Early-onset Severe Preeclampsia Research Articles

Plasma Level of Umbilical Cord Hemeoxygenase-1 (HO-1) and Neonatal Outcome in Early Onset and Late Onset Severe Preeclampsia

Background: Many studies had discovered that early onset severe preeclampsia (EO-PE) has worst maternal and neonatal outcome compared to late-onset type (LO-PE), related to its placental involvement. Severe preeclampsia was defined as newly onset severe hypertension developed after 20 weeks gestation in previously normal blood pressure women, with coexistence of proteinuria, or maternal organ or uteroplacental dysfunction. Hemeoxygenase-1 (HO-1) is an enzyme with multiple effect which is protective to pregnancy.Materials and Methods: The total study subjects were 40 pregnant women consisted of 10 EO-PE, 10 normal early onset pregnancy (EO-NP), 10 LO-PE, and 10 normal late onset pregnancy (LO-NP). As much as 5 cc of plasma from umbilical cord was taken as soon as the baby was born, and the HO-1 level was examined by enzyme-linked immunosorbent assay (ELISA). The primary outcome were umbilical cord HO-1 level and neonatal composite morbidity (low Apgar score, low birthweight, length of stay >5 day, respiratory distress syndrome, jaundice and neonatal death).Results: The plasma level of HO-1 in EO-PE subjects were lower than EO-NP (0.96±0.37 ng/mL vs. 2.43±0.58 ng/mL, p<0.001). There were no significant differences in the level of HO-1 in LO-PE and LO-NP (2.18±1.07 ng/mL vs. 3.02±0.64 ng/mL, p=0.277). Plasma level of umbilical cord HO-1 of EO-PE patients was lower compared to LO-PE (0.96±0.37 ng/mL vs. 2.18±1.07 ng/mL, p=0.034). Neonatal outcome of EO-PE was worse than EO-NP (p=0.033), and LO-PE (p=0.003), while in LO-PE did not different with LO-NP (p=0.211).Conclusion: EO-PE is associated with lower plasma umbilical cord level of HO-1 and worse neonatal outcome compared to LO-PE. This indicating abnormal placental blood vessel development, placental ischemia in EO-PE, lead to reduced uteroplacental perfusion and significantly worse neonatal outcome compared to LO-PE.Keywords: severe preeclampsia, early onset preeclampsia, late onset preeclampsia, hemeoxygenase-1

Glycosylation Profile of the Transferrin Receptor in Gestational Iron Deficiency and Early-Onset Severe Preeclampsia.

Objective To examine the expression of hypoxia-inducible factor-1α (HIF-1α), TfR1, and TfR1-attached terminal monosaccharides in placentas of women with IDAP and severe preeclampsia. Methods TfR1 and HIF-1α were detected by western blot. Immunoadsorption of TfR1 was performed to characterize the terminal monosaccharides by specific lectin binding. Results There was no difference in the expression of TfR1 and HIF-1α between groups. Lectin blot analysis pointed out an overexpression of galactose β1-4 N-acetylglucosamine (Gal-GlcNAc) and mannose in severe preeclampsia. Conclusion The increase in Gal-GlcNAc may be due to the increased presence of antennary structures and the mannose glycans of TfR1 may indicate the presence of misfolded or incomplete proteins. These findings may be associated with the low expression of placental TfR1 in women with preeclampsia.

Placental CX3CL1 is Deregulated by Angiotensin II and Contributes to a Pro-Inflammatory Trophoblast-Monocyte Interaction.

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was addressed whether angiotensin II can deregulate placental CX3CL1 expression, and whether CX3CL1 can promote a pro-inflammatory status of monocytes. qPCR analysis of human placenta samples (n = 45) showed stable expression of CX3CL1 and the angiotensin II receptor AGTR1 throughout the first trimester, but did not show a correlation between both or any influence of maternal age, BMI, and gestational age. Angiotensin II incubation of placental explants transiently deregulated CX3CL1 expression, while the angiotensin II receptor antagonist candesartan reversed this effect. Overexpression of recombinant human CX3CL1 in SGHPL-4 trophoblasts increased adhesion of THP-1 monocytes and significantly increased IL8, CCL19, and CCL13 in co-cultures with human primary monocytes. Incubation of primary monocytes with CX3CL1 and subsequent global transcriptome analysis of CD16+ subsets revealed 81 upregulated genes, including clusterin, lipocalin-2, and the leptin receptor. Aldosterone synthase, osteopontin, and cortisone reductase were some of the 66 downregulated genes present. These data suggest that maternal angiotensin II levels influence placental CX3CL1 expression, which, in turn, can affect monocyte to trophoblast adhesion. Release of placental CX3CL1 could promote the pro-inflammatory status of the CD16+ subset of maternal monocytes.

