucocorticoid (GR) and mineralocorticoid (MR) receptors and impair the feedback regulation of the hypothalamic-pituitary adrenal (HPA) axis in infancy and adulthood. The impairment in HPA axis activity can be prevented by maternal adrenalectomy and mimicked by administration of glucocorticoids. Gestational stress also increases CRH activity in the amygdala and the incidence of anxiogenic and depressive-like behavior in rats and non-human primates, which can be ameliorated by CRH antagonists. Excess amounts of CRH and cortisol reaching the human fetal brain during periods of chronic maternal stress could alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity.