Symptoms Of Preeclampsia Research Articles

Elevations in Endothelin‐1 Predate and are Strongly Diagnostic for the Development of Human Preeclampsia

Preeclampsia (PE), a hypertensive disorder in pregnancy, affects 5–7% of all U.S. pregnancies. It is a leading cause of worldwide obstetric mortality and is associated with 50,000 maternal and 500,000 neonatal deaths yearly. Additionally, PE is known to cause immediate and long‐term maternal‐fetal morbidity. The diagnosis, prevention, and treatment of preeclampsia are limited due to the fact that the mechanisms and physiologic antecedents are largely unknown. Endothelin‐1 (ET‐1) is a potent vasoconstrictor that may be mediating this vascular dysfunction as it is known to be implicated in hypertensive disease and endothelial dysfunction. We have shown that first trimester ET‐1 can be predictive of this, often late, pregnancy disease. It is unknown if ET‐1 is elevated at the time when human physiologic symptoms arise. The objective of this study was to determine the diagnostic characteristics of Endothelin‐1 in women who present for evaluation for PE. This was a nested case‐control study (IRB# 201611746) of pregnant women who were being evaluated at a single tertiary center for PE due to having signs or symptoms of PE (N=130; cases=78, controls=52). Excess plasma and urine from clinical samples used during the PE evaluation were collected. Using commercially available assays, ET‐1 was measured via ELISA and total protein concentration was measured via bicinchoninic acid assay. Reported ET‐1 measurements are reported as ET‐1/total protein (pg/g). Demographic and clinical data for the pregnancy and neonatal outcomes were obtained through the electronic medical record. Cases and controls were gestationally age matched. Women with a PE diagnosis had significantly lower gravidity, parity, and gestational age at delivery; their babies had a lower birthweight and higher admission rate to the NICU. Plasma ET‐1 was higher in patients with PE (Control=18.8 ± 1.3 vs. PE=25.9 ± 3.0 pg/g, p=0.03). Those with early onset PE (<34wks) also had a higher plasma ET‐1 compared to those diagnosed with late onset PE (>34wks) in comparison to controls (Early=38.3 ± 7.8 vs. Late=20.2 ± 2.1 vs. Control=18.8 ± 1.3 pg/g, p<0.001, ANOVA). Conversely, urine ET‐1 was lower in those with PE (Control=128.3 ± 23.5 vs. PE=56.3 ± 13.4 pg/g, p=0.01) and was also lower in patients with more severe disease (Early=24.8 ± 10.6 vs. Late=81.5 ± 19.6 vs. Control=128.3 ± 23.5 pg/g, p<0.011, ANOVA). ET‐1 urine plasma ratio (UPR) at the time of diagnosis strongly predicted PE (AUC=0.84, p=0.0025). In this high‐risk cohort (PE incidence=60%), the ET‐1 UPR at a cutoff of 3.4 pg/g exhibited a sensitivity=87%, specificity=83%, positive predictive value=87%, and negative predictive value=81%. ET‐1 UPR may prove to be a strong diagnostic tool for PE. Further, the differential expression of ET‐1 in plasma and urine according to disease severity suggests ET‐1 may play a role in PE pathogenesis.Support or Funding InformationAHA Postdoctoral Fellowship (SS), AHA SFRN in Hypertension (AB‐O, GP, MS), U of Iowa Women's Health Tissue Repository.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Postpartum Changes in Microglia Density and Activation in a Rat Model of Superimposed Preeclampsia

Microglia are the primary immune cells of the central nervous system, surveying the microenvironment and responding to cell injury or tissue damage. The Dahl Salt Sensitive (Dahl‐S) rat model of superimposed preeclampsia (PE) has preexisting hypertension and chronic kidney disease and exhibits characteristic symptoms of PE during pregnancy. Preexisting cardiovascular and renal disease increase the risk of superimposed PE, which further increases risk of maternal complications. Recently, we showed that the rat model of placental ischemia (induced preeclampsia) has increased posterior cortical microglia activation 2 months postpartum. However, whether superimposed PE exacerbates postpartum microglia activation is not known. Because the Dahl‐S rat has increased peripheral inflammation (increased circulating TNFα) during pregnancy and exacerbated hypertension and proteinuria with subsequent pregnancies, we hypothesized that the Dahl‐S model has increased microglia activation after two pregnancies. Dahl‐S rats were randomly assigned to virgin (DSV) or postpartum (DSP) groups (n=3 per group). Postpartum rats were mated twice (3 and 5 months of age) and brains were collected at 8 months of age. Posterior cerebrum was cryo‐sectioned and immuno‐stained using ionized calcium binding adapter molecule (Iba1). Microglia density and morphology were analyzed using ImageJ in 3 images per region and averaged per rat. There was no difference in microglia density (number of Iba1+ microglia per image) in the hippocampus (10±2 in DSV vs. 9±1 in DSP) or cortex (7±1 in DSV vs. 7±2 in DSP). DSP rats had higher proportion of hippocampal Type 3 (78% vs. 62% in DSV) and fewer Type 4 (5% vs. 22% in DSV) microglia (p<0.05). DSP had fewer hippocampal amoeboid (activated) microglia and higher cortical ramified (surveying) microglia compared to DSV (Figure). Taken together, history of superimposed preeclampsia symptoms in DSP rats does not induce exacerbated microglia activation suggesting that pregnancy is either protective to the brain or that following damage, microglia fail to activate, contributing to incomplete repair processes. These hypotheses will be tested in future studies. Future studies will also determine cortical and hippocampal cytokine levels and astrocyte activation in the postpartum Dahl‐S rats.Support or Funding InformationNIH R00HL129192, R25HL121042, 5T32HL105324‐09, R01HL134711This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Increased vasopressin secretion during preeclampsia despite normal plasma osmolality

Preeclampsia (PE) is a cardiovascular disorder that affects 4–7% of pregnancies and typically involves new onset hypertension, proteinuria, and edema. Diagnosis of the disorder is formally performed in the second half of gestation based upon clinical signs, but we and others have discovered that maternal plasma levels of copeptin (CPP, the stable C‐terminal fragment of arginine vasopressin, AVP) are elevated already in the first trimester and are highly predictive of the development of PE. Further, chronic low‐dose AVP infusion is sufficient to model almost all the clinical features of PE in pregnant mice. Our objective is therefore to understand the cause of elevated AVP secretion in human PE. Previous studies indicate that blood volume is reduced during PE, but no change in osmolality has been noted. We therefore hypothesized (i) that plasma AVP levels are elevated in early gestation of pregnancies that later develop PE, and (ii) that elevated AVP and CPP secretion during PE is secondary to altered volume regulation. Blood samples (1st and 2nd trimester) from women who later developed PE or represent clinically‐matched case controls were obtained from the Maternal Fetal Tissue Bank (IRB#200910784) at the University of Iowa. Consistent with our first hypothesis, plasma levels of AVP, assessed by ELISA after Sep‐Pak C18 reversed solid phase extraction, were increased in 1st and 2nd trimester from women who later developed PE (25.5±3.6, n=63 vs 52.1±22.2, n=5 pg/mL, mean±SEM, p=0.01) despite no change in osmolality (279.6±0.7, n=46 vs 277.5±1.2, n=4 mOsm/kg H2O). Plasma sodium was increased in 1st and 2nd trimesters before the onset of PE (133.9±0.6, n=91 vs 138.5±0.6, n=6 mmol/L, p<0.05), but potassium was unchanged (4.13±0.05 vs 4.38±0.14 mmol/L). These findings support the conclusions that (i) AVP levels are indeed increased in early pregnancy before the onset of clinical symptoms of PE, as was suspected based upon previous studies of CPP; that (ii) the defended osmolality set‐point is similar between control and PE pregnancies, and therefore chronically elevated osmolality is unlikely to be the major cause of elevated AVP secretion during PE, and that (iii) offsetting changes in concentrations of individual osmolytes may be present during PE.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Resveratrol improves endothelial cell markers impaired by plasma incubation from women who subsequently develop preeclampsia.

In this study, we demonstrated that plasma collected from women who subsequently developed preeclampsia caused increased heme oxygenase-1 (HO-1) production and decreased levels of nitric oxide (NO) markers in endothelial cells (HUVECs). Conversely, no changes in HO-1 or NO markers were found when HUVECs were treated with plasma from women who remained healthy throughout pregnancy. These alterations in HO-1 and NO markers were prevented by cotreatment with the polyphenol resveratrol, which also improved GSH levels. In addition, we evaluated changes induced by plasma incubation in the expression of genes and their related pathways associated with antioxidant defenses, such as Nrf2, ARE activity, and GSR. Collectively, our findings suggest that even before the appearance of clinical symptoms of preeclampsia, plasma from affected women is able to induce modifications in endothelial cells with respect to HO-1 production and NO markers. We believe that this in vitro strategy may offer an attractive alternative to the exploitation of candidate markers or screening molecules, such as resveratrol, for the prevention and management of preeclampsia.

Improving the Predictive Accuracy for Pre-eclampsia by Combining Demographic and Socio-economic Risk Factors with Biochemical Indicators

Objective: Since prevention of pre-eclampsia is not possible, the target should be to estimate the severity of the disease that will provide intensive supervision during the further course of pregnancy. So, the aim of this study is to improve the predictive accuracy for pre-aclampsia by defining the demographic and socio-economic characteristics of pregnant women with pre-eclampsia in Macedonia combined with certain biochemical indicators. Methods and materials: The data used in this study are collected from a case control study which was conductedat the University Clinic of Gynecology and Obstetrics, University "Ss. Cyril and Methodius" in Skopje, Macedonia. The study included 50 pregnant women with singleton pregnancies between 28 and 40 gestational weeks hospitalized with symptoms of pre-eclampsia, determined by standard clinical laboratory analysis. The control group consisted of 50 normotensive pregnant women of the same gestational age. After obtaining consent for participation in the examination of every pregnant woman, a detailed history was taken, cardiotocography and ultrasound biometry were preformed. Also a blood sample was drawn to determine serum concentrations of appropriate markers and clinical laboratory testing to assess the severity of pre-eclampsia (moderate or severe). Inflammatory cytokines IL-10 was analyzed from peripheral blood 1-1,5ml by enzymatic amplification chemiluminescence on the device Immulite 1000, Siemens Healthcare Diagnostics, USA. The data were digitized and all statistical tests were performed using SPSS version 13.0. Logistic regression analysis (Binary Logistic Regression) was used to determine the predictive value of the different parameters for the occurrence of severe preeclampsia. Rates of probability - odds ratios (OR) and 95% Confidence Intervals (CI) were calculated in order to quantify independent associations. Results: Analysis applied in this study for several of the demographic and clinical risk factors for pre-eclapsia showed that elevated systolic blood pressure of 160 mmHg or higher, diastolic blood pressure of 100 mmHg or higher, pregnancy at older age than 35 years as is nulliparity are associated with highly significant risk for developing severe form of pre-eclampsia. Other risk factors examined in this survey such as duration of gestation, BMI, number of pregnancies, previous pregnancy with pre-eclampsia, diabetes and smoking status according to the results of this study, are risk factors that insignificantly increase the risk for severe form of pre-eclapmsia. As for the biochemical indicators, reduced serum concentrations of IL10 are statistically significantly associated with the development of severe form of preeclampsia in pregnant women. IL10 was also found to be negatively correlated with proteinuria, and positively correlated with blood platelets. Significantly higher concentration of IL10 was confirmed in patients with higher number of platelets in the blood, and vice versa. On the other hand, the serum concentration of IL10 was significantly lower in patients with higher amount of proteins in the urine, and vice versa. Conclusions: Examination of clinical risk factors combined with biochemical markers can improve the predictive success of pre-eclampsia and has important clinical values in improving the prognosis of pregnant women and fetuses.

Pregnancy and Labors at Women with Preeclampsia Against Early Endothelial Dysfunction

The objective: to study features of course of pregnancy and labors at women with preeclampsia against endothelial dysfunction.Materials and methods. For the solution of goal we conducted complex examination of 90 pregnant women who were divided into three groups. The control (1) group was made by 30 patients without endothelial dysfunction with the uncomplicated course of pregnancy and labors. The 2nd group – pregnant women with the early endothelial dysfunction (n=30) which pregnancy proceeded without clinical symptoms of preeclampsia at which mild disturbances in hemodynamic system mother–placenta–fetus were taped. The 3rd group (main) – pregnant women with early endothelial dysfunction (n=30), with clinical implications of preeclampsia, passed pregnancy with disturbances in maternal and fetus hemodynamic, ended with the birth of children with hypoxia signs.Results. Results of the conducted researches testify that the majority of pregnant women of the main group were primapara. 73,3% of women had an extragenital pathology, mainly vegeto vascular dystonia, anemia, an obesity, diseases of kidneys. Pathology of genesial system was presented by inflammatory diseases and hormonal disturbances. The course of the previous pregnancy became complicated relapsing threat of discontinuing, placental dysfunction, a fetal infection and a fetus hypoxia, and also puerperal infectious complications. Premature births were in 46,7% of cases, and pathological hemorrhage took place at 53,3% of women. All newborns of this group were born with signs of an acute hypoxia of varying severity. Infectious complications in the puerperal period developed at nearly a half of puerperas. The extract of women came from maternity hospital for 6–10 days after the delivery. About a third of newborns it was transferred to the second stage of nursing.Сonclusion. The received results are for us the basis for carrying out further researches of this scientific problem.

Effect of stretching exercises versus autogenic training on preeclampsia.

Preeclampsia (PE) is the most common medical complication of pregnancy characterized by hypertension and significant proteinuria after the 20th week of gestation, its prevalence is about 2%–8% of pregnancies. Antihypertensive drugs were found to have an adverse effect to both the mother and the fetus so interest is increased in nonchemical treatment. This study was conducted to compare between the effects of stretching exercises versus autogenic training (AT) on PE. This study was carried out on 40 preeclamptic primiparous women, their gestational age was exceeding 20 weeks. They were randomly divided into two equal groups; group A consisted of 20 women received stretching exercises and group B consisted of 20 women received relaxation training in the form of AT. All patients in both groups A and B received (3 sessions per week for 6 weeks) and received methyldopa as the antihypertensive drug. Evaluation of all patients in both groups A and B was done before and after the treatment program by assessing arterial blood pressure and proteinuria. Results of this study revealed that there is a significant decrease in systolic blood pressure, diastolic blood pressure and proteinuria in both groups A and B after 6 weeks of treatment. There was no significant difference between both groups post-treatment in systolic blood pressure, diastolic blood pressure, and proteinuria. It can be concluded that both stretching exercise and AT were found to be effective nonchemical methods which control the symptoms of PE.

Microalbuminuria as an early predictor of preeclampsia in the pre-gestational diabetic population: A prospective cohort study.

To determine if microalbuminuria can be used as a predictive marker of preeclampsia and adverse pregnancy and neonatal outcomes in women with pre-existing diabetes and to compare the prognostic utility of urinary albumin to creatinine ratio (uACR) and urinary protein to creatinine ratio (uPCR). Multicentre prospective cohort study. Antenatal Diabetes in Pregnancy clinics at three tertiary referral hospitals in Western Sydney, Australia. 158 women with pre-existing diabetes requiring insulin in pregnancy. A spot uPCR and uACR was performed in each trimester. Pregnancy and fetal outcomes were investigated using linear models and receiver-operating characteristic (ROC) curves. The primary outcome was preeclampsia (PE). Secondary outcomes investigated were other adverse pregnancy and neonatal outcomes. Increased levels of both uPCR and uACR in trimester 3 were associated with the occurrence of PE (p = 0.007, 0.010 respectively). In the 113 patients with normal pregnancy uPCR (<30 mg/mmol) in trimester 1, microalbuminuria was found to be predictive of PE (p = 0.01) and need for operative delivery (p = 0.03). In women with pre-existing diabetes, uPCR and uACR appear to have similar ability to diagnose PE, but microalbuminuria demonstrates prognostic ability at a much earlier gestation, prior to the onset of other signs or symptoms of PE. We therefore suggest that assessing microalbuminuria rather than overt proteinuria in trimester 1 provides prognostic information in women with pre-existing diabetes requiring insulin and should be used routinely to evaluate risk of PE in this high-risk cohort of women.

Evaluation of the effects of Uncaria rhynchophylla alkaloid extract on LPS-induced preeclampsia symptoms and inflammation in a pregnant rat model.

Excessive pro-inflammatory cytokines result in adverse pregnancy outcomes, including preeclampsia-like phenotypes, and fetal growth restriction. Anti-inflammation might be an effective therapy. The aim of this research was to investigate whether Uncaria rhynchophylla alkaloid extract (URE), a highly safe anti-inflammation constituent of the herb, can inhibit inflammation and improve clinical characteristics of preeclampsia in a lipopolysaccharide (LPS)-induced preeclampsia rat model. The rat model was established by daily administration of LPS (1 μg/kg body weight per day) from gestational day (GD) 14 to 19. Different doses of URE (35, 70, and 140 mg/kg body weight per day) were administered from GD 14 to GD 19. The effects of URE on proteinuria, maternal hypertension, pregnancy outcomes, as well as pro-inflammatory cytokines levels in serum and placenta were measured. High-dose URE (HURE) treatment decreased LPS-induced mean 24-h proteinuria and systolic blood pressure, and increased fetal weight, placental weight, and the number of live pups (P<0.05). Moreover, increased serum and placental levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and interferon-γ in the LPS-treated group were obviously inhibited after HURE administration (P<0.01). URE improved preeclampsia symptoms and mitigated inflammatory responses in the LPS-induced preeclampsia rat model, which suggests that the anti-inflammation effect of URE might be an alternative therapy for preeclampsia.

A double-hit pre-eclampsia model results in sex-specific growth restriction patterns.

ABSTRACTPre-eclampsia is a multifactorial pregnancy-associated disorder characterized by angiogenic dysbalance and systemic inflammation; however, animal models that combine these two pathophysiological conditions are missing. Here, we introduce a novel double-hit pre-eclampsia mouse model that mimics the complex multifactorial conditions present during pre-eclampsia and allows for the investigation of early consequences for the fetus. Adenoviral overexpression of soluble fms-like tyrosine kinase (sFlt-1) and lipopolysaccharide (LPS) administration at mid-gestation in pregnant mice resulted in hypertension and albuminuria comparable to that of the manifestation in humans. A metabolomics analysis revealed that pre-eclamptic dams have increased plasma concentrations of phosphadytilcholines. The fetuses of both sexes were growth restricted; however, in males a brain-sparing effect was seen as compensation for this growth restriction. According to the plasma metabolomics, male fetuses showed changes in amino acid metabolism, while female fetuses showed pronounced alterations in lipid metabolism. Our results show that combined exposure to sFlt-1 and LPS mimics the clinical symptoms of pre-eclampsia and affects fetal growth in a sex-specific manner, with accompanying metabolome changes.

Epidemiological Aspects and Prognosis of Severe Pre-eclampsia in Bangui, Central African Republic

Introduction: Severe preeclampsia is one of the most serious pathologies during pregnancy, with heavy morbidity and maternal-fetal mortality. The aim of our study was to help improve the management of severe preeclampsia. Methods: We conducted a cross-sectional analytical study from 1st September 2015 to 30th August 2016, at the Obstetrics and Gynecology Department of the Hopital communautaire of Bangui. The study population was pregnant and parturient patients with severe pre-eclampsia. Results: Out of 4021 registered cases, 41 met the inclusion criteria, with a prevalence of 1.0%. The primiparous were the most represented (48.8%). Magnesium sulfate was the most used as an anticonvulsant (70.7%) and dihydralazine was the most used for the High Blood Pressure (HBP). The main complications of pre-eclampsia were eclampsia (29.3%) and acute renal failure (19.5%). Overall, maternal mortality was 9.8% and perinatal mortality was 31.7%. Conclusion: The complications of severe preeclampsia are common in our study. The maternal and fetal prognosis remains a concern. Hence, we suggest early screening of pre-eclampsia symptoms during prenatal consultations to improve pregnancy outcome.

162: How often do physicians follow national guidelines for the diagnosis of hypertensive diseases of pregnancy?

The formulation of an accurate diagnosis influences delivery timing, and thus impacts pregnancy outcomes.It remains unclear how often physicians in clinical practice follow our national organization’s diagnostic criteria recommendations for hypertensive diseases of pregnancy (HDP). Our aim was to compare HDP diagnoses made by clinicians to those generated by experts who reviewed charts and adjudicated diagnoses.Further, we reviewed the clinical implications of the diagnoses made on timing of delivery. We conducted a secondary analysis of a multicenter prospective cohort study designed to evaluate serum PlGF in predicting adverse pregnancy outcome in women who presented with signs or symptoms of preeclampsia (PE). The study was performed in 24 centers in the US and Canada. The diagnosis and management criteria used were prior to the Hypertension in Pregnancy Task Force Guidelines publication. We reviewed patients who received the final diagnosis of preeclampsia (mild or severe), atypical preeclampsia, chronic hypertension, gestational hypertension (mild or severe), HELLP, eclampsia and those who remained non hypertensive.We then compared the diagnosis made by managing physicians to that adjudicated by experts who reviewed the charts. We also valuated the impact of asynchronous diagnosis on gestational age at delivery recommendations. 869 patients were included,of which 404 (46%) had a discordant diagnosis between investigator and adjudicators (figure 1). These differences in diagnoses would have affected delivery recommendations for 314 patients. All 31 patients undergoing immediate delivery per the investigator diagnosis, received diagnoses by the adjudicators that did not warrant immediate delivery (figure 2). On the other hand, all 25 patients that had a diagnosis consistent with expectant management by the investigators, would have been delivered earlier based on adjudicated diagnosis. Furthermore 65% of patients with a clinician diagnosis that recommended delivery at 37-39 weeks would have been delivered earlier by the expert adjudicator. The implications of lack of compliance with guideline recommendations for diagnosis and management of HDP amongst clinicians are concerning since they could lead to adverse pregnancy outcome. Future studies are needed to investigate the reasons for non-adherence with guideline recommendations in clinical practice.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

161: The impact of class III obesity on maternal and neonatal outcomes in preeclamptic patients

The rate of obesity is increasing in women of reproductive age, and obesity is a major risk factor for preeclampsia. Our objective was to compare maternal and neonatal morbidity and mortality in preeclamptic patients between those with a BMI <40 and a BMI ≥ 40 (class III obesity). We conducted a secondary analysis of a multicenter prospective cohort study (PE Triage by Rapid Assay-PETRA trial). The study’s primary objective was to validate placental growth factor as a biomarker for preeclampsia. Pregnant women at 200/7 to 400/7 weeks gestation who presented with signs or symptoms of preeclampsia (PE) were enrolled at 24 centers in the United States and Canada. The diagnosis of preeclampsia and other pregnancy complications were subsequently formulized by an adjudication group using standardized diagnostic criteria. Primary outcome was a composite neonatal morbidity (CNM) comprised of IVH (grade 3-4), NEC, BPD and perinatal death. Secondary outcomes were the components of CNM; small for gestational age (SGA) and gestational age at delivery (GA at del.) as well as maternal morbidity: abruption, renal failure, pulmonary edema, HELLP and eclampsia. Data were analyzed with the use of chi-square test and ANOVA as appropriate. 701 women with preeclampsia were evaluated: 585 (83%) had a BMI < 40 and 116 (17%) had a BMI ≥ 40. Baseline characteristics were different between groups regarding chronic hypertension and pre-gestational diabetes which were higher in those with a BMI ≥ 40 (Table 1). There were no significant differences in CNM between the 2 groups, however the BMI <40 subgroup had a higher rate of delivery at early and late preterm gestations (Table 2). Maternal morbidity was rare in both groups. In preeclamptic patients, maternal and neonatal morbidity is not increased in women with class III obesity. However, patients with class III obesity developed preeclampsia at a later gestational age.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Serum Adropin Levels in a Preeclampsia Like L-Name Rat Model Treated with Sildenafil Citrate

AbstractBackground: Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. Sildenafil been proposed as a potential therapy to reduce blood pressure and improve uteroplacental perfusion in preeclamptic patients. Adropin is a novel secreted energy homeostasis protein regulating carbohydrate, lipid and protein metabolism, maternal adropin levels in Preeclampsia were still controversy.Aim of the Work: To evaluate serum levels of adropin in preeclampsia-like rat model and in preeclamptic rats treated with Sildenafil and to investigate their associations with some inflammatory, oxidative stress, and metabolic parameters.Material and Methods: 32 pregnant rats were divided randomly into four groups (n=8): Control group, sildenafil treated group, L-NAME group to induce pre-eclampsia and L-NAME with sildenafil treated group. In all groups, maternal Body Mass Index (BMI), placental weights, fetal weights, maternal mean arterial blood pressure (MAP), total urinary proteins, serum glucose, insulin and calculated Homeostatic Model Assessment of Insulin Resistance index (HOMA-IR), serum urea, creatinine, Triglycerides (TGs), Total Cholesterol (TC), Low Density Lipoproteins-cholesterol (LDL-c), High Density Lipoproteins-cholesterol (HDL-c), C Reactive Protein (CRP), Endothelin-1 (ET-1), and adropin were measured, also placental Malondialdehyde (MDA) levels, and activities of the antioxidant enzymes Superoxide Dismutase (SOD) and glutathione peroxidase (GSH) in placental homogenates were determined plus histopathological examination of placental sections were done.Results: L-NAME induced preeclampsia in rats and they showed significant increase in MAP, total urinary proteins, serum levels of glucose, insulin, calculated HOMA-IR, serum urea, creatinine, CRP, ET-1, TGs, TC, LDL-c, adropin and placental tissue MDA with significant reduction in maternal BMI, placental weights, fetal weights, serum HDL-c and placental tissue SOD and GSH activities as compared to other groups, additionally, L-NAME treated and L-NAME + SILD treated groups revealed positive significant correlations between adropin levels and MAP, total urinary proteins, serum levels of urea, creatinine, CRP, ET-1, TGs, TC, LDL-c, and placental tissue MDA, however they showed negative corre-lations between adropin and BMI, placental weights, fetal weights, serum HDL-c and placental tissue SOD and GSH activities.Conclusion: Increased maternal adropin levels in preec-lampsia like model in rats might represent a regulatory feed-back mechanism against endothelial placental dysfunction, insulin resistance, inflammation and oxidative stress which associated with preeclampsia, hence identify it as a potentially protective agent against preeclampsia development. Sildenafil ameliorates preeclampsia symptoms, inflammation and oxi-dative stress in a rat model of preeclampsia.

Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers

Preeclampsia is the most frequent pregnancy-related complication worldwide with no cure. While a number of molecular features have emerged, the underlying causal mechanisms behind the disorder remain obscure. Here, we find that increased complex formation between angiotensin II AT1 and bradykinin B2, two G protein-coupled receptors with opposing effects on blood vessel constriction, triggers symptoms of preeclampsia in pregnant mice. Aberrant heteromerization of AT1-B2 led to exaggerated calcium signaling and high vascular smooth muscle mechanosensitivity, which could explain the onset of preeclampsia symptoms at late-stage pregnancy as mechanical forces increase with fetal mass. AT1-B2 receptor aggregation was inhibited by beta-arrestin-mediated downregulation. Importantly, symptoms of preeclampsia were prevented by transgenic ARRB1 expression or a small-molecule drug. Because AT1-B2 heteromerization was found to occur in human placental biopsies from pregnancies complicated by preeclampsia, specifically targeting AT1-B2 heteromerization and its downstream consequences represents a promising therapeutic approach.

Extracellular Vesicle microRNA: A Biomarker for Vascular Dysfunction in Pregnancy?

Placental dysfunction, including preeclampsia and fetal growth restriction, is a leading contributor to maternal and fetal morbidity and mortality. Development of effective prevention and treatment strategies has been limited by lack of identification of at-risk pregnancies. We performed small RNA sequencing of maternal serum microRNAs (miRNAs) to discover and independently verify biomarkers differentially expressed in patients who later developed preeclampsia. In this study, maternal serum was collected between 17-28 weeks gestation in two cohorts: The high-risk UCSD Placenta Study (19 cases, 29 controls); and the Sera Prognostics PAPR Study (54 cases, 110 controls). Samples were divided into Discovery (2/3) and Verification sets (1/3). Cases and controls were matched for gestational age (GA) at blood draw. miRNAs were isolated and sequenced to yield miRNA counts. Individual miRNAs and pairwise ratios (reversals) were tested in blinded verification. Biomarker discovery and verification were performed on the entire GA range and for 3 GA windows: 170/7 - 215/7 (Early); 195/7 - 244/7 (Middle); and 222/7 - 280/7 (Late) weeks. In Discovery, best performing miRNAs and reversals were selected for each GA window. Performance was then confirmed in blinded Verification (Table 2). 7/50 Early GA reversals had significant AUCs (mean Discovery AUC 0.78, mean Verification AUC 0.79). 21/50 Late GA reversals had significant AUCs (mean Discovery AUC 0.71, mean Verification AUC 0.68). Of biological importance, verified reversals contained a high proportion of miRNAs that were strongly expressed in placenta and/or encoded in the chr14q32 and chr19q13 miRNA clusters. miR-155-5p, present in 21 verified reversals, has been reported to mediate repression of eNOS by TNFα, which is a regulatory interaction associated with preeclampsia. We identified and verified differentially abundant miRNAs in maternal serum at 17-28 weeks GA in pregnancies that later developed signs and symptoms of preeclampsia compared to pregnancies with uncomplicated outcomes. Our findings suggest that maternal serum miRNAs may be useful as biomarkers for prediction of placental dysfunction and warrant validation in large independent cohorts. DisclosuresNo relevant conflicts of interest to declare.

Assessment of occurrence of preeclampsia and some clinical and demographic risk factors in Zahedan city in 2017

ABSTRACTBackground: Blood pressure dysfunctions are one of the biggest complications and causes of maternal mortality during pregnancy. The aim of the present study is to evaluate some of the clinical and demographic risk factors in various aspects, both of which can help to better understand the causes and reduce the incidence of preeclampsia.Method: This nested case–control study was carried out on 270 pregnant women with preeclampsia as the case group and 270 pregnant women who did not have symptoms of preeclampsia at the time of referral were interviewed according to inclusion criteria as the control group. The factors studied included age, body mass index, history of hypertension in mother, history of diabetes in mother, history of lupus in mother, number of pregnancies, history of preeclampsia in previous pregnancies, twin or more pregnancies, season of occurrence, maternal educational level, maternal blood group, maternal occupation status, infant’s sex and smoking status which were compared etween the two groups. t test and Chi-square tests were used to compare the variables in both groups. Fisher's exact test or Mann–Whitney U test was used if necessary.Findings: Of the 6929 pregnant women who participated in our study, 541 (7.8%) had preeclampsia. The means of body mass index (BMI) (24.86% versus 23.52%) (P = 0.032), the history of hypertension (19.3% versus 10.7%) (P = 0.006), history of preeclampsia in previous pregnancies (60.2% versus 13.3%) (P < 0.001), low level of education and illiteracy (51.1% versus 39.6%) (P = 0.028), and twin or more pregnancies (5.6% versus 2.2%) (P = 0.045) were significantly higher in the case group when compared to the control group. There was no statistically significant difference between the mean and standard deviation of age and number of pregnancies and the frequency of diabetes and lupus, the frequency of maternal occupation, maternal smoking, maternal blood group, and season of occurrence in the two groups (P > 0.05).Conclusion: Maternal BMI, maternal hypertension, history of preeclampsia in previous pregnancies, low maternal educational status, and twin or multiple pregnancies might be the risk factors for preeclampsia during pregnancy.

Placental CD4+ T cells isolated from preeclamptic women cause preeclampsia-like symptoms in pregnant nude-athymic rats.