Genetic Aspects of Preeclampsia: The Role of Polymorphisms in the Genes of the Renin-Angiotensin System.

Preeclampsia (PE) is a severe complication that develops in 10% pregnant women. It is the leading cause of maternal and perinatal morbidity and mortality worldwide. The goal of this study was to reveal the frequency of polymorphisms in the angiotensin-converting enzyme gene (ACE I/D) and type 1 angiotensin II receptor gene (AGTR1 A1166C) in pregnant women with severe early- and late-onset PE. A retrospective case-control study of 55 pregnant women with PE (main group) and 30 patients with uncomplicated pregnancy (control group) was conducted. In the main group, we considered two subgroups - early-onset PE (20 patients) and late-onset PE (36 patients). The I/D polymorphism of the ACE gene is associated with the risk of developing PE. The presence of the D allele increases the risk of severe PE. In case of DD genotype, the probability of early-onset PE is 5 times higher than that of the late-onset PE. The analyzed data confirm the involvement of renin-angiotensin system in the PE development. We conclude that the ACE gene polymorphism is a genetic predictor of the early-onset severe PE. Studying the polymorphic loci of the ACE gene makes it possible to use them for the individualized prognosis of the development and course of PE in patients.

Effect of predictive nursing on pregnancy outcome of early onset severe preeclampsia patients

Objective To explore the effect of predictive nursing on pregnancy outcome of early onset severe preeclampsia. Methods A total of 100 patients of early onset severe preeclampsia treated in the hospital were selected from January 2014 to April 2017.According to the different nursing intervention patterns, they were divided into the observation group and the control group, 50 cases of each group.Patients in the control group received conventional intervention. Patients in the observation group were given predictive nursing mode.Patients in both groups were given continuous intervention for 1 month.Pregnancy outcomes and perinatal outcomes were recorded and compared between the two groups.The occurrence of complications and patients' satisfaction were compared between the two groups. Results The incidence of postpartum hemorrhage and eclampsia in the observation group was significantly lower than that in the control group, and the difference was statistically significant(P<0.05). The incidence of intrauterine death, fetal distress and neonatal asphyxia in the observation group was significantly lower than that in the control group, and the difference was statistically significant(P<0.05). The incidence of complications in the observation group was significantly lower than that in the control group, and the difference was statistically significant(P<0.05). The satisfaction of the observation group was significantly higher than that of the control group, and the difference was statistically significant(P<0.05). There was no significant difference in diastolic blood pressure, systolic blood pressure and delivery gestational age between the two groups.The SAS score of patients in the observation group was significantly lower than that in the control group, and the difference was statistically significant(P<0.01). Conclusion Predictive nursing intervention for patients with early onset severe preeclampsia can significantly improve maternal and infant outcomes and anxiety, lessen the incidence of complications, and improve the satisfaction of patients.It is worthy of clinical application. Key words: Early onset severe preeclampsia; Predictive care; Pregnancy outcome; Satisfaction degree

Expression of S100 calcium-binding protein A8 in peripheral blood of patients with preeclampsia during pregnancy

A total of 30 late onset severe preeclampsia (LS-PE) patients and 30 early onset severe preeclampsia (ES-PE) patients were selected as Experimental group, and 30 normal pregnant were selected as Control group. Expression of S100 calcium-binding protein A8 (S100A8) mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect expression of S100A8 protein and inflammatory factors. Levels of uric acid (UA) and creatinine (CRE) were measured using an automatic biochemical analyzer. Urinary protein (UPRO) content was measured using biuret colorimetry. S100A8 levels were significantly higher in experimental groups than in control groups at mRNA and protein levels ( P &lt; 0.05). Significantly increased contents of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, UA, CRE, and UPRO, and decreased level of IL-10 were found in experimental groups than in control groups ( P &lt; 0.05). Compared with patients with ES-PE, significantly higher levels of TNF-α, IL-12, IL-6, UA, CRE, and UPRO, and lower level of IL-10 were found in patients with LS-PE. S100A8 plays pivotal roles in the development of preeclampsia through the interactions with other inflammatory factors.

Let-7a-3 Promoter Hypomethylation Induces Apoptosis of Trophoblast Cells in Early-Onset Severe Preeclampsia by Targeting Bcl-xl and YAP1

Let-7a-3 Promoter Hypomethylation Induces Apoptosis of Trophoblast Cells in Early-Onset Severe Preeclampsia by Targeting Bcl-xl and YAP1

Pre-eclampsia and the foetus: a cardiovascular perspective.

Pre-eclampsia is the leading cause of perinatal morbidity and mortality. A full understanding of the pathogenesis of this enigmatic condition is essential if we are to develop new prophylactic and therapeutic interventions. Central to our understanding of the pathogenesis of early-onset preeclampsia is absolute utero-placental ischaemia, which is lack of placental vascular transformation in early pregnancy. By contrast, relative utero-placental ischaemia, due to a mismatch between utero-placental blood flow and increased demand for nutrients occurring later in pregnancy, may be central to the development of late-onset pre-eclampsia. These pathogenic mechanisms have advanced our understanding of this condition, leading to better prediction, screening and intervention modalities. Screening for pre-eclampsia in the first and second trimesters by investigating the maternoplacental circulation and placental hormones could identify a high-risk subgroup. The advantage of screening in the first trimester is that a prophylactic intervention is available in the form of low-dose aspirin, if started before 16 weeks' gestation in the high-risk group, resulting in a substantial reduction in severe early-onset pre-eclampsia, while identification of a high-risk group in the second trimester will lead to focused management in this group. Using a combination of cardiac Doppler, multi-vessel Doppler assessment of the foetal circulation and biomarkers in established pre-eclampsia in the third trimester could predict adverse outcomes and guide clinicians to timeous delivery. Hopefully, advances in our understanding of this enigmatic disease will lead to further prophylactic and new therapeutic interventions.

Clinical application evaluation of serum C1q and other complement factors in the diagnosis and prediction of preeclampsia

Objective To observe the levels of serum complement C1q, C3, C4 and factor B in different phases during normal pregnancy; To evaluate the diagnostic value and the predictive value of serum complement C1q, C3, C4 and factor B in preeclampsia (PE). Methods Three groups of subjectes were enrolled from January 2017 to March 2018 in Department of Obstetrics and Gynecology, Peking University Third Hospital. (1) 30 pregnant women in each group at 8-14 weeks, 20-26 weeks and 28-36 weeks were retrospectively selected, and the serum levels of complement C1q, C3, C4 and B factors were measured and compared. (2)Selecting 17 cases of early-onset mild PE, 47 cases of early-onset severe PE, 24 cases of late-onset mild PE, 27 cases of late-onset severe PE, and 30 normal pregnant cases of the same gestational stage as early-onset / late-onset controls, through ANOVA analysis and comparison between two groups, this study evaluated the diagnostic value of serum complement C1q, C3, C4 and factor B in PE. (3)To evaluate the predictive effect in PE, it analyzed serum C1q and factor B levels of pregnant women at 20-26 gestation weeks through prospective nested case-control study of 214 cases. Results The levels of serum C1q remained stable in the whole pregnancy. The levels of C3 and factor B increased at the early stage of pregnancy and remained stable after the middle stage. C4 increased early in pregnancy and then remained stable. Compared with the control group, the levels of serum C1q in all four types of PE patients were significantly decreased (median: 169 mg/L, 161 mg/L, 165 mg/L, 163 mg/L; early-onset, late-onset control group: 187 mg/L, 194 mg/L; U=130.500, 426.500, 159.500, 130.500, all P 0.05). 33 (15.4%) cases developed PE out of 214 pregnant women with PE risk factors. Compared to those who didn′t develop PE, it showed no statistical difference of serum C1q, C3, C4, and factor B levels at 20-26 gestational weeks of the women who subsequently developed PE (C1q: 175 mg/L vs. 184 mg/L; C3: 1 523 mg/L vs. 1 467 mg/L; C4: 230 mg/L vs. 229 mg/L; FB: 344 mg/L vs. 320 mg/L; U=2 090.000, 1 575.000, 2 058.500, 1 362.000, all P>0.05). Compared to those of the healthy pregnant controls, it showed no statistical difference of serum C1q, C3 and C4 levels of 20-26 gestational weeks of the women who subsequently developed PE (C1q: 175 mg/L vs. 190 mg/L; C3: 1 523 mg/L vs. 1 428 mg/L; C4: 230 mg/L vs. 227 mg/L; U=353.000, 395.000, 493.500, all P>0.05), while it showed statistical difference (344 mg/L vs. 306 mg/L; U= 233.500, P=0.007) for factor B. Conclusions Serum C1q level of PE patients significantly decreased, which can be used as potential indicators of PE diagnosis, but serum C1q, C3, C4 level of 20-26 gestational weeks cannot predict risk of PE. Factor B cannot serve as serum index of PE diagnosis, but its serum levels at 20-26 gestational weeks werer higher than those of normal pregnant controls, factor B may be a potential predictor, but need further verification. (Chin J Lab Med, 2018, 41: 934-942) Key words: Preeclampsia; Complement; C1q; C3; C4; factor B

Maternal Cardiac Output Response to Colloid Preload and Vasopressor Therapy During Spinal Anesthesia for Cesarean Section in Patients With Severe Preeclampsia: A Randomized, Controlled Trial

(Anaesthesia. 2018;73:23–31) Minimally invasive cardiac output monitors have been used in parturients to assess the hemodynamic effects of spinal anesthesia and the commonly used vasopressors phenylephrine and ephedrine. However, studies utilizing these devices have been performed mostly in healthy parturients, with data lacking for those with severe preeclampsia. This randomized study’s objective was to compare the cardiac output response to phenylephrine or ephedrine administered for spinal hypotension during cesarean delivery in women with severe early-onset preeclampsia as well as to measure the stroke volume response to administration of a colloid preload.

Association between polymorphism in Cyclophilin A gene and its serum and placental expression in Han Chinese women with severe preeclampsia.

Cyclophilin A (CypA) plays important roles in inflammation and oxidative stress and is significantly increased in serum of preeclampsia (PE) patients. We aimed to investigate CypA genetic polymorphism and its serum and placenta expressions in severe PE of Han Chinese women. A case-control study of 82 severe PE patients and 179 healthy pregnancies was conducted. Single-nucleotide polymorphism (SNP) sites of rs3735481, rs9638978 and rs11984372 were analyzed by TaqMan assay. CypA serum levels were determined by enzyme-linked immunosorbent assay (ELISA). CypA mRNA levels and protein expressions in placentas were assessed by quantitative real-time polymerase chain reaction (PCR), western blot, and immunofluorescence assay, respectively. There were significantly lower frequency of rs3735481 allele C (odds ratio (OR): 0.60, 95% confidence interval (CI): 0.36-0.98; p = .04), and significantly higher frequency of rs9638978 allele A in severe PE especially in early onset PE patients (OR: 2.23, 95% CI: 1.35-3.71, p = .002). Frequency of rs9638978 AA genotype was significantly higher in early onset PE (p < .001). CypA serum levels were significantly higher in severe PE especially in early onset PE (p < .001). Meanwhile, CypA serum levels were significantly lower in carriers with the AC genotype of rs3735481 (p = .019) and significantly higher in carriers with the AA genotype of rs9638978 (p = .017). CypA mRNA levels and protein expressions were found to be significantly increased in PE placentas (both p < .01). The CypA genetic polymorphisms of rs3735481 and rs9638978 may be associated with severe PE, and rs9638978 AA genotype may be associated with an increasing risk of early onset severe PE in Han Chinese women. High CypA levels in serum and placenta may contribute to the pathogenesis of severe PE. Our results may provide a new clue for the etiology of severe PE.

Preeclampsia - Current Management and Future Approach.

Preeclampsia is one of the most serious pregnancy - specific medical conditions of increasing incidence. It remains a major cause of maternal and fetal morbidity and mortality. Although maternal mortality is especially high in developing countries, preeclampsia and its complications are one of the top four causes of maternal deaths even in developed societies. Unfortunately, yet the only effective and definitive treatment of preeclampsia is delivery of the baby and placenta, and its time depends on the disease severity and gestational age. In this review, we report principles of management of preeclampsia in the light of current international recommendations. Suggested failure of the placental development and significant role of angiogenic factors and their receptors in etiology of preeclampsia give the possibility for their future use in diagnosis and risk assessment of the disease and open new chapter of possible solutions also in the field of treatment of this serious pregnancy complication. Introduction of an advanced form of therapy that could safely prolong the duration of pregnancy would be invaluable in the area of preeclampsia management and lowering perinatal complications, especially in women with early-onset severe preeclampsia.

Screening of differentially expressed proteins from syncytiotrophoblast for severe early-onset preeclampsia in women with gestational diabetes mellitus using tandem mass tag quantitative proteomics

BackgroundPrevious studies have revealed that women with gestational diabetes mellitus (GDM) have an increased risk of developing preeclampsia (PE). The possible reason is the abnormal lipid metabolism caused by GDM that leads to dysfunction of vascular endothelial cells and atherosclerosis, resulting in the onset of PE. However, studies focusing on the pathogenesis of PE in syncytiotrophoblast of GDM patients are lacking. This study aimed to compare differentially expressed proteins from syncytiotrophoblast between women with GDM and women with GDM with subsequently developed PE.MethodsSyncytiotrophoblast samples were obtained from pregnant women immediately after delivery. To explore the protein expression changes of syncytiotrophoblast that might explain the pathogenesis of PE in women with GDM, quantitative proteomics was performed using tandem mass tag (TMT) isobaric tags and liquid chromatography-tandem mass spectrometry. Bioinformatics analysis was performed to enrich the biological processes that these differentially expressed proteins were involved in.ResultsA total of 28,234 unique peptides and 4140 proteins were identified in all samples. Among them, 23 differentially expressed proteins were identified between patients with GDM and patients with GDM with subsequently developed PE. Therein, 11 proteins were upregulated and 12 proteins were downregulated. Two relative proteins (FLT1 and PABPC4) were independently verified using immunoblotting analysis. Bioinformatic results indicated that the onset of PE in patients with GDM is a multifactorial disorder, involving factors such as apoptosis, transcriptional misregulation, oxidative stress, lipid metabolism, cell infiltration and migration, and angiogenesis.ConclusionThese results indicated that the inadequacy of endometrium infiltration, angiogenic disorder, and oxidative stress in syncytiotrophoblast are more likely to occur in patients with GDM and may be the potential mechanisms leading to such patients secondarily developing severe early-onset PE.

Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks' gestation.

Severe pre-eclampsia can cause significant mortality and morbidity for both mother and child, particularly when it occurs remote from term, between 24 and 34 weeks' gestation. The only known cure for this disease is delivery. Some obstetricians advocate early delivery to ensure that the development of serious maternal complications, such as eclampsia (fits) and kidney failure are prevented. Others prefer a more expectant approach, delaying delivery in an attempt to reduce the mortality and morbidity for the child that is associated with being born too early. To evaluate the comparative benefits and risks of a policy of early delivery by induction of labour or by caesarean section, after sufficient time has elapsed to administer corticosteroids, and allow them to take effect; with a policy of delaying delivery (expectant care) for women with severe pre-eclampsia between 24 and 34 weeks' gestation. For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) on 27 November 2017, and reference lists of retrieved studies. Randomised trials comparing the two intervention strategies for women with early onset, severe pre-eclampsia. Trials reported in an abstract were eligible for inclusion, as were cluster-trial designs. We excluded quasi-randomised trials. Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. We assessed the quality of the evidence for specified outcomes using the GRADE approach. We included six trials, with a total of 748 women in this review. All trials included women in whom there was no overriding indication for immediate delivery in the fetal or maternal interest. Half of the trials were at low risk of bias for methods of randomisation and allocation concealment; and four trials were at low risk for selective reporting. For most other domains, risk of bias was unclear. There were insufficient data for reliable conclusions about the comparative effects on most outcomes for the mother. Two studies reported on maternal deaths; neither study reported any deaths (two studies; 320 women; low-quality evidence). It was uncertain whether interventionist care reduced eclampsia (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.58; two studies; 359 women) or pulmonary oedema (RR 0.45, 95% CI 0.07 to 3.00; two studies; 415 women), because the quality of the evidence for these outcomes was very low. Evidence from two studies suggested little or no clear difference between the interventionist and expectant care groups for HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome (RR 1.09, 95% CI 0.62 to 1.91; two studies; 359 women; low-quality evidence). No study reported on stroke. With the addition of data from two studies for this update, there was now evidence to suggest that interventionist care probably made little or no difference to the incidence of caesarean section (average RR 1.01, 95% CI 0.91 to 1.12; six studies; 745 women; Heterogeneity: Tau² = 0.01; I² = 63%).For the baby, there was insufficient evidence to draw reliable conclusions about the effects on perinatal deaths (RR 1.11, 95% CI 0.62 to 1.99; three studies; 343 women; low-quality evidence). Babies whose mothers had been allocated to the interventionist group had more intraventricular haemorrhage (RR 1.94, 95% CI 1.15 to 3.29; two studies; 537 women; moderate-quality evidence), more respiratory distress caused by hyaline membrane disease (RR 2.30, 95% CI 1.39 to 3.81; two studies; 133 women), required more ventilation (RR 1.50, 95% CI 1.11 to 2.02; two studies; 300 women), and were more likely to have a lower gestation at birth (mean difference (MD) -9.91 days, 95% CI -16.37 to -3.45 days; four studies; 425 women; Heterogeneity: Tau² = 31.74; I² = 76%). However, babies whose mothers had been allocated to the interventionist group were no more likely to be admitted to neonatal intensive care (average RR 1.19, 95% CI 0.89 to 1.60; three studies; 400 infants; Heterogeneity: Tau² = 0.05; I² = 84%). Babies born to mothers in the interventionist groups were more likely to have a longer stay in the neonatal intensive care unit (MD 7.38 days, 95% CI -0.45 to 15.20 days; three studies; 400 women; Heterogeneity: Tau² = 40.93, I² = 85%) and were less likely to be small-for-gestational age (RR 0.38, 95% CI 0.24 to 0.61; three studies; 400 women). There were no clear differences between the two strategies for any other outcomes. This review suggested that an expectant approach to the management of women with severe early onset pre-eclampsia may be associated with decreased morbidity for the baby. However, this evidence was based on data from only six trials. Further large, high-quality trials are needed to confirm or refute these findings, and establish if this approach is safe for the mother.

Induction of Labor for Maternal Indications at a Periviable Gestational Age; Survey on Management, Reporting and Auditing amongst Dutch Maternal-Fetal Medicine Specialists and Neonatologists.

Background In cases of life-threatening maternal conditions in the periviable period, professionals may consider immediate delivery with fetal demise as a consequence of the treatment. We sought the opinion of involved medical professionals on management, reporting, and auditing in these cases. Methods We performed an online survey amongst all registered maternal-fetal medicine (MFM) specialists and neonatologists in the Netherlands. The survey presented two hypothetical cases of severe early-onset pre-eclampsia at periviable gestational ages. Management consisted of immediate termination or expectant management directed towards newborn survival. Findings In the case managed by immediate termination, 62% percent answered that fetal demise resulting from induction of labor for maternal indications should be audited only within the medical profession. In the case of expectant management, 17% of the participants agreed with this management. Some answers revealed a significant difference in opinion between the medical specialists. Conclusion Perspective of MFM specialists and neonatologists differs with regard to counseling prospect parents in case of severe early onset pre-eclampsia. The majority of professionals is willing to report late termination (after 24 weeks' gestation) for severe maternal disease to medical experts for internal audits but not for legal auditing.

296. Loss of Placental NR4A2 may contribute to the pathogeneisis of pre-eclampsia

Introduction Placental dysfunction is a key contributor in the development of pre-eclampsia. Recently, we identified NR4A2 mRNA to be altered in the maternal circulation in pregnancies complicated by severe, early onset fetal growth restriction and pre-eclampsia (PE). Objective The current study aimed to determine whether NR4A2 expression was altered in the human placenta with hypoxic insult and pre-eclampsia. Methods Isolated primary cytotrophoblasts (n = 5) and placental explant tissue (n = 4) from normal term placentas were cultured under normoxia (8% oxygen) and hypoxia (1% oxygen) for 24 h. Expression of NR4A2 was assessed by qPCR. Placental tissue was collected from severe early onset PE (n = 49) and gestation matched controls (n = 47) to test NR4A2 mRNA expression. NR4A2 protein was assessed in PE (n = 31) and preterm (n = 22) placenta by Western blotting. Primary cytotrophoblasts were transfected with NR4A2 siRNA (n = 3) to silence gene expression (under normoxia and hypoxia for 48 h). sFLT-1 secretion was assessed by ELISA and expression of the sFLT-1 variants (e15a and i13) and cell survival associated genes by qPCR. Normality (Gaussian distribution) was assessed in each case and appropriate post hoc analysis was performed. Results NR4A2 mRNA expression was significantly reduced with hypoxia in trophoblast, but not placental explants. Additionally, NR4A2 mRNA expression was significantly reduced in PE placenta. However, there was no difference in NR4A2 protein expression between PE and controls. Silencing NR4A2 significantly increased anti-angiogenic factor sFLT-1 secretion, but not sFLT-1 mRNA expression. Furthermore, loss of NR4A2 in the trophoblast reduced pro-survival IGF2 gene expression and increased NOX4 (oxidative stress marker) expression. Conclusion NR4A2 is reduced in the trophoblast with hypoxia and mRNA expression is low in the PE placenta. Signs of placental dysfunction were observed with the silencing of NR4A2 in the trophoblast and an increase in sFLT-1 secretion suggests potential roles for NR4A2 in the pathogenesis of PE.

286. Endothelin-1 is elevated prior to the development of term preeclampsia and is exacerbated in established severe early onset preeclampsia

Introduction Preeclampsia (PE) is a serious complication of pregnancy, the pathophysiology remains unclear and diagnosis and treatment strategies are limited. The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of PE. Previously we observed ET-1 levels were significantly higher in a cohort of women at high risk of developing PE as early as the first trimester[a]. We set out to measure ET-1 in the circulation in women destined to develop PE, and in women with established severe PE. Methods Plasma samples were collected as part of two separate studies and used to assess ET-1 levels by ELISA. Plasma was collected from women 1) from a case control prospective cohort study (Fetal Longitudinal Assessment of Growth; FLAG) at both 28 (n = 106 Controls and n = 38 PE) and 36 weeks (n = 99 Controls and n = 39 PE) gestation, prior to diagnosis of term PE; and 2) with established severe early onset PE ( Results Plasma ET-1 levels were significantly higher in women destined to develop term PE (FLAG cohort) at 28 (p Conclusions We identified increased ET-1 levels in women destined to develop term PE and massively elevated levels in women with severe early onset PE. ET-1 may provide a useful biomarker alone or in combination with other markers to predict PE. ET-1 has potent vasoconstrictory activities, and likely plays considerable roles in the pathogenesis of PE; neutralising ET-1 action may offer therapeutic strategies to treat PE. 1 Groom et al., AmJOG, 2017.

14. Maternal and neonatal outcome in vaginal delivery versus caesarean section in severe early onset preeclampsia prior to 28 weeks’ gestation, a systematic review

Introduction preeclampsia with an onset prior to 28 weeks’ gestation poses a dilemma for the obstetrician with regard to mode of delivery for optimal maternal and neonatal outcome. Objective To analyze the succes rate of attempted vaginal delivery (VD) in preeclampsia prior to 28 weeks’ gestation and the maternal and neonatal outcome according to mode of delivery (VD versus CS). Methods A comprehensive search was performed in the bibliographic databases Pubmed, Embase.com and Wiley Cochrane Library from inception up to June 2017. Main outcome was succes rate of attempted vaginal delivery in women with preeclampsia prior to 28 weeks’ gestation. Secondary outcomes were maternal outcomes: maternal death, ICU admission, postpartum hemorrhage > 1 liter, placental abruption and manual removal of placenta after VD or CS. Neonatal outcomes were: neonatal death, neonatal morbidity (composite outcome) and live discharge from NICU after VD versus CS. Results Eight studies, either retrospective or prospective cohort studies, describing a total of 162 women, were included for this review. No RCT’s were found. Succes rates of vaginal delivery varied from 1.8 to 80% and rates for CS after attempted vaginal delivery after induction of labor varied from 13 to 51%. Two studies (n = 53) described no statistical significant difference in maternal outcomes according to delivery mode. Two other studies (n = 107) described no statistical significant difference in neonatal outcomes according mode of delivery. Conclusions There are no RCT’s on mode of delivery in women with severe early-onset preeclampsia prior to 28 weeks’ gestation. Studies that do report the primary outcome are small, therefore no firm conclusions can be made. However, giving the available evidence in the reported studies, a trial of labor can be considered in preeclamptic patients prior to 28 weeks’ gestation.

