Ischemic placental disease: epidemiology and risk factors

Objective

Preeclampsia, small for gestational age (SGA) and placental abruption - conditions that constitute the syndrome of “ischemic placental disease” (IPD) - may portend different clinical manifestations of a common underlying pathophysiology. We examined if (i) preeclampsia, SGA and abruption share similar risk profiles; and (ii) if there are any differences in these profiles between patients with IPD that delivered at term and preterm gestations.

Study design

We utilized data from the US Collaborative Perinatal Project, a multicenter, prospective cohort study (1959-1966), restricted to women that delivered singleton births at ≥20 weeks (n = 47,495.) We compared risk factors between women with and without IPD as well as preeclampsia, SGA and abruption.

Results

A strong overlap in risk factors for all 3 conditions was evident. Socio-economic class, income, age, parity, education, race, BMI, marital status, and history of preterm birth were different between preterm and term gestations in women with IPD. Although rates of preeclampsia only, SGA only and preeclampsia with SGA were similar between term and preterm birth, rates of other conditions were higher at preterm gestations, with abruption being the driving condition behind these associations.

Conclusions

The similar risk profiles for preeclampsia, SGA, and abruption provide compelling evidence to suggest that these conditions may share common pathophysiological mechanisms—ischemic placental disease. Greater homogeneity in risk profiles within preterm than term births suggests that IPD may be a syndrome that has strong underpinnings at preterm gestations.     

Expression of EGF,EGFR, and proliferation in placentas from pregnancies complicated with preeclampsia

Objective: To investigate proliferation, EGF and EGFR expression of villous trophoblast (VTB), decidual cells (DC), and extravillous trophoblast (EVTB) in the placentas from pregnancies complicated with preeclampsia (PE) and to compare them with placentas from normal pregnancies. Methods: Twenty-nine PE placentas and 19 control placentas were studied for EGF and EGFR immunohistochemical expression (noted as week, moderate or strong). Proliferation was expressed as the proliferation index. The CK7 antibody was used to distinguish DC from EVTB. Results: DC and EVTB proliferation was significantly higher in PE placentas. EGFR and EGF expression showed no significant difference. Conclusion: Higher DC and EVTB proliferation in PE could contribute to PE development.     

Cord serum glycodelin concentrations in normal pregnancies and pregnancies complicated by diabetes

Objective Glycodelin is a glycoprotein released by secretory/decidualized endometrial glands. Its synthesis increases during pregnancy. Hormonal factors whose levels have been shown to change in diabetes (vascular endothelial growth factor, relaxin) may mediate the actions or regulate the synthesis of glycodelin. Cord serum glycodelin levels have not been studied in pregnancies complicated by diabetes.Methods Cord serum glycodelin concentrations were measured at birth by an immunofluorometric assay in 62 normal pregnancies, in 67 pregnancies complicated by type 1 diabetes, and in 28 pregnancies complicated by insulin-treated gestational diabetes.Results The mean glycodelin concentration in cord serum was 2.7 ng/ml (standard error of the mean 0.6) in normal pregnancies. The concentration was not altered in pregnancies complicated by diabetes. Cord serum glycodelin concentrations were also unaltered in diabetic pregnancies with hypertensive disorders (chronic hypertension, pregnancy-induced hypertension or pre-eclampsia) or fetal macrosomia. There was a negative borderline correlation between cord serum glycodelin concentrations and the birth weight in pregnancies complicated by diabetes (r=–0.21, p=0.049).Conclusions Decidual function, as assessed by cord serum glycodelin levels, is not markedly altered in diabetic pregnancies. The negative correlation between cord serum glycodelin and the birth weight of the newborns in diabetic pregnancies may be due to the decline in glycodelin levels with advancing pregnancy in the third trimester.     

血清、脐血中MPO水平变化及胎盘组织MPO mRNA表达与子痫前期发病的关系

目的:研究重度子痫前期(PE)患者血清MPO及胎盘组织中MPO mRNA表达水平变化与PE发病的关系,探讨糖脂代谢异常及氧化应激在PE病理生理机制中的可能作用。方法:选取60例重度PE孕妇,按发病时孕周不同分为早发型PE组(孕周34周)和晚发型PE组(孕周≥34周)各30例。另选取同期健康晚期妊娠孕妇60例,分为对照1组(孕周34周)和对照2组(孕周≥34周)各30例。采用实时荧光定量PCR技术检测胎盘组织中MPO mRNA表达水平;ELISA法检测血清MPO水平。检测患者血压、血脂、血糖、胰岛素水平等指标,进行相关性分析。结果:PE组的血清MPO水平高于对照组(P0.05),且早发型高于晚发型PE组(P0.05);但对照组间比较无差异(P0.05)。PE组的血清TC、TG、LDL、FINS、HOMA-IR分别高于对照组(P0.05),HDL水平低于对照组(P0.05);但PE组间比较及对照组间比较,均无差异(P0.05)。PE组的脐血MPO水平、胎盘组织中MPO mRNA表达水平均高于对照2组(P0.05),且早发型高于晚发型组(P0.05)。PE组的血清MPO水平与TG、HoMA-IR、FINS、胎盘组织MPO mRNA表达水平均呈正相关(r=0.557、0.615;0.694、0.511;0.766、0.717;0.696、0.695),与血HDL呈负相关(r=-0.697,-0.576);对照2组则无相关性。结论:MPO可能参与了PE的病理生理过程。胎盘组织中MPO mRNA表达水平升高可能是血清MPO水平升高的重要原因。PE患者血脂代谢异常及胰岛素抵抗增加与血清MPO水平升高有关,它们可能参与了血清MPO水平升高后促发PE的氧化应激的病理生理过程。     

JunB/Cyclin-D1 imbalance in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise

Introduction

In the present study, we characterized the expression of Activating Protein 1 (AP-1) factors, key cell cycle regulators, in primary placental mesenchymal stromal cells (PDMSCs) derived from normal and preeclamptic (PE) pregnancies with fetal-placental compromise.

Methods

PDMSCs were isolated from control (n = 20) and preeclamptic (n = 24) placentae. AP-1 expression was determined by semi-quantitative RT-PCR (sqRT-PCR), Real Time PCR and Western Blot assay. PDMSCs were plated and JunB siRNA was performed. JunB and Cyclin-D1 expression were assessed by Real Time and Western Blot analyses.

Results

JunB expression was significantly increased while Cyclin-D1 expression was significantly down-regulated in PE relative to control PDMSCs. JunB siRNA was accompanied by JunB down-regulation and increased Cyclin-D1 in normal PDMSCs.

Conclusions

We described, for the first time, AP-1 expression in PDMSCs derived from physiological and PE placentae. Importantly, we demonstrated that JunB over-expression in PE-PDMSCs affects Cyclin-D1 regulation. Our data suggest a possible contribution of these pathological placental cells to the altered cell cycle regulation typical of preeclamptic placentae.     

Evaluation of the maternal and umbilical vein serum sFas/sFasL system in pregnancies complicated by preeclampsia with intrauterine growth retardation

OBJECTIVE: The aim of this study was to determine the maternal and umbilical vein soluble Fas and its ligand (sFasL) serum levels in pregnancies complicated by preeclampsia with intrauterine growth retardation (IUGR). PATIENTS AND METHODS: The study was carried out on 11 preeclamptic delivering patients in the third trimester of pregnancy with severe preeclampsia complicated by intrauterine growth retardation. The control group consisted of 12 healthy normotensive delivering patients with singleton uncomplicated pregnancies, without any renal, heart and vascular diseases and with normal laboratory tests. Maternal and umbilical serum soluble Fas and FasL concentrations were estimated using a sandwich ELISA assay. RESULTS AND CONCLUSIONS: Increased maternal and umbilical vein serum sFas and increased umbilical vein serum sFasL levels were found in the study group in comparison with the control group. In our study in both groups of patient higher maternal sFas values were observed in comparison with the umbilical cord blood. Further studies are necessary to evaluate the role of Fas/FasL pathway in pregnancies complicated by preeclampsia and intrauterine growth retardation.     

Unfractionated heparin and placental pathology in high-risk pregnancies: Secondary analysis of a pilot randomized controlled trial

Introduction

Heparin is often prescribed during pregnancy with the intention of improving perinatal outcomes on the basis that it exerts an anticoagulant action in the inter-villous space. Accumulating in-vitro and in-vivo evidence indicates that heparin's beneficial effects in pregnancy may result from ‘non-anticoagulant’ effects including the promotion of angiogenesis.

Methods

To study the effect of heparin within the placenta, we performed secondary analyses on a pilot trial where 32 women with negative thrombophilia screens and second-trimester evidence of placental insufficiency were randomized to standard care or antenatal self-administration of unfractionated heparin (UFH) 7500IU twice-daily. Serial placental ultrasound images were reviewed and compared with histo-pathologic findings following delivery.

Results

There were no differences between the two arms in either the evolution of abnormal placental lesions on ultrasound (p = 0.75) or evidence of maternal vascular under-perfusion on histopathology (p = 0.89). In pregnancies considered at increased risk for adverse pregnancy outcomes based on previous history or abnormal serum marker screen, early (second-trimester) placental ultrasound, reflecting developmental pathology had better test characteristics (sensitivity 77.8%; positive predictive value 80.8%) for predicting adverse pregnancy outcomes than third-trimester ultrasound that is reflective of placental thrombotic injury.

Conclusions

Administration of UFH did not prevent the development or evolution of abnormal placental lesions on placental ultrasound or evidence of maternal vascular underperfusion on placental histo-pathology. Second-trimester placental ultrasound may be of value in predicting those at greatest risk of adverse outcomes.     

