Severe Preterm Preeclampsia Research Articles

Circulating vascular endothelial growth factor receptor-3, a pro-lymphangiogenic and pro-angiogenic mediator, is decreased in pre-eclampsia.

To compare circulating levels of vascular endothelial growth factor receptor 3 (VEGFR-3) in women with pregnancy-induced hypertension (PIH) and in non-pregnant (NP) and healthy pregnant (HP) women. We conducted a case-control study including PIH (n = 135), HP (n = 68), and NP (n = 49) women from southeastern Brazil. PIH were diagnosed according to international guidelines, and defined as gestational hypertension (GH, n = 61) or pre-eclampsia (n = 74). VEGFR-3 was measured in plasma using ELISA. Plasma VEGFR-3 was increased in HP (1207 pg/mL) compared with NP (133 pg/mL) women; however, PIH (729 pg/mL) patients exhibited lower levels than HP women (both p < 0.05). In addition, plasma VEGFR-3 was decreased in pre-eclampsia compared with GH (537 versus 980 pg/mL; p < 0.05). When pre-eclampsia was classified according to different clinical presentations, plasma VEGFR-3 was further decreased in the cases identified as pre-eclampsia with severe features, preterm pre-eclampsia, and pre-eclampsia accompanied by small for gestational age (all p < 0.05). Our data indicate reduced circulating VEGFR-3 levels in patients with PIH, specifically in those diagnosed with pre-eclampsia. Moreover, decreased VEGFR-3 was associated with adverse clinical outcomes in pre-eclampsia. These findings expand previous evidence of reduced VEGFR-3 expression in pre-eclampsia. Future studies should investigate whether it can be used as a predictive biomarker and/or therapeutic target for pre-eclampsia.

Mode of delivery and neonatal outcomes with early preterm severe preeclampsia: does fetal growth restriction matter?

Objective Severe preeclampsia diagnosed at or prior to 34 weeks is an indication for preterm delivery. Many patients with severe preeclampsia develop fetal growth restriction as a result of the placental dysfunction associated with both conditions. The ideal mode of delivery in cases of preterm severe preeclampsia with fetal growth restriction remains controversial, with providers often proceeding directly to cesarean delivery rather than attempting a trial of labor due to theoretic concerns about the harms of labor in the face of placental dysfunction. There are limited data supporting this approach. This study evaluates whether the presence of fetal growth restriction affects the ultimate mode of delivery or neonatal outcomes among pregnancies with severe preeclampsia undergoing induction of labor at or before 34 weeks. Methods This was a retrospective cohort study of singletons with severe preeclampsia undergoing induction of labor ≤ 34 weeks at a single center between January 2015 and April 2022. The primary predictor was fetal growth restriction, defined as estimated fetal weight < 10th percentile for gestational age on ultrasound. Mode of delivery and neonatal outcomes were compared between those with and without fetal growth restriction using Fisher’s exact and Kruskal-Wallis tests, and multivariate logistic regression was used to obtain adjusted odds ratios. Results 159 patients were included (N = 117 without fetal growth restriction, N = 42 with fetal growth restriction). There was no difference in vaginal delivery between the groups (70% vs 67%, p = .70). While those with fetal growth restriction had a higher incidence of respiratory distress syndrome and longer neonatal hospital stay, these differences were not statistically significant after adjusting for gestational age at delivery. There were no significant differences in other neonatal outcomes, including Apgar score, cord blood gases, intraventricular hemorrhage, necrotizing enterocolitis, neonatal sepsis, and neonatal demise. Conclusion For pregnancies complicated by severe preeclampsia that require delivery ≤ 34 weeks, the likelihood of successful vaginal delivery following induction of labor does not differ based on presence of fetal growth restriction. Furthermore, fetal growth restriction is not an independent risk factor for adverse neonatal outcomes in this population. Induction of labor should be considered a reasonable approach and should be routinely offered to patients with concurrent preterm severe preeclampsia and fetal growth restriction.

Non-invasive hemodynamic trends before and after delivery in severe preterm preeclampsia patients

Cardiac output (CO) increases in normal pregnancy and decreases in the postpartum period. However, there is limited data on hemodynamic trends in patients with severe preterm preeclampsia. Our objective was to evaluate hemodynamics using non-invasive bioreactance (Starling, Baxter Medical) during the antepartum and postpartum periods for patients with severe preterm preeclampsia.

Soluble Flt1 levels are associated with cardiac dysfunction in Black women with and without severe preeclampsia

ABSTRACT Background: We evaluate soluble fms-like tyrosine kinase-1 (sFlt-1) levels and cardiac function during pregnancy and postpartum among Black women with and without preeclampsia. Study design: Prospective longitudinal cohort study from 2015 to 2017 of Black women with preterm severe preeclampsia and normotensive pregnant controls.We obtained echocardiograms and sFlt-1 levels during pregnancy and postpartum. Results: 93 Black women were included (43 cases, 50 controls). Higher sFlt1 levels were correlated with worse longitudinal strain, diastolic dysfunction, decreased ventricular-arterial coupling, and increased chamber and arterial elastance at the time of preeclampsia diagnosis and postpartum. Conclusions: Higher sFlt1 levels are associated with cardiovascular dysfunction during pregnancy and postpartum.

Severe preterm preeclampsia: an examination of outcomes by race

Preeclampsia complicates 5% to 8% of all pregnancies. Previous studies have examined the maternal morbidity and mortality associated with preeclampsia and the expectant management of severe preterm preeclampsia. However, these studies either did not comment on outcomes by race or were primarily made up of nonblack participants. This study aimed to determine whether maternal morbidity associated with the expectant management of severe preterm preeclampsia varied by race. We performed a retrospective cohort study of women with a diagnosis of severe preterm preeclampsia at <34 weeks' gestation between 2008 and 2017 at our institution. Severe preterm preeclampsia was defined by current American College of Obstetricians and Gynecologists guidelines. The primary outcome was a maternal morbidity composite, defined as experiencing ≥1 of the following: hemolysis, elevated liver enzymes, and low platelet count; eclampsia; pulmonary edema; severe renal dysfunction; abruption; maternal intensive care unit admission; venous thromboembolism; blood transfusion; hysterectomy; stroke; or death. Secondary outcomes included a composite of neonatal morbidity. Outcomes were compared between self-reported black and nonblack women. In this study, 275 women were included; among those women, 91 (33%) were nonblack, and 184 (67%) were black. In addition, 203 of 275 women (approximately 74%) underwent expectant management with no difference by race (75.8% of nonblack vs 72.8% of black women; P=.6). When examining maternal morbidity, 62 of the expectantly managed women (30.5%) developed the composite maternal morbidity outcome, with no difference by race (27.5% of nonblack vs 32.1% of black women; P=.5) even when adjusting for confounders such as maternal age, body mass index, and parity (adjusted odds ratio, 1.02; 95% confidence interval, 0.97-1.35). The median time from diagnosis to delivery (latency time) was 3 days, with no difference between the 2 groups (P=.9) and no difference in neonatal morbidity (60.9% nonblack vs 53% black; P=.3). Within our population, there were no differences in maternal outcomes between black and nonblack women who were undergoing expectant management of severe preterm preeclampsia. More research is needed to determine if the known disparities in maternal morbidity among races are due to factors beyond the antepartum management of severe preterm preeclampsia.

Receipt of Proton-Pump Inhibitors during Pregnancy and Risk for Preeclampsia.

This study aimed to determine whether receiving a proton-pump inhibitor (PPI) prescription during pregnancy was associated with decreased risk for preeclampsia. The Truven Health MarketScan database was used to determine whether receiving a PPI prescription was associated with risk for preeclampsia. Risk for preeclampsia was evaluated based on the presence or absence of receiving a PPI prescription (1) any time during pregnancy, and 2) individually during the 1st, 2nd, and 3rd trimesters. In addition to evaluating risk for all preeclampsia, severe preeclampsia and preterm severe preeclampsia were evaluated. Adjusted models including risk factors such as chronic hypertension, maternal age, multiple gestation, and diabetes were performed with adjusted risk ratios (aRR) with 95% confidence intervals [CIs] as measures of effect. A total of 2,755,885 women were included in the analysis of whom 69,249 were prescribed a PPI during pregnancy (2.5%). In adjusted models, receiving a PPI prescription anytime during pregnancy (aRR 1.28, 95% CI 1.24-1.32), the 1st trimester (aRR 1.12, 95% CI 1.04-1.22), the 2nd trimester (aRR 1.20, 95% CI 1.15-1.26), and the 3rd trimester (aRR 1.41, 95% CI 1.35-1.47) were all associated with increased risk for preeclampsia. Risk for severe preeclampsia was also significantly increased with receiving a PPI prescription anytime during pregnancy (aRR 1.21, 95% CI 1.15-1.27), during the 2nd trimester (aRR 1.14, 95% CI 1.06-1.23), and during the 3rd trimester (aRR 1.33, 95% CI 1.24-1.43), but not the first trimester (aRR 1.04, 95% CI 0.92-1.19). Evaluating the risk for preterm severe preeclampsia, adjusted risk was significantly increased with receiving a PPI prescription in the second trimester (aRR 1.35, 95% CI 1.21-1.52) but not the first trimester (aRR 1.06, 95% CI 0.86-1.32). In this analysis of payer data, receiving a PPI prescription during pregnancy was not associated with decreased risk for preeclampsia. Further empiric research is required to determine whether an effect may be present. · Proton pump inhibitors were not associated with decreased risk for preeclampsia.. · Proton pump inhibitors were not associated with decreased risk for severe preterm preeclampsia.. · Proton pump inhibitors are commonly prescribed during pregnancy..

463: Placental expression of HLA-G,C,E, and F in preterm severe preeclampsia and preterm labor

Human pregnancy is one of the most interesting examples of immune tolerance seen in mammalian biology. The placenta, is the single organ tissue that simultaneously expresses each of the non-classical antigens - HLA- G, C, E and F. Interestingly, activated lymphocytes express HLA-F on their cell-surface. We recently showed that HLA-G, C, and F were expressed by 1st-trimester normal EVT and became intracellular and weaker as gestation progressed, HLA-E was only expressed in 1st trimester. HLA-F and HLA-C mRNA and protein expression levels showed a significant increase in the fetal mesenchyme across gestation and HLA-C levels increased with labor. In this study we evaluate the placental expression of non classical HLA in preterm severe preeclampsia (psPrE) not delivered spontaneously and in preterm labor delivered spontaneously (PTL) as controls Immunohistochemistry of serial sections of placental tissue was used to evaluate placental HLA expression from 9 psPrE and 6 PTL matched GA. Location and intensity of immunostaining was determined by two reviewers blinded to the identity of tissue. Comparison were made using Student's t-test The expression of HLA-G and C in proximal EVT is significantly higher in PTL than psPrE, wheras HLA-E expression is significantly lower in distal EVT. Furthermore, HLA-C is higher in placental syncytiotrophablast and HLA-E was significantly lower in the distal EVT in PTL. HLA-C and E in fetal mesenchyme is higher in PTL The increased HLA-C expression in preterm labor placentas, similar to our prior study - supports our prior observation that HLA-C may be related to parturition. 2. HLA-E placental expression -beyond the first trimester - in both PTL and in psPrE is opposed to our prior finding and may suggest abnormal early placentation in both entities particularly in psPrE. 3. We show a different HLA placental profile between psPrE and PTL that may elucidate the immune activity of the non classical HLA in PTL and psPrE and in implantation and parturitionView Large Image Figure ViewerDownload Hi-res image Download (PPT)

429. Preeclampsia Treatment Strategies: Subtraction vs. Addition

Preeclampsia can be complicated by end-organ damage, including severe hypertension, cerebral edema, and kidney and liver failure. Impending end-organ damage necessitates immediate delivery, often at the expense of the fetus in cases of preterm preeclampsia. Methods to prolong pregnancy may benefit the fetus, if of course maternal signs and symptoms can be tempered. Towards that end, we have developed a novel method to remove circulating sFlt-1 from maternal circulation in hopes to prolong pregnancy in women presenting with severe preterm preeclampsia. Such a strategy is novel for preeclampsia, but not entirely new in general Obstetrics, since historically and even today pregnant women undergo chronic hemodialysis, and plasma pheresis, during pregnancy for a variety of indications. Implementing such a strategy was stepwise, with a gradual increase in the duration and frequency of apheresis. Care was taken to avoid changes in blood pressure during the treatments, and management of flow rates and anticoagulation had to be modified appropriately. Nevertheless, we have shown that such a strategy has the potential to safely prolong pregnancy, potentially by weeks, in the setting of severe preterm disease. We have also followed women and their offspring now for 3–8 years following treatments, and no adverse events related to the intra-partum interventions were noted. Clinical trials are now underway to examine the utility of both selective and semi-selective removal strategies, and in the coming years we believe such a strategy will be available for women with this devastating condition.

53. Expectant management of severe preeclampsia in a developing country: Maternal outcomes and perinatal survival

Background Management of severe preeclampsia which develops prior to 34 still debatable. Immediate delivery leads to high neonatal mortality and morbidity due to prematurity, conversely expectant management may potentially increase maternal morbidity and mortality. Objective of this study was to determine maternal outcomes and perinatal survival achieved with expectant management in patients presenting with preeclampsia Study Design A retrospective cohort analysis of outcome in patients with severe preeclampsia in a tertiary hospital in Indonesia during 3 years: 165 patients (178 fetuses) managed expectantly were studied. Neonatal outcomes (birth weight, APGAR score, fetal growth restriction (FGR), intrauterine fetal death (IUFD), early neonatal death, and maternal complications (HELLP syndrome, pulmonary edema, eclampsia, renal insufficiency, and placental abruption) were registered. Results 25 patients had a preeclampsia disease onset Conclusion Neonatal outcome in preterm severe preeclampsia depends mainly on GA at onset of preeclampsia and GA at delivery. Expectant management of preeclampsia presenting at less

Chronic hypertension: first-trimester blood pressure control and likelihood of severe hypertension, preeclampsia, and small for gestational age

There is extensive evidence that prepregnancy chronic hypertension is associated with a high risk of development of severe hypertension and preeclampsia and birth of small-for-gestational-age neonates. However, previous studies have not reported whether antihypertensive use, blood pressure control, or normalization of blood pressure during early pregnancy influences the rates of these pregnancy complications. The purpose of this study was to stratify women with prepregnancy chronic hypertension according to the use of antihypertensive medications and level of blood pressure control at the first hospital visit during the first trimester of pregnancy and to examine the rates of severe hypertension, preeclampsia, and birth of small-for-gestational-age neonates according to such stratification. We conducted a prospective study of 586 women with prepregnancy chronic hypertension, in the absence of renal or liver disease, that was booked at a dedicated clinic for the management of hypertension in pregnancy. The patients had singleton pregnancies and were subdivided according to findings in their first visit: group 1 (n=199), blood pressure <140/90 mm Hg without antihypertensive medication; group 2 (n=220), blood pressure <140/90 mm Hg with antihypertensive medication; and group 3 (n=167), systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg, despite antihypertensive medication. In the subsequent management of these pregnancies, our policy was to maintain the blood pressure at 130-140/80-90 mm Hg with the use of antihypertensive medication; antihypertensive drugs werestopped if the blood pressure was persistently <130/80 mm Hg. Theoutcome measures were severe hypertension (systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥110 mm Hg), preterm and term preeclampsia (in addition to hypertension at least 1 of renal involvement, liver impairment, neurologic complications, or thrombocytopenia), and birth of small-for-gestational-age neonates (birthweight <5th percentile for gestational age). The incidence of these complications was compared in the 3 strata. The median gestational age at presentation was 10.0 weeks (interquartile range, 9.1-11.0 weeks). In groups 2 and 3, compared with group 1, there was a significantly higher body mass index, incidence of black racial origin, and history of preeclampsia in a previous pregnancy. There was a significant increase from group 1 to group 3 in the incidence of severe hypertension (10.6%, 22.2%, and 52.1%), preterm preeclampsia with onset at <37 weeks of gestation (7.0%, 15.9%, and 20.4%), and small for gestational age (13.1%, 17.7%, and 21.1%), but not term preeclampsia with onset at ≥37 weeks of gestation (9.5%, 9.1%, and 6.6%). In women with prepregnancy chronic hypertension, the rates of development of severe hypertension, preterm preeclampsia, and small for gestational age are related to the use of antihypertensive medications and the level of blood pressure control at the first hospital visit during the first trimester of pregnancy.

Neonatal Outcomes in Preterm Severe Preeclampsia as Compared to Other Etiologies of Prematurity [25K

Neonatal Outcomes in Preterm Severe Preeclampsia as Compared to Other Etiologies of Prematurity [25K

Expectant management of severe preterm preeclampsia: a comparison of maternal and fetal indications for delivery

Objective: To examine the delivery indication (maternal or fetal) for patients with preterm preeclampsia and assess whether disease characteristics at presentation are predictive of delivery indication.Methods: We conducted a retrospective cohort study at a tertiary hospital in Melbourne, Australia (Mercy Hospital for Women). We assessed indication for delivery for participants presenting with preeclampsia from 23+0 to 32+6 weeks gestation. We compared baseline disease characteristics, disease features at delivery and postnatal outcomes between those delivered for maternal or fetal indications, or for both maternal and fetal indications.Results: Two hundred sixty six participants presented with preterm preeclampsia and 108 were eligible for inclusion in our study. More participants were delivered for maternal indications at 65.7% compared to those requiring delivery on fetal grounds at 19.4% or for both indications at 14.8% (p < 0.0001). Maternal disease characteristics at presentation were similar between groups; however, there was a higher proportion of growth restriction and abnormal Dopplers among those delivered on fetal grounds. Participants delivered on maternal grounds gained less gestation, had higher blood pressure and higher incidence of abnormal liver function tests than those delivering for fetal indications at delivery.Conclusion: Participants with preterm preeclampsia were predominantly delivered due to maternal disease progression compared to fetal compromise.

Hallazgos ecocardiográficos en pacientes con preeclampsia en la Unidad de alta dependencia obstétrica del Hospital Universitario de San José, 2012-2014

&lt;p&gt;&lt;strong&gt;Materiales y métodos:&lt;/strong&gt; estudio de corte transversal. Se describen los hallazgos ecocardiográficos en las pacientes con preeclampsia severa (PS), de acuerdo con los criterios del Congreso Americano de Obstetras y Ginecólogos, atendidas en un hospital universitario de referencia ubicado en Bogotá (Colombia), entre enero 1 de 2012 y junio 30 de 2014. Se excluyeron las pacientes con control adecuado de tensión arterial o con patología cardiaca estructural previa conocida. Se describen las variables sociodemográficas, clínicas y los hallazgos ecocardiográficos más frecuentes, globalmente y por momento de aparición. Se presentan los datos mediante estadística descriptiva.&lt;/p&gt;&lt;p&gt;&lt;br /&gt;&lt;strong&gt;Resultados:&lt;/strong&gt; se diagnosticaron 228 pacientes con PS. A 124 se les realizó ecocardiograma: en 8 de ellas el informe de ecocardiografía fue no concluyente. Se hallaron 78 pacientes (67 %) con alguna alteración. Los principales hallazgos fueron: hipertensión pulmonar leve, n = 34 (29 %); hipertrofia del ventrículo izquierdo, n = 32 (27 %); hipertensión pulmonar moderada, n = 21 (18 %); disfunción diastólica, n = 16 (13 %). Las pacientes con PS pretérmino (69 %) presentaron alteraciones ecocardiográficas más frecuentes que las pacientes a término (20 %) y que las que comenzaron con PS en el puerperio (11 %). La disfunción diastólica se presentó más en pacientes con preeclampsia que comenzó en el puerperio.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusiones:&lt;/strong&gt; la prevalencia de alteraciones ecocardiográficas en PS es del 67 %, con mayor frecuencia de hipertensión pulmonar e hipertrofia ventricular izquierda. Se requieren más estudios que validen estos hallazgos regionalmente.&lt;/p&gt;

Removal of Soluble Fms-like Tyrosine Kinase (sFlt-1) by Plasma-Specific Apheresis: A Pilot Study in Women with Severe Preterm Preeclampsia

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is a potential therapeutic target in preeclampsia. We evaluated the safety and efficacy of treating women with very preterm preeclampsia using a plasma-specific dextran sulfate (PSDS) column to remove circulating sFlt-1.

Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia

IntroductionThe dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. Materials and MethodsThis study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. Results and DiscussionThe villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5’ untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. ConclusionsThese findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.

Differential regulation of TNF receptors in maternal leukocytes is associated with severe preterm preeclampsia

We tested the hypothesis that maternal peripheral blood leukocytes contribute to elevated levels of soluble TNF receptors (sTNFR) in preeclampsia (PE) with concomitant intrauterine growth restriction (IUGR). TNFR1 and TNFR2 were evaluated in a cross-sectional study comparing preeclamptic (n = 15) with or without IUGR versus normotensive pregnant women (PREG, n = 30), and non-pregnant controls (Con; n = 20). Plasma levels of sTNFR1 were higher in PE (1675.0 ± 227.1 pg/mL) compared with PREG (1035.0 ± 101.1 pg/mL) and Con (589.3 ± 82.67 pg/mL), with the highest values observed in PE with IUGR (2624.0 ± 421.4 pg/mL; n = 6). Plasma sTNFR2 was higher during pregnancy (PE: 1836.0 ± 198.7 pg/mL; PREG: 1697.0 ± 95.0 pg/mL) compared with Con (598.3 ± 82.7 pg/mL). Urinary levels of sTNFR1 and sTNFR2 were higher in PE and PREG compared with the Con group. Abundance of TNFR1 mRNA in peripheral blood leukocytes was strongly correlated with plasma levels of sTNFR1 in PE. However, TNFR2 mRNA accumulation in leukocytes did not correlate with sTNFR2 plasma levels. The level of sTNFR1 in plasma was correlated with body weight of the newborn (r = −0.56). The data suggest that maternal leukocytes contribute to sTNFR1 levels in plasma in association with decreasing newborn weight and PE with concomitant IUGR.

Only humans have human placentas

of preeclamptic patients. Furthermore, sEng appeared to exacerbate the vascular damage mediated by sFlt1 in pregnant rats, resulting in severe preeclampsia-like illness, including the development of thrombocytopenia and fetal growth restriction. Measurement of angiogenic markers in the serum/plasma is particularly useful for the diagnosis and prediction of preterm preeclampsia. Methods aimed at interfering with sFlt1 and/or sEng actions may be a novel therapeutic strategy in severe preterm preeclampsia.

Corin, an enzyme with a putative role in spiral artery remodeling, is up-regulated in late secretory endometrium and first trimester decidua

What is the nature of cellular Corin expression in human gestational tissues? CORIN is expressed in non-pregnant late secretory phase endometrium, first trimester human implantation sites and is up-regulated with decidualization ex vivo. Adequate trophoblast invasion and spiral artery remodeling/transformation is critical for successful implantation. CORIN, best known for its role in activating atrial natruietic peptide (ANP) to regulate blood pressure, has recently been proposed to be centrally involved in trophoblast invasion and spiral artery remodeling. It is postulated that ANP, activated by CORIN, promotes trophoblast invasion and that a deficiency causes pre-eclampsia. Mice deficient in either Corin or ANP displayed poor trophoblast invasion, impaired spiral artery remodeling and phenocopied human pre-eclampsia. However, the precise cellular localization of CORIN within human gestational tissues has not been well characterized. We measured CORIN protein localization in a number of human gestational tissues relevant to early embryo/placental implantation: non-pregnant (NP) endometrial biopsies (n = 5 per phase of the menstrual cycle), first trimester placental bed biopsies (n = 12) and pre-term control (n = 10) and severe early onset preeclamptic placentas (n = 15). Endometrial stromal cells were isolated from human endometrial biopsies (n = 5) and induced to decidualize ex vivo. Finally, CORIN concentrations were measured in serum obtained from pregnant women during the first trimester of whom, 56 subsequently ended up with a healthy term delivery (controls), 18 developed fetal growth restriction (FGR) and 21 had a miscarriage. We performed immunohistochemistry to assess CORIN localization. Changes in Corin mRNA expression in human endometrial stromal cells decidualized ex vivo were measured by quantitative RT-PCR, and levels of CORIN within human sera were measured by ELISA. CORIN was expressed in both NP late secretory phase endometrium and first trimester decidua within placental bed biopsies. Importantly, decidualization of primary human endometrial cells ex vivo significantly increased Corin expression (P < 0.05). CORIN was also detected within the villous cytotrophoblast, but there was no change in mRNA levels in placentas complicated by severe preterm pre-eclampsia when compared with pre-term controls. Although CORIN was detected in first trimester serum, levels did not change across gestation, nor could they predict miscarriage or FGR (other disorders of impaired placental invasion). Owing to the fact that we utilized early pregnancy human specimens, this is mainly a descriptive study with a limited amount of functional experiments. This is the first study to thoroughly characterize Corin mRNA and protein expression in human gestational tissue. Our findings support recent data from murine studies collectively suggesting that CORIN plays a critical role in trophoblast migration and spiral artery remodeling during early pregnancy in humans. Therefore, further studies of CORIN biology in early pregnancy may identify new therapeutic targets to improve implantation quality in early pregnancy and potentially reduce the rates of pregnancy complications caused by inadequate implantation (pre-eclampsia, FGR and miscarriage). This study was supported by The National Health and Medical Research Council of Australia (Salary support #490970, #490995). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors declare that no competing interests exist.

Circulating RNA coding genes regulating apoptosis in maternal blood in severe early onset fetal growth restriction and pre-eclampsia

To determine whether the intrinsic apoptosis pathway is differentially expressed in placenta and maternal blood in severe preterm fetal growth restriction (FGR) and pre-eclampsia (PE), and to examine whether circulating RNA in maternal blood may be potential biomarkers. Maternal blood samples and placental biopsies were collected from women with preterm: FGR (n=20), PE without FGR (n=8) and controls (n=20). Real-time PCR examined the expression of genes in the intrinsic apoptosis pathway in FGR and PE, stratified according to the severity of placental insufficiency. Severe preterm FGR, with or without PE, was associated with increased expression of BCL2, BCL-XL, BIM, BAD and Survivin in both the placenta and maternal blood (1.6 to 3.3-fold, P<0.05). In preterm PE, but not FGR, there was increased placental expression of BCL-XL and BCL2 (1.6 to 2.5-fold, P<0.05), but only BCL2 was significantly increased in the maternal blood (1.8-fold, P<0.05). Increased expression of genes of the intrinsic apoptosis pathway reflected the severity of FGR as determined by deteriorations in umbilical artery Doppler velocimetry. In severe early onset FGR there was increased expression of genes regulating intrinsic apoptosis in both the placenta and maternal blood. Circulating RNA regulating placenta apoptosis may be used to develop noninvasive novel biomarkers for FGR.

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.