13. Induction of labor for maternal indications at a periviable gestational age; survey on management, reporting and auditing amongst dutch maternal-fetal medicine specialists and neonatologists

Background In exceptional cases of severe and life-theatening maternal conditions in the periviable period, professionals may consider immediate delivery the only option to prevent deterioration of the maternal illness. Fetal demise is then the inevitable consequence of the treatment of the mother. We sought the opinion of involved medical specialists on management, reporting and auditing in these difficult cases. Methods All registered fetal-maternal medicine specialists (MFM-specialists) (n = 197) and neonatologists (n = 282) were invited to participate in an online survey. The survey presented to hypothetical cases of severe early-onset preeclampsia at periviable gestational age. Two management-options were presented: immediate delivery and expectant management directed towards newborn survival. During expectant management two epsiodes with eclamptic seizures occured. Findings In the case managed by immediate termination, 62% answered that fetal demise resulting from induction of labor for severe maternal illness should be audited within the medical profession only. In the case managed expectantly, 17% agreed with this management. 75% of MFM-specialists answered that an eclamptic seizure is always a reason for immediate delivery. Some answers revealed a significant difference in opinion between the MFM-specialists and the neonatologists. The first concern of the MFM-specialists is the health of the mother, while the first concern of the neonatologists is, to achieve optimal gestational age for the newborn. Conclusion Perpective of MFM-specialists and neonatologists differs with regard to counseling prospect parents in case of severe early-onset preeclampsia. The majority of professionals is willing to report late termination of pregnancy (after 24 weeks’ gestation) for severe maternal disease to medical experts for internal audits, but not for legal auditing.

Severe preeclampsia and gene mutation HNF4A (MODY1): а case report

Preeclampsia is an obstetric complication that is becoming a major cause of maternal and perinatal morbidity and mortality. The rate of preeclampsia in diabetes mellitus is 3 to 5-fold higher than in the population. Heparin is used for prevention of preeclampsia due to its experimentally shown important role in the trophoblast invasion and differentiation, as well as its influence on the production of proangiogenic factors. The paper gives a clinical case report that broadens our understanding on the preeclampsia pathophysiology and possibilities of its prevention. A 30-year old patient with no past history of serious physical illnesses had her two previous pregnancies with severe preeclampsia of early onset (arterial hypertension, massive proteinuria, thrombocytopenia, renal and hepatic insufficiency). Both babies were born extremely preterm (24 to 25 weeks of gestation) and died. Her hereditary background included type 2 diabetes in her maternal grandmother. At early terms of both pregnancies she had her fasting venous plasma glucose of 3.8 to 4.6 mmol/L (normal, &lt; 5.1 mmol/L). Oral glucose tolerance test which had to be performed at 24 to 28 weeks of gestation, according to the protocol, was not performed. While planning for the third pregnancy, her body mass index was 29 kg/m 2 , with normal values of the blood pressure and renal function, no proteinuria and no evidence of the anti-phospholipid syndrome. In the 1 st trimester, she had her fasting venous plasma glucose of 4.4 mmol/L. From the early term of her pregnancy, the patient was administered low molecular weight heparin; from the week 15, she was started with antihypertensive medications due to gestational arterial hypertension. Manifest diabetes was diagnosed at week 24 to 25 based on the results of the oral glucose tolerance test (4.96–10.42–11.46 mmol/L). With diet treatment, she had her postprandial glycaemia of up to 8.9 mmol/L, causing the initiation of basal-bolus insulin therapy from week 25 of gestation (0.4 U/kg), with achievement of good glucose control. At week 16, she had her sFlt1/PlGF level of 44 (high risk of preeclampsia). Molecular genetic assessment identified a HNF4A gene mutation, associated with MODY1. From week 34, she had moderate preeclampsia and fetal growth delay. An elective cesarean section was performed at week 38, with a healthy boy of 2300 g and 48 cm. After delivery, her diabetes was controlled by diet. The baby had an identical mutation. Thus, one cannot exclude a genetically determined link between complications of previous pregnancies and manifest diabetes diagnosed during the current pregnancy. Diagnosis of MODY1 in a pregnant patient would require the earliest initiation insulin treatment to prevent fetal macrosomia and neonatal hypoglycemia, as well as to prevent preeclampsia. The reason of successful outcome of this pregnancy could be related to heparin administration at the early terms of pregnancy that allowed for appropriate implantation and placenta formation, as well as for timely good glucose control.