Protein composition of microparticles shed from human placenta during placental perfusion: Potential role in angiogenesis and fibrinolysis in preeclampsia

Shedding of syncytiotrophoblast microparticles (MPs) from placenta to maternal blood occurs in normal pregnancy and is enhanced during preeclampsia (PE). The syncytiotrophoblast synthesizes plasminogen activator inhibitors (PAIs) which regulate fibrinolysis, as well as soluble forms of the fms-like tyrosine kinase (sFlt-1) and endoglin, which exert anti-angiogenic actions. An increase in the ratio of PAI-1/PAI-2 and elevated levels of sFlt-1 and sEng in maternal serum are linked to placental damage and maternal endothelial cell dysfunction in PE. The goal of the current study was to determine whether MPs released to maternal perfusate during dual perfusion contain these factors associated with placental pathophysiology in PE. Initially, high levels of alkaline phosphatase activity and Annexin V binding were found in MPs isolated by sequential centrifugation of maternal perfusates at 10,000 and 150,000×g(10 K and 150 K MPs), indicating their plasma membrane origin. ELISA revealed the presence of these factors at the following relative levels: Eng>PAI-2?PAI-1>sFlt-1. Based on comparisons of their concentration in perfusates, MPs, and MP-free 150 K supernatants, we determined that MPs constitute a significant portion of Eng released by placenta. Flow cytometric analysis of 10 K MPs supported the levels of expression found by ELISA and indicated that Eng and PAI-2 were almost exclusively localized to the surface of MPs, a site with biological potential. These results indicate that MPs shed from the syncytial surface express factors which may alter the fibrinolytic and angiogenic balance at the maternal-fetal interface and play a role in the pathophysiology of PE.     

IFPA Meeting 2013 Workshop Report I: Diabetes in pregnancy,maternal dyslipidemia in pregnancy,oxygen in placental development,stem cells and pregnancy pathology

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2013 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) diabetes in pregnancy; 2) lipids, fatty acids and the placenta; 3) oxygen in placental development and pathologies; 4) stem cells and pathologies.     

Review: Placental mitochondrial function and structure in gestational disorders

The aetiology of many gestational disorders is still unknown. However, insufficient trans-placental nutrient and oxygen transfer due to abnormal placentation is characteristic of several pathologies, and may alter the function of placental mitochondria. Mitochondria are multifunctional organelles that respond to a wide range of stimuli – such as physiological changes in cellular energy demands or various pathologies – by reshaping via fusion or fission, increasing/decreasing in number, altering oxidative phosphorylation, and signalling cellular functions such as apoptosis. Mitochondrial function is integral to tissue functions including energy production, metabolism, and regulation of various cellular responses including response to oxidative stress. This review details the functions of placental mitochondria and investigates mitochondrial function and structure in gestational disorders including preeclampsia, intrauterine growth restriction, diabetes mellitus, and obesity. Placental mitochondrial dysfunction may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health.     

Intrapartum application of the continuous glucose monitoring system in pregnancies complicated with diabetes: A review and feasibility study

Intrapartum maternal normoglycemia seems to play an important role in the prevention of adverse perinatal, maternal and neonatal outcomes. Several glucose monitoring protocols have been developed, aiming to achieve a tight glucose monitoring and control. Depending on the type of diabetes and the optimal or suboptimal glycemic control, the treatment options include fasting status of the parturient, frequent monitoring of capillary blood glucose, intravenous dextrose infusion and subcutaneous or intravenous use of insulin. Continuous glucose monitoring system (CGMS) is a relatively new technology that measures interstitial glucose at very short time intervals over a specific period of time. The resulting profile provides a more comprehensive measure of glycemic excursions than intermittent home blood glucose monitoring. Results of studies applying the CGMS technology in patients with or without diabetes mellitus (DM) have revealed new insights in glucose metabolism. Moreover, CGMS have a potential role in the improvement of glycemic control during pregnancy and labor, which may lead to a decrease in perinatal morbidity and mortality. In conclusion, the use of CGMS, with its important technical advantages compared to the conventional way of monitoring, may lead into a more etiological intrapartum management of both the mother and her fetus/infant in pregnancies complicated with DM.     

Dynamic maternal and fetal Notch activity and expression in placentation

IntroductionMurine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch proteins and ligands.MethodsNotch reporter transgenic mice were used to define canonical Notch activity and immunofluorescence staining performed to characterize expression of Notch1, 2, 3, 4 and ligands, Delta-like 4 (Dll4) and Jagged1 (Jag1) during early placentation and in the mature placenta.ResultsNotch signaling is active in maternal and fetal endothelial cells and trophoblasts during early placentation and in the mature placenta. Dll4, Jag1, Notch1, and Notch4 are expressed in maternal vasculature in the decidua. Dll4, Jag1 and Notch1 are expressed in fetal vasculature in the labyrinth. Dll4, Notch2 and Notch4 are co-expressed in the ectoplacental cone. Notch2 and Notch4 are expressed in parietal-trophoblast giant cells and junctional zone trophoblasts with active canonical Notch signaling and in labyrinthine syncytiotrophoblasts and sinusoidal-trophoblast giant cells.DiscussionCanonical Notch activity and distinct expression patterns for Notch proteins and ligands was evident in endothelium and trophoblasts, suggesting Notch1, Notch2, Notch4, Dll4, and Jag1 have distinct and overlapping functions in placentation. Characterization of Notch signaling defects in existing mouse models of preeclampsia may shed light on the role of Notch in developing the preeclampsia phenotype.