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with a proinflammatory profile compared to normal pregnancy (NP). We hypothesize that CD4+ T cells from PE patient placentas cause PE symptoms during pregnancy compared to those from NP women. CD4+ T cells were isolated from placentas of PE and NP women using anti-CD4 magnetic separation, cultured in TexMACS medium at 37 °C in 5% CO2, and injected intraperitoneally into nude-athymic rats on day 12 of gestation. On day 18, carotid catheters were implanted and on day 19, mean arterial pressure (MAP) was measured and blood and tissues were collected. MAP was 125 ± 2 mmHg in rats with NP CD4+ T cells but increased to 140 ± 4 mmHg in rats with PE CD4+ T cells. Significant differences in circulating cytokines tumor necrosis factor-alpha (TNF-α), interleukin-17 (IL-17) and soluble fms-like tyrosine kinase-1 (sFlt-1) were found with PE vs NP CD4+ T cells (TNF-α- PE = 167.4 pg/mL, NP = 79.4 pg/mL; IL-17-PE = 7.054 pg/mL, NP = 3.185 pg/mL; sFlt-1-PE = 90.7 pg/mL, NP = 58.2 pg/mL. In addition, renal cortical endothelin-1 (ET-1) mRNA expression increased 4.5 fold in rats with PE CD4+ T cells versus those receiving to NP CD4+ T cells. These data indicate an important role for placental PE CD4+ T cells to cause many characteristics of PE during pregnancy.

297. Attenuation of angiotensin II-induced preeclamptic symptoms by recombinant thrombomodulin in mice – A novel therapeutic approach for preeclampsia

Introduction Placental dysfunction and disturbance of systemic endothelial function in the mother is involved in the pathetiology of preeclampsia (PE). According to the recent reports, recombinant thrombomodulin (rTM), an anticoagulant clinically used as a treatment for disseminated intravascular coagulation, plays a protective role to diminish endothelial damage under variety of pathological situations. Objective To examine the efficacy of rTM administration in PE developed by angiotensin II (AngII) infusion in pregnant mice. Methods Pregnant mice were continuously infused with AngII for 7 days from pc 10 to 17 using the osmotic mini pump. rTM was administered intraperitoneally for 4 days from pc 13 to 16. In the control group, saline was administered instead of rTM during the same period. Blood pressure (BP) was monitored daily. Blood and urine samples were collected before and after rTM or saline injection. On pc 17, the mice were sacrificed to check the fetal growth and the placental status. Results Continuous infusion of Ang II induced the symptoms mimicking human PE. Significant elevation of BP was confirmed from day 3 after starting Ang II infusion. Occurrence of proteinuria on pc 17 was limited to AngII infused pregnant mice. AngII infusion caused growth restriction to the fetuses. Administration of rTM significantly attenuated all three symptoms of PE. Discussion rTM attenuated Ang II-induced PE symptoms in the mouse model. Our findings suggest that rTM could be a novel approach for the tretment of PE.

62. Very preterm preeclampsia and treatment by heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) apheresis: The Freiburg preeclampsia H.E.L.P.-apheresis study

Objective Soluble Fms-like tyrosine kinase-1 (sFlt-1) is thought to be causative in the pathogenesis of preeclampsia (PE) and specific removal of sFlt-1 via dextran sulfate cellulose (DSC)-apheresis was suggested as a cure to allow for prolongation of pregnancy in preterm PE. However, in addition a deranged lipoprotein metabolism may impact endothelial and placental function in PE. Lipoprotein-apheresis by heparin-mediated extracorporeal LDL-precipitation (H.E.L.P.) was previously applied and has been shown to alleviate symptoms in PE. This clinical trial reevaluates the clinical efficacy of H.E.L.P.-apheresis in PE considering sFlt-1. Methods Open pilot study assessing the prolongation by H.E.L.P.-apheresis in 6 women (30–41 years) with very preterm PE (24 + 4 to 27 + 0 gestational weeks (GW)) (NCT01967355) compared to a historic control-group matched for GW at admission. Clinical outcome of mothers and babies, and pre- and post H.E.L.P.-apheresis levels of sFlt-1and PlGF were monitored. Results In apheresis patients (2–6 treatments), average time from admission to birth was 15.0 days (6.3 days in controls; p = 0.027). Lung maturation was induced in all treated cases, and all children were released in healthy condition. Apheresis reduced triglycerides and LDL-cholesterol by more than 40%. Although H.E.L.P.-apheresis induced a transient peak, baseline levels did not change and rather stabilized sFlt-1 levels at pre-apheresis levels Discussion Lipoprotein-apheresis proved again to be safe and prolongs pregnancies in PE. However, without changing sFlt-1 levels below baseline lowering lipids or other yet undefined factors appear to be of more relevance than reducing sFlt-1.