Early-onset Severe Preeclampsia Research Articles

Analysis on application and gestational outcomes of expectant management in treatment of early onset severe preeclampsia

Objective To explore the curative effect and influence of expectant management on early-onset severe preeclampsia.Methods According to gestational age,126 cases of early-onset severe preeclampsia from 2009 to 2011 were divided into group A (＜28 weeks),group B (28～31 weeks) and group C (32～34 weeks).Each group was given an expectant management then analyzed the outcomes of the patients as well as the maternal and perinatal complications.Results Expectant number of treatment days and termination of pregnancy in group A were lower than those of group B and C while the incidence of maternal and perinatal infants complications was higher (P＜0.05).Conclusion The early onset of severe preeclampsia on maternal and child health leads to serious harm,the shorter the gestational age is,the worse the prognosis becomes.Giving expectant treatment can extend the gestational age to a degree,thus improve the prognosis. Key words: Early-onset severe preeclampsia; Expectant management; Gestational outcomes

Reduced Cystathionine γ-Lyase and Increased miR-21 Expression Are Associated with Increased Vascular Resistance in Growth-Restricted Pregnancies: Hydrogen Sulfide as a Placental Vasodilator

Increased vascular impedance in the fetoplacental circulation is associated with fetal hypoxia and growth restriction. We sought to investigate the role of hydrogen sulfide (H2S) in regulating vasomotor tone in the fetoplacental vasculature. H2S is produced endogenously by catalytic activity of cystathionine β-synthase and cystathionine γ-lyase (CSE). Immunohistochemical analysis localized CSE to smooth muscle cells encircling arteries in stem villi. Immunoreactivity was reduced in placentas from pregnancies with severe early-onset growth-restriction and preeclampsia displaying abnormal umbilical artery Doppler waveforms compared with preeclamptic placentas with normal waveforms and controls. These findings were confirmed at the protein and mRNA levels. MicroRNA-21, which negatively regulates CSE expression, was increased in placentas with abnormal Doppler waveforms. Exposure of villus explants to hypoxia-reoxygenation significantly reduced CSE protein and mRNA and increased microRNA-21 expression. No changes were observed in cystathionine β-synthase expression, immunolocalized principally to the trophoblast, in pathologic placentas or in vitro. Finally, perfusion of normal placentas with an H2S donor, after preconstriction with a thromboxane mimetic, resulted in dose-dependent vasorelaxation. Glibenclamide and NG-nitro-l-arginine methyl ester partially blocked the effect, indicating that H2S acts through ATP-sensitive K+ channels and nitric oxide synthesis. These results demonstrate that H2S is a powerful vasodilator of the placental vasculature and that expression of CSE is reduced in placentas associated with increased vascular resistance.

MMP-9 (-1562 C:T) Polymorphism as a Biomarker of Susceptibility to Severe Pre-Eclampsia

To investigate the role of MMP-9 (-1562 C:T) polymorphism as a biomarker for susceptibility to pre-eclampsia. MMP-9 variants were detected in 160 women with mild and severe pre-eclampsia and 112 healthy pregnant women. A significantly higher frequency of MMP-9 CT genotype was observed in both mild and severe pre-eclamptic women compared with controls. In the presence of CT + TT genotype the risk of severe pre-eclampsia increased 2.37-fold (p = 0.02). In women with early-onset pre-eclampsia the frequency of MMP-9 CT + TT genotype was significantly higher (p = 0.045) compared with those with late-onset pre-eclampsia. The MMP-9 variant could be a useful biomarker of susceptibility to severe pre-eclampsia and early-onset severe pre-eclampsia.

PLAC4 is upregulated in severe early onset preeclampsia and upregulated with syncytialisation but not hypoxia

IntroductionSevere early onset preeclampsia is one of the most serious complications of pregnancy. Placental specific 4 (PLAC4) is very highly expressed in placenta relative to all other tissues. Recently in a biomarker screening study, we found PLAC4 mRNA was significantly upregulated in maternal whole blood and placenta obtained from cases of severe preeclampsia. Intriguingly however, very little is known about its expression or functional role in either normal pregnancy or pregnancies complicated by preeclampsia. MethodsThe objective of this study was to characterize the protein expression and localization of PLAC4 in severe early onset preeclamptic placenta. Given so little of the biology of PLAC4 is known, we also examined whether the expression of PLAC4 alters with syncytialisation or placental hypoxia. ResultsWe found PLAC4 protein expression was significantly (p < 0.05) upregulated in severe early onset preeclamptic placentas (n = 24) compared to gestationally matched preterm controls (n = 12). PLAC4 protein was specifically localized to the syncytiotrophoblast of preterm, preeclamptic and term placentas. Functional analysis of PLAC4 mRNA and protein expression revealed a significant (p < 0.05) increase with syncytialisation of BeWo cells. However, exposure of either syncytialised BeWo cells or primary term placental explants to hypoxia (1% oxygen) did not alter the expression of either PLAC4 mRNA or protein. ConclusionIn conclusion, we have found PLAC4 is significantly upregulated in association with severe preterm preeclampsia. Furthermore, it is upregulated with syncytialisation, but not hypoxia. It is possible PLAC4 may have a role in the pathogenesis of preeclampsia, and its biology merits further investigation.

617: The association of VDR and angiogenic potential in early onset severe preeclampsia (EOSPE)

early onset severe preeclampsia (EOSPE) Angela Hawk, Satomi Kohno, Donna Johnson, Christopher Robinson Medical University of South Carolina, Obstetrics and Gynecology, Charleston, SC, Medical University of South Carolina, Hollings Marine Laboratory, Charleston, SC OBJECTIVE: Both pro and antiangiogenic factors are essential for normal placentation. Recent cardiovascular literature has revealed the important role of vitamin D in angiogenesis. Vitamin D deficiency has been linked with both increased risk for preeclampsia and intrauterine growth restriction (IUGR) in patients with EOSPE. Our goals were to identify the association between vitamin D signal, angiogenesis, IUGR and EOSPE. mRNA expression in EOSPE placenta was compared by race and IUGR. Vitamin D receptor(VDR), vascular endothelial growth factor (VEGF), placental growth factor(PlGF), retinoid X receptor(RXR), and soluble fms-like tyrosine kinase(sFlt-1) mRNA were quantified by real-time PCR(Q-PCR). STUDY DESIGN: RNA was extracted from placental samples (n 32) and quality/quantity verified via gel electrophoresis; non-contamination of genomic DNA was validated by Q-PCR. Primers were chosen via a literature/database search for genes of interest and housekeeping genes. RNA samples were reverse-transcribed, and expression levels quantified by comparison with serially diluted standard samples with known concentrations of target cDNA. Statistical analysis was performed with Wilcoxon Rank Sum tests and simple linear regression. RESULTS: African Americans (AA) showed significantly lower expression levels of sFlt-1 than Caucasians(C). VEGF expression level was lower in AA than in C, although it was not statistically significant (p 0.09). Presence of IUGR did not show any effects on mRNA expression. VDR expression was positively correlated with PlGF, sFlt-1, RXR-A and RXR-B, but not with VEGF. CONCLUSION: These associations suggest that Vitamin D signal could be responsible for an increase in both proand antiangiogenic factors. mRNA expression levels do not simply equate to amount of translated protein, indicating that the relationship of VDR to race and IUGR in EOSPE patients represents a more complex pathway. More investigation on vitamin D and angiogenesis in placenta is required to better understand its relationship with EOSPE. 618 Persistent urinary podocyte loss after preeclamptic pregnancies may be a possible mechanism of chronic renal injury Angelica Garrett, Iasmina Craici, Wendy White, Carl Rose, Brian Brost, Steven Wagner, Joseph Grande, Vesna Garovic Mayo Clinic College of Medicine, Maternal Fetal Medicine, Rochester, MN, Mayo Clinic College of Medicine, Hypertension and Nephrology, Rochester, MN OBJECTIVE: Studies show that proteinuria in preeclampsia is associated with podocyturia. Epidemiological studies have shown that preeclampsia is associated with future proteinuria and renal disease. Little is known about the resolution of podocyturia from time of delivery to 6wks postpartum. We postulate that persistent urinary podocyte loss after preeclamptic pregnancies may lead to proteinuria and chronic renal injury. STUDY DESIGN: The diagnoses of preeclampsia and HELLP were confirmed using standard clinical criteria. Random urine samples were obtained within 24hrs prior to delivery and 5-8wks postpartum (on average, 44 7d and 43 4d after delivery for cases and controls, respectively). Urine sediments were cultured for 24hrs to select for viable cells. Podocin staining was used to identify podocytes and podocyturia was expressed as a ratio of the number of podocytes to the creatinine (Cr) content of the respective urine sample. RESULTS: Delivery samples were obtained from 15 patients in the PE/ HELLP group and 23 normotensive controls. Postpartum samples were available for 10 of 15 cases and 18 of 23 controls. At delivery, patients with PE/HELLP had significantly higher proteinuria, (median 0.78g/24hrs; IQR 0.16-1.21) than normotensive controls (median 0.09g/24hrs; IQR 0.07-0.2). Podocyturia was present in all patients with PE/HELLP (median 0.77 podocytes/mg Cr; IQR 0.28-1.78) and in one patient (0.06 podocytes/mg Cr) from the control group. Postpartum proteinuria was similar between women with PE/HELLP (median 0.03g/24hrs; IQR 0.02-0.04) and those with normotensive pregnancies (median 0.03g/24hrs; IQR 0.02-0.05). Podocyturia was present in 3 of 10 women with PE/HELLP (median 0.63 podocytes/mg Cr; IQR 0.43-1.14) and in none of the normotensive controls. CONCLUSION: Persistent urinary podocyte loss after preeclamptic pregnancies may constitute a marker of ongoing renal injury. Longitudinal studies of the time course alteration of urinary podocyte loss after the affected pregnancies are needed. VDR and angiogenic factors

Increased expression levels of vitronectin in the maternal-fetal interface of placenta in early-onset severe preeclampsia

Preeclampsia(PE) is a pregnancy-specific disease, the pathogenesis of which remains unclear. The present study was designed to analyze whether vitronectin(VN), a multifunctional human glycoprotein, is expressed in PE and normal placentas. Furthermore, we aimed to explore VN expression profiles in relation to the pathogenesis of PE. Placental samples and plasma of early-onset severe PE (EOSP), late-onset severe PE (LOSP) and 2control groups corresponding to EOSP and LOSP were collected. Immunohistochemistry, immunofluorescence and western blot analysis were used to detect VN protein expression profiles. mRNA expression levels of VN were detected by reverse transcription polymerase chain reaction (RT-PCR). The impact of VN on coagulation was investigated by comparing differences in coagulation parameters. Our results demonstrate that expression levels of VN in the maternal-fetal interface of the EOSP group are the highest (P<0.001). The expression levels of VN in descending order in infarct center, infarct edge, near infarct tissues and away from infarct tissues were identified (P<0.001). Immunofluorescence and immunoblotting were consistent with immunohistochemical results. The VN mRNA expression was detected. Prothrombin time (PT) was significantly shorter in EOSP compared with the control group (P<0.05), which had a significant negative correlation with expression levels of VN in the placental tissue of the group. VN may play a key role in repairing the lesions and limiting necrotic components into maternal blood through its adhesion. VN may be involved in the pathogenesis of EOSP by inducing an imbalance between coagulation and fibrinolysis.

W243 MATERNAL PLASMA LEVELS OF PLACENTAL GROWTH FACTOR (PLGF) IN PATIENTS WITH SEVERE EARLY-ONSET PREECLAMPSIA

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S784-S784 Poster presentations W243 MATERNAL PLASMA LEVELS OF PLACENTAL GROWTH FACTOR (PLGF) IN PATIENTS WITH SEVERE EARLY-ONSET PREECLAMPSIA E. Scazzocchio, E. ScazzocchioSearch for more papers by this authorF. Figueras, F. FiguerasSearch for more papers by this authorE. Gratacos, E. GratacosSearch for more papers by this author E. Scazzocchio, E. ScazzocchioSearch for more papers by this authorF. Figueras, F. FiguerasSearch for more papers by this authorE. Gratacos, E. GratacosSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61967-5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S784-S784 RelatedInformation

O253 PROGNOSTIC ROLE OF NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IN WOMEN WITH SEVERE EARLY-ONSET PREECLAMPSIA

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S349-S350 Free communication (oral) presentations O253 PROGNOSTIC ROLE OF NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN (NGAL) IN WOMEN WITH SEVERE EARLY-ONSET PREECLAMPSIA F. Figueras, F. FiguerasSearch for more papers by this authorE. Gratacos, E. GratacosSearch for more papers by this authorE. Scazzocchio, E. ScazzocchioSearch for more papers by this author F. Figueras, F. FiguerasSearch for more papers by this authorE. Gratacos, E. GratacosSearch for more papers by this authorE. Scazzocchio, E. ScazzocchioSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)60683-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S349-S350 RelatedInformation

Expression of lipoxin A4, leukotriene C4 and lipoxygenase-5 in severe preeclampsia

Objective To investigate the expression and clinical significance of lipoxin A4,leukotrienc C4,lipoxygenase-5 in peripheral blood of pregnant women with different types of severe preeclampsia.Methods Forty-five singleton pregnant women who accepted antenatal care and delivered in First Affiliated Hospital of Wenzhou Medical College were enrolled in this study from December 2010 to June 2011.All objects were divided into normal pregnancy group (n=20),early onset severe preeclampsia group (n=10) and late onset severe preeclampsia group (n=15).Enzymelinked immunosorbent assay was used to detect lipoxin A4 and leukotriene C4 levels in peripheral blood.The level of lipoxygenase-5 mRNA in white blood cells was detected by real time fluorescence quantitative reverse transcription-polymerase chain reaction.The differences of lipoxin A4,leukotriene C4 and lipoxygenase-5 mRNA among groups were compared by analysis of variance and LSD-t test;and correlations among their expressions were analyzed by linear regression.Results Lipoxin A4 level in early and late onset severe preeclampsia group was (355.3±116.0) pg/ml and (389.7±117.5) pg/ml,which were both significantly lower than that in normal pregnancy group [(555.0±139.8) pg/ml] (t=-4.03 and-3.77,P＜0.05 respectively).The leukotriene C4 level in early and lateonset severe preeclampsia and normal pregnaney group was (591.3±185.5) pg/ml,(510.3±197.1) pg/ml and (496.9 ± 158.8) pg/ml,no statistical difference were found (F=0.889,P＞0.05) ; neither did the expression of lipoxygenase 5 mRNA,which was 4.2± 1.9 in normal pregnancy group,4.8 ± 2.0 in early onset severe preeclampsia group and 4.4 ± 1.2 in late onset severe preeclampsia group (F=0.311,P＞0.05).There was no correlation among the levels of lipoxin A4,leukotriene C4 and lipoxygenase-5 mRNA in each group (P ＞ 0.05).Conclusions Early and remarkable decreasing of lipoxin A4 level might contribute to the development of early onset severe preeclampsia. Key words: Pre-eclampsia; Lipoxins; Leukotriene C4 ; Arachidonate 5-lipoxygenase

Syncytiotrophoblast-derived microparticle shedding in early-onset and late-onset severe pre-eclampsia

ObjectiveTo determine the concentration of syncytiotrophoblast-derived microparticles (STBMs) in the maternal circulation and the rate of syncytiotrophoblast apoptosis in the placenta of patients with early-onset and late-onset severe pre-eclampsia. MethodsA prospective case–control study was conducted that enrolled 15 women with early-onset severe pre-eclampsia, 15 women with late-onset severe pre-eclampsia, and 10 women with normal pregnancies. Plasma STBM levels were measured by enzyme-linked immunosorbent assay, while placental levels of active caspase-3 were determined by western blotting. Human umbilical vein endothelial cells (HUVECs) were cultured with STBMs and the proliferation and apoptosis rates of the HUVECs assessed. ResultsLevels of STBMs in the early-onset group (71.2±20.7ng/mL) were significantly higher than those detected in the late-onset group (41.9±29.7ng/mL) and the control group (26.3±11.2ng/mL) (P<0.05). The amount of active caspase-3 was increased in the early-onset (0.85±0.61) and late-onset groups (0.77±0.46) relative to the control group (0.32±0.15) (P<0.05). Proliferation of HUVECs was inhibited, while apoptosis was elevated, following co-culture with STBMs. ConclusionShedding of STBMs into the maternal circulation occurs in greater amounts in early-onset pre-eclampsia than in late-onset pre-eclampsia.

Angiogenic Factors in Women Ten Years after Severe Very Early Onset Preeclampsia

BackgroundWomen with a history of mainly severe and early onset preeclampsia have an increased risk of future cardiovascular disease. During these complicated pregnancies increased levels of anti-angiogenic factors can be found. We hypothesize that women with a history of severe very early onset preeclampsia still have increased levels of these biomarkers years after this pregnancy, resulting in increased risk for cardiovascular disease.MethodsTwenty women with severe early onset preeclampsia before 24 weeks' gestation, who delivered between 1993–2003 in a tertiary referral centre and twenty matched controls with uncomplicated pregnancies and healthy term infants, were addressed for participation in the study. Venous plasma samples were analyzed for basic fibroblast growth factor (bFGF), placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1), vascular endothelial growth factor (VEGF), E- and P-selectin, soluble intercellular adhesion molecule-3 (sICAM-3) and thrombomodulin by ELISA.ResultsSixteen case subjects and 18 control subjects consented participation. The median time interval index pregnancy to study was 9.4 and 9.7 years for cases and controls, respectively. Median levels for cases-controls (p-value) were not different; bFGF: 17.43–11.11 pg/mL (0.33), sFlt-1: 102.98–101.92 pg/ml (0.84), PLGF: 3.57–4.20 pg/mL (0.38), VEGF: 64.05–45.72 pg/mL (0.73), E-selectin: 5.11–4.68 ng/mL (0.20), P-selectin: 85.35–71.69 ng/mL (0.69), sICAM-3: 0.42–0.63 ng/mL (0.41) and Thrombomodulin: 0.92–0.93 ng/mL (0.59).ConclusionThere were no differences in angiogenic biomarkers between women with a history of severe early onset preeclampsia versus uncomplicated pregnancy almost 10 years later, suggesting that these angiogenic factors will not contribute to the early detection of women at risk for future cardiovascular disease.

Influence of nursing intervention on the complications of early onset severe preeclampsia

Objective To discuss the influence of nursing intervention on the complications of early onset severe preeclampsia.Methods 120 patients with early onset severe preeclampsia from January 2010 to December 2011 were selected and randomly divided into two groups:the control group and the observation group.The control group received conventional treatment and nursing,while the observation group received nursing intervention in addition,and two groups' complications were compared.Results In the observation group,there was one placental abruption case,three hypoproteinemia,no HELLP syndrome,no heart failure,no renal failure,no eclampsia,no maternal death and no neonatal death,and the maternal-infant outcome was good.In the control group,there were 5 placental abruption cases,16 hypoproteinemia,4 HELLP syndrome,3 heart failure,4 renal failure,2 eclampsia,no maternal death but 2 neonatal death caused by severe perinatal asphyxia.The difference of the complications was statistically significant ( P ＜ 0.05 ).Conclusions Nursing intervention for patients with early onset severe preeclampsia is clinically effective to reduce the incidence rate of complications such as placental abruption,eclampsia in hospital,heart failure,renal failure,hypoproteinemia and HELLP syndrome,as well as to improve the life quality of both the patients and the perinatal child. Key words: Eclampsia; Early onset severe preeclampsia; Pregnancy complications; Nursing intervention

Decreased expression of complement 3a receptor (C3aR) in human placentas from severe preeclamptic pregnancies

The aim of this study was to determine the expression of the anaphylatoxin receptors complement C3a receptor (C3aR) and C5a receptor (C5aR) in the placentas of pregnancies complicated by severe early onset preeclampsia. We recruited women with pregnancies complicated by severe early-onset preeclampsia (n=19, 11 of which were further complicated with IUGR) and women with preterm pregnancies not affected by preeclampsia (n=8). Gene and protein expression of C3aR and C5aR was analysed by quantitative RT-PCR and Western blotting, respectively. C3aR was detected in the Hofbauer cells in the villous stroma of the placenta. C5aR staining was detected in the syncytiotrophoblast and endothelial cells. We found significantly decreased expression of C3aR mRNA and protein expression in placentas with preeclampsia compared to controls. However, C5aR expression was not significantly different between preeclamptic and control placentas at either the mRNA or protein level. Decreased C3aR expression indicates a dysregulation of the complement system in the placentas of preeclamptic women. Further studies would elucidate the exact mechanisms that complement has in preeclampsia.

Association of Maternal Vitamin D and Placenta Growth Factor with the Diagnosis of Early Onset Severe Preeclampsia

Decreased maternal 25-hydroxyvitamin D (25-OH-D) and placenta growth factor (PlGF) have both been associated with the diagnosis of early onset severe preeclampsia (EOSPE). This investigation aimed to define the association of these biomarkers with EOSPE. Patients with EOSPE (n = 40) and healthy controls (n = 40) were recruited and information on demographics, outcomes, and plasma was collected at diagnosis of EOSPE or gestational age-matched controls. 25-OH-D was assessed by radioimmunoassay and reported in nanogram per milliliter. PlGF was assessed by enzyme-linked immunosorbent assay and reported in picogram per milliliter. Kruskal-Wallis test was used to compare biomarkers between groups. Multivariable logistic regression was used to determine associations between 25-OH-D or PlGF and the diagnosis of EOSPE. In EOSPE, both 25-OH-D and PlGF were decreased significantly compared with controls. After controlling for age, race, body mass index, and gestational age at sample collection, both 25-OH-D (adjusted odds ratio 0.14 [0.05, 0.36]) and PlGF (adjusted odds ratio 0.03 [0.01, 0.24] were significantly associated with diagnosis of ESOPE (p < 0.001 for both markers). PlGF and 25-OH-D are both associated with the diagnosis of EOSPE. These biomarkers may be helpful in development of novel rapid diagnostic tests for preeclampsia.

Human placental transthyretin in fetal growth restriction in combination with preeclampsia and the HELLP syndrome

Fetal growth restriction is a serious, still poorly understood pregnancy-related pathology often associated with preeclampsia. Recent studies speculate on the role of human transthyretin, a carrier protein for thyroxin and retinol binding protein, in the etiology of both pregnancy pathologies. Objective was to investigate the localization and abundance of transthyretin (TTR) in placentas of pregnancies suffering from fetal growth restriction with and without preeclampsia and HELLP. This was a retrospective case control study on human paraffin-embedded placentas from pregnancies with a gestational age at delivery between the 24th and 34th week of gestation. 16 placentas were included in this study, 11 cases and 5 from normotensive pregnancies as controls. Cases were divided into three groups: four from early onset idiopathic intrauterine growth restriction (IUGR), four from early-onset severe preeclampsia (PE), and three from early-onset IUGR with preeclampsia plus HELLP syndrome. Distribution and abundance of TTR were investigated by means of immunohistochemistry. Semi quantitative analysis of TTR staining of placental sections revealed that TTR was mostly expressed in the villous trophoblast covering placental villi. Only weak staining of TTR in villous stroma could be detected. The comparison of placentas revealed that in pure IUGR and severe PE there is a much stronger TTR reactivity compared to controls and cases with IUGR+PE+HELLP. Concluding, the study showed that TTR is dysregulated in cases of IUGR and severe early onset preeclampsia. Interestingly, TTR expression is not affected in cases with HELLP syndrome that reveal the same staining intensities as age-matched controls.

The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1)

Preeclampsia is a pregnancy-specific syndrome mainly characterized by hypertensive disorder and proteinuria after gestational weeks 20. So far the etiology of preeclampsia remains unclear. We previously reported that preeclamptic placentas exhibited decreased mRNA expression and hypermethylation in promoter region of the paternally imprinted H19 gene compared with normal placentas. H19 has recently been identified to encode the precursor of miR-675, indicating a possible novel functional pathway of the imprinting gene. The aim of the present study was to identify the roles of H19 gene via miR-675 pathway in human trophoblast cells, and to figure out the involvement of this pathway in pathogenesis of preeclampsia. Knockdown of H19 gene or inhibition of miR-675 exhibited similar proliferation-promoting effect in human trophoblastic JEG-3 cells. Target gene prediction in combination with luciferase assay revealed that miR-675 could directly downregulate Nodal Modulator 1 (NOMO1) protein expression by binding to 3′-UTR sequence of NOMO1. Overexpression of NOMO1 in JEG-3 cells could rescue miR-675-surppressed cell proliferation and phosphorylation of Smad2, while Nodal had additive effect with miR-675 in suppression cell proliferation and activation of Smad2. In early-onset preeclamptic placentas, expression levels of H19 gene and miR-675 were appreciably lower, while NOMO1 protein level was higher than those in normal placentas. Taken together, our data suggested that H19 gene could inhibit human trophoblast cell proliferation via encoding miR-675 that targeted NOMO1, and aberrantly lowered expression of H19 in placenta may participate in the excessive proliferation of trophoblast cells observed in early-onset severe preeclampsia by downregulating miR-675 which targets NOMO1 and interferes with nodal signaling.

Association of 14 bp insertion/deletion polymorphism of the HLA‐G gene in father with severe preeclampsia in Chinese

Preeclampsia (PE), especially severe PE including early (before 34 weeks' gestation) and late (after 34 weeks' gestation) onset PE, is one of the leading causes of maternal and fetal mortality and morbidity. It is well known that abnormal human leukocyte antigen subtype G (HLA-G) expression may contribute to PE. In this study, we investigated allelic and genotypic frequencies of the 14 bp deletion/insert polymorphism in the 3(')-untranslated region (3(')-UTR) of the HLA-G gene in cases (120 pairs of mother-offspring, 82 couples, and 67 pairs of father-offspring with severe PE) and controls (158 pairs of mother-offspring, 87 couples, and 75 pairs of father-offspring with normal pregnancy). We found that the frequencies of the +14 bp/+14 bp HLA-G genotype of the offspring were significantly higher in the severe and early onset severe PE cases compared with controls, and the frequencies of the -14 bp/-14 bp HLA-G genotype of the offspring were significantly lower in the early onset severe PE cases compared with controls. The frequency of combined -14 bp/+14 bp mother/+14 bp/+14 bp offspring genotypes was significantly higher in the severe and early onset severe PE cases compared with controls, and the frequency of combined -14 bp/+14 bp mother/-14 bp/-14 bp offspring genotypes was significantly lower in the early onset severe PE cases compared with late onset severe PE cases. The frequency of combined -14 bp/-14 bp father/-14 bp/-14 bp offspring genotypes was significantly lower in the early onset severe PE cases compared with late onset severe PE cases and controls. In overview, the HLA-G 14 bp deletion/insert polymorphism is associated with severe PE in father-offspring, and its distribution is different between the early and late onset severe PE.

OS068. 25-Hydroxyvitamin D and angiogenic factors in early-onset severe preeclampsia

Introduction: Alterations in proand anti-angiogenic factors have been demonstrated to precede the clinical onset of preeclampsia. Objectives: The objective of this investigation was to understand the possible relationship of maternal vitamin D status and angiogenic factors at the diagnosis of early onset, severe preeclampsia (EOSPE). Methods: This prospective case-control study enrolled patients with EOSPE or healthy pregnancy. Plasma samples were obtained at the time of diagnosis of EOSPE and from a contemporaneous healthy control patient. 25-hydroxyvitamin D (25-OH-D) was assayed using radioimmunoassay. PlGF, VEGF, and s-Flt1 were assayed using ELISA. Results were analyzed with Kruskal–Wallis test between groups and Spearman correlation coefficients were calculated for 25-OH-D and angiogenic factors. Results: Fourty patients with EOSPE and 40 healthy controls were enrolled. Patients with EOSPE were noted to have greater deficiency of 25-OH-D (16.9 vs. 33.2 ng/mL; p < 0.001). PlGF and VEGF were significantly decreased while s-Flt1 was significantly increased in EOSPE relative to controls(table). Significant negative correlations were observed between plasma 25-OH-D and s-Flt1 ( 0.38; p < 0.001) and s-Flt1/PlGF ratio ( 0.32; p = 0.003). Significant positive correlations were noted between plasma 25-OH-D and PlGF (0.27; p = 0.02) and VEGF (0.25; p = 0.001). Vitamin D and angiogenic factors in EOSPE vs. control (median (IQR)).

PP161. Association of maternal vitamin D and placenta growth factor with early-onset severe preeclampsia

Decreased maternal 25-hydroxy vitamin D (25-OH-D) and placenta growth factor (PlGF) have both been associated with the diagnosis of early-onset severe preeclampsia (EOSPE). Prior investigations have identified these biomarkers to be decreased at the time of diagnosis of preeclampsia and prior to the onset of clinical diagnosis of preeclampsia. This investigation aimed to define the association of these biomarkers with EOSPE. This will yield information concerning possible potential for these biomarkers to be used in diagnosis of preeclampsia. Patients with EOSPE and healthy controls were recruited and demographics, outcomes, and plasma were collected at matched gestational age. 25-OH-D was assessed by radioimmunoassay and reported in ng/mL. PlGF was assessed by ELISA and reported in pg/mL. Receiver operator curves were constructed for each regression model and sensitivity and specificity were reported for each biomarker. In EOSPE, both 25-OH-D and PlGF were decreased significantly compared to controls. The combination of age, race, and PlGF or 25-OH-D performed well in discrimination of EOSPE and controls. The logistic regression model using both PlGF and 25-OH-D is shown below: PlGF and 25-OH-D are sensitive and specific markers for diagnosis of EOSPE. However, PlGF provided a higher sensitivity and specificity for EOSPE diagnosis.

OS086. Methylation status of the HOXA13 promoter region in placental tissue of pregnancies complicated by early onset severe preeclampsia

Compromised placental function and morphology found in early onset preeclampsia as well as a modified phenotype of the fetus may derive from a deviation in the normal gene expression pattern. Previous studies demonstrated by experimental animal models, that the gene HOXA13 plays an essential role in the arrangement of the placental vascular net, identifying direct and indirect target functions this gene has on the endothelial component. Research in model systems and now expanding to human studies has suggested that the causes and consequences of a variety of pregnancy-related pathologies are connected to epigenetic regulation. To evaluate the methylation status of the promoter region of HOXA13 within placental tissue and its association with specific clinical signs of severe early onset preeclampsia. A prospective case - control study was performed to evaluate the methylation status of the promoter region of HOXA13 by pyrosequencing analysis within placental tissue and its association with specific clinical signs of severe early onset preeclampsia (EOSP). The group of preeclamptic patients reached a mean methylation degree of 27.06% (±8.94) and 30.56% (±8.08) on two CpG islands of HOXA13 5' promoter respectively. Conversely in the group of physiologic controls the mean degree of methylation resulted 15.12%(±3.64) (p<0.0016) and 18.25% (±3.45) (p<0.0005). This study firstly demonstrated that an hypermethylation of placental HOXA13 exists in preeclamptic placental tissues and concentrates only on the gene promoter. Additionally, the existence of a correspondence between themethylation process of the gene promoter HOXA 13 and the clinical manifestation of severe early onset preeclampsia supports the original hypothesis that this process may be at the base of the preeclamptic pathogenesis.