U Lang

Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1

Although maternal–fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (−70%) and HDL3 (−57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood.

Angiogenic growth factor levels in maternal and fetal blood : correlation with doppler ultrasound parameters in pregnancies complicated by pre-eclampsia and intrauterine growth restriction

To correlate levels of angiogenic growth factors with Doppler ultrasound parameters in pregnancies complicated by pre‐eclampsia and intrauterine growth restriction (IUGR).

Calibrated automated thrombin generation in normal uncomplicated pregnancy

Pregnancy is associated with substantial changes in the haemostatic system and a six-fold higher incidence of venous thromboembolism. Conventional global tests, such as prothrombin time and activated partial thromboplastin time, do not definitely detect this hypercoagulable condition. We investigated whether the changes in haemostatic system during pregnancy are reflected in the calibrated automated thrombography (CAT). Thrombin generation was measured in platelet-poor plasma (PPP) of 150 healthy pregnant women without any pregnancy associated diseases by means of CAT. In addition, prothrombin (FII), antithrombin (AT), protein S, protein C, tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), and prothrombin fragments 1+2 (F1+2) were measured. Endogenous thrombin potential (ETP) and peak of thrombin generation increased significantly with gestational weeks, while lag time and time to peak remained unchanged. A significant increase of PAI-1, TFPI, F1+2 and TAT as well as a significant decrease of free protein S, protein S antigen, and protein S activity was observed. Levels of AT and protein C remained stable during pregnancy. Division of population in trimester of pregnancy and analysis of differences between the trimesters showed rather similar results. Our study shows that endogenous thrombin potential does increase with duration of normal uncomplicated pregnancy. Whether parameters of continuous thrombin generation will correlate with thrombembolic disease remains to be shown.

Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction

OBJECTIVE The objective of the study was to evaluate perinatal and long-term complications of fetuses with intrauterine growth restriction (IUGR) compared with constitutionally small for gestational age (SGA) ones. STUDY DESIGN The outcome of infants with IUGR and SGA born at the Medical University Graz (Austria) between 2003 and 2009 was retrospectively analyzed. Group assignment was based on birthweight, Doppler ultrasound, and placental morphology. The primary outcome was neurodevelopmental delay at 2 years corrected age. The secondary outcomes were perinatal complications. RESULTS We included 219 IUGR and 299 SGA infants for perinatal and 146 and 215 for long-term analysis. Fetuses with IUGR were delivered earlier (35 vs 38 weeks) and had higher rates of mortality (8% vs 1%; odds ratio [OR], 8.3) as well as perinatal complications (24.4% vs 1.0%; OR, 31.6). The long-term outcome was affected by increased risk for neurodevelopmental impairment (24.7% vs 5.6%; OR, 5.5) and growth delay (21.2% vs 7.4%; OR, 3.4). CONCLUSION IUGR infants are subject to an increased risk for adverse short- and long-term outcome compared with SGA children.

Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial

Please cite this paper as: Moertl M, Friedrich S, Kraschl J, Wadsack C, Lang U, Schlembach D. Haemodynamic effects of carbetocin and oxytocin given asintravenous bolus on women undergoing caesarean delivery: a randomised trial. BJOG 2011;118:1349–1356.

Quality of life outcomes in pregnancy and postpartum complicated by hypertensive disorders, gestational diabetes, and preterm birth

Health problems can develop during a pregnancy, turning it into a high risk. The aim of this study was to explore the influence of hypertensive disorders, gestational diabetes, and preterm birth as risk factors for health-related quality of life (HRQL) and depressive symptoms during late pregnancy and postpartum. A prospective, longitudinal study was performed with three assessments. Ninety women were recruited in the study including 29 controls. HRQL was measured using the WHO-QOL-BREF questionnaire. Depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS). Statistical analyses were performed using ANOVA and the chi-square test to explore HRQL and depressive symptoms between three pregnancy risk groups and controls. Women of the preterm group had statistically significant higher depression scores and lower HRQL scores on the physical domain during pregnancy than those without complications. Women with hypertensive disorders showed the second most depressive symptoms. Physical and global HRQL improved and depressive symptoms decreased significantly from late pregnancy and early postpartum period to late postpartum. Pregnant specific health problems, especially the risk for preterm delivery is associated with more depressive symptoms and decreased HRQL in pregnancy. Guidance and communication for these women is important. The counseling should be multi professional to reduce childbirth burdens.

Assessment of the in vivo biomechanical properties of the human uterine cervix in pregnancy using the aspiration test A feasibility study

OBJECTIVE To date no diagnostic tool is yet available to objectively assess the in vivo biomechanical properties of the uterine cervix during gestation. METHODS We show the first clinical application of an aspiration device to assess the in vivo biomechanical properties of the cervix in pregnancy with the aim to describe the physiological biomechanical changes throughout gestation in order to eventually detect pregnant women at risk for cervical insufficiency (CI). RESULTS Out of 15 aspiration measurements, 12 produced valid results. The stiffness values were in the range between 0.013 and 0.068 bar/mm. The results showed a good reproducibility of the aspiration test. In our previous test series on non-pregnant cervices our repetitive measurements showed a standard deviation of >20% compared to <+/-10% to our data on pregnant cervices. Stiffness values are decreasing with gestational age which indicates a progressive softening of cervical tissue towards the end of pregnancy. Three pregnant women had two subsequent measurements within a time interval of four weeks. Decreasing stiffness values in the range of 20% were recorded. DISCUSSION This preliminary study on the clinical practicability of aspiration tests showed promising results in terms of reproducibility (reliability) and clinical use (feasibility). Ongoing studies will provide further insights on its usefulness in clinical practice and in the detection of substantial changes of the cervix in pregnancy indicative for threatened preterm birth or cervical insufficiency.

Insulin Action on the Human Placental Endothelium in Normal and Diabetic Pregnancy

The placental endothelium is unique among the entire human vasculature. The blood enriched in oxygen and nutrients is transported in the veins, whereas the arteries contain deoxygenated blood coming from the fetus. The placental vasculature has to develop rapidly to ensure adequate supply of the fetus. Therefore, factors present in the fetal circulation will stimulate placental angiogenesis. In the third trimester of pregnancy the placental endothelium is richly endowed with insulin receptors. In a pregnancy complicated by maternal diabetes, fetal hyperinsulinemia resulting from maternal and, hence, fetal hyperglycaemia induces changes in the placental vasculature such as increased growth and angiogenesis. This review will discuss general effects of insulin on endothelial cells and further focus on insulin effects on the placental endothelium. Isolation and culture of placental endothelial cells has allowed the identification of insulin effects in vitro. These include metabolic effects of insulin i.e. stimulation of glycogen synthesis, and modulation of angiogenesis on the placental arterial endothelium i.e. regulation of ephrin-B2 expression, an arterial specific signalling molecule implicated in sprouting. The effect of insulin on ephrin-B2 in placental arterial endothelial cells as well as their particularly high expression levels of insulin receptors and receptors for vascular endothelial growth factors indicate that placental angiogenesis is likely to emanate from the arterial compartment and is stimulated by insulin.

MT1-MMP Expression in First-Trimester Placental Tissue Is Upregulated in Type 1 Diabetes as a Result of Elevated Insulin and Tumor Necrosis Factor-α Levels

OBJECTIVE—In pregestational diabetes, the placenta at term of gestation is characterized by various structural and functional changes. Whether similar alterations occur in the first trimester has remained elusive. Placental development requires proper trophoblast invasion and tissue remodeling, processes involving matrix metalloproteinases (MMPs) of which the membrane-anchored members (MT-MMPs) such as MT1-MMPs are key players. Here, we hypothesize a dysregulation of placental MT1-MMP in the first trimester of type 1 diabetic pregnancies induced by the diabetic environment. RESEARCH DESIGN AND METHODS—MT1-MMP protein was measured in first-trimester placentas of healthy (n = 13) and type 1 diabetic (n = 13) women. To identify potential regulators, first-trimester trophoblasts were cultured under hyperglycemia and various insulin, IGF-I, IGF-II, and tumor necrosis factor-α (TNF-α) concentrations in presence or absence of signaling pathway inhibitors. RESULTS—MT1-MMP was strongly expressed in first-trimester trophoblasts. In type 1 diabetes, placental pro–MT1-MMP was upregulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts, insulin, IGF-I, IGF-II, and TNF-α upregulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on phosphatidylinositol 3-kinase, the IGF-I effect on mitogen-activated protein kinase, and the IGF-II effect on both. CONCLUSIONS—This is the first study reporting alterations in the first-trimester placenta in type 1 diabetes. The upregulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF-α levels. We speculate that the elevated MT1-MMP will affect placental development and may thus contribute to long-term structural alterations in the placenta in pregestational diabetes.

Neonatal outcome and two-year follow-up after expectant management of second trimester rupture of membranes

Objective: To assess neonatal outcome and 2‐year follow‐up of pregnancies complicated by second trimester preterm premature rupture of membranes (PPROM). Methods: A retrospective review of obstetric and neonatal records for 87 pregnancies (56 singletons, 6 twins, 1 triplet) with PPROM between 14 + 0 and 24 + 6 weeks of gestation. Patients received antibiotics and steroids for fetal lung maturity once they reached 24 weeks of gestation. Placentas were examined histopathologically. Surviving infants were followed‐up at 2 years of age. Results: Median latency from PPROM to delivery was 4 days. Survival rate of 56 singletons was 45% (25/56); and 13 died in hospital. Survival rate of infants discharged from hospital was 23% (12/56). Chorioamnionitis was seen histologically in 42% (5/12) of surviving infants compared with 92% (12/13) of those that died in hospital. Of the 12 surviving infants, 50% had a normal neurological and developmental outcome at 2 years of age. Conclusion: Gestational age, birth weight, and histologic chorioamnionitis have prognostic importance in pregnancies complicated by PPROM. Surviving infants have a 50% chance of achieving an adequate health status at 2 years of age.