Early-onset Preeclampsia Patients Research Articles

Association between rs1799724 of TNF- α gene and early onset preeclampsia in Chinese: A pilot study

ObjectiveTo investigate the association between polymorphisms of TNF- α (rs1799724, rs1800629), VEGF (rs3025039) and VEGFR1 (rs 722503) and early onset preeclampsia (EOPE) in Chinese. MethodsA total of 132 EOPE patients from January 2016 to December 2018 at the Second Hospital of Tianjin Medical University were selected as the EOPE group, and 156 normal pregnant patients as the Control group. In both groups, 5 ml of peripheral venous blood was obtained after admission. The characteristics of genotype and allele distribution at the four SNPs in the study subjects were examined by matrix-assisted laser desorption ionization time-of-flight mass spectrometric genotyping. ResultsThe genotype frequency distribution and allele frequency distribution of rs1799724 were significantly different between the EOPE group and the Control group (P = 0.002，P = 0.003). The T allele was statistically associated with the development of EOPE under a dominant genetic model (P = 0.001). The genotype and allele frequency distributions of rs1800629, rs3025039, and rs 722503 did not differ significantly between the EOPE group and the Control group (P > 0.05). There was no linkage disequilibrium among rs1799724, rs1800629 and rs3025039 loci, the corresponding haploid cannot be formed. ConclusionsThe rs1799724 of TNF- α gene is a genetic susceptibility locus for EOPE and may be a potential predictors of preeclampsia.

Serum protein profile analysis via label-free quantitation proteomics in patients with early-onset preeclampsia

Background Preeclampsia (PE) is a serious pregnancy complication, resulting in potentially life-threatening conditions for both mother and foetus. It is worth noting that early-onset PE has become a great challenge for clinicians due to its complex manifestation, rapid progression and serious complications. This study aims to investigate differential serum proteome profiles in patients with early-onset PE. Methods Each serum sample was separated using a nanoliter flow rate Easy-nLC chromatography system. Then the samples were analysed by mass spectrometry. Bioinformatics analyses were conducted to analyse the functional categories or signal transduction pathways for differentially abundant proteins. Key proteins identified by mass spectrometry were verified by ELISA. Results We found 30 and 34 proteins were upregulated and downregulated in early-onset PE patients (n = 3) vs controls (n = 3), respectively. Functional enrichment analysis revealed differentially expressed proteins related to the immune response and regulation of peptidase activity. ELISA confirmed that there were lower CSH1 levels and higher LPA concentrations in the serum samples of early-onset PE patients (n = 22) than in healthy controls (n = 19) (p < 0.05 for CSH1 and p < 0.001 for LPA). Conclusions This study revealed the critical features of serum proteins in early-onset PE patients. LPA and CSH1 may serve as biomarkers for early-onset PE diagnosis and therapy.

Risk Prediction Model of Early-Onset Preeclampsia Based on Risk Factors and Routine Laboratory Indicators.

Background: Globally, 10-15% of maternal deaths are statistically attributable to preeclampsia. Compared with late-onset PE, the severity of early-onset PE remains more harmful with higher morbidity and mortality. Objective: To establish an early-onset preeclampsia prediction model by clinical characteristics, risk factors and routine laboratory indicators were investigated from pregnant women at 6 to 10 gestational weeks. Methods: The clinical characteristics, risk factors, and 38 routine laboratory indicators (6-10 weeks of gestation) including blood lipids, liver and kidney function, coagulation, blood count, and other indicators of 91 early-onset preeclampsia patients and 709 normal controls without early-onset preeclampsia from January 2010 to May 2021 in Peking University Third Hospital (PUTH) were retrospectively analyzed. A logistic regression, decision tree model, and support vector machine (SVM) model were applied for establishing prediction models, respectively. ROC curves were drawn; area under curve (AUCROC), sensitivity, and specificity were calculated and compared. Results: There were statistically significant differences in the rates of diabetes, antiphospholipid syndrome (APS), kidney disease, obstructive sleep apnea (OSAHS), primipara, history of preeclampsia, and assisted reproductive technology (ART) (p < 0.05). Among the 38 routine laboratory indicators, there were no significant differences in the levels of PLT/LYM, NEU/LYM, TT, D-Dimer, FDP, TBA, ALP, TP, ALB, GLB, UREA, Cr, P, Cystatin C, HDL-C, Apo-A1, and Lp(a) between the two groups (p > 0.05). The levels of the rest indicators were all statistically different between the two groups (p < 0.05). If only 12 risk factors of PE were analyzed with the logistic regression, decision tree model, and support vector machine (SVM), and the AUCROC were 0.78, 0.74, and 0.66, respectively, while 12 risk factors of PE and 38 routine laboratory indicators were analyzed with the logistic regression, decision tree model, and support vector machine (SVM), and the AUCROC were 0.86, 0.77, and 0.93, respectively. Conclusions: The efficacy of clinical risk factors alone in predicting early-onset preeclampsia is not high while the efficacy increased significantly when PE risk factors combined with routine laboratory indicators. The SVM model was better than logistic regression model and decision tree model in early prediction of early-onset preeclampsia incidence.

Evaluation of Platelet Count’s Role in the Prediction of Pregnancy-Induced Hypertension

Pregnancy-induced hypertension (PIH) is the main pregnancy-specific disease that causes maternal and perinatal death. In recent years, active treatment of pre-eclampsia after 34 weeks of gestation has resulted in good maternal and perinatal outcomes, but the treatment of early-onset pre-eclampsia patients is still unsatisfactory. So the prediction of PIH has become a research hot spot. Therefore, this study attempted to evaluate if a change in platelet count during pregnancy can be used to predict the development of PIH. A comparative cross-sectional study was conducted among 30 healthy normotensive pregnant women and 30 women with PIH. Face-to-face interviews’ using a structured questionnaire and physical examination supplemented with laboratory investigations were used for data collection. Statistical data analysis was done using an independent t-test, linear regression, and one-way ANOVA. The ROC curve was used to determine the optimal cut-off point of platelet count for the prediction of the development of PIH. The mean platelet count in the case was found to be 154.87 (± 42.56) × 103/µL while in controls the mean platelet count was 273.47 (± 34.08) × 103/µL. The ROC analysis showed that platelet count < 225 × 103/µL was a cut-off point to differentiate whether the pregnant women develop PIH or not with a sensitivity of 96.7% and specificity of 90%. In conclusion, a decrease in platelet count was significantly associated with the development and severity of PIH.

Risk prediction model of early-onset preeclampsia based on risk factors and routine laboratory indicators

Background: 10% - 15% of maternal deaths are statistically attributable to preeclampsia. Compared with late-onset PE, the severity of early-onset PE remains greater harm, with higher morbidity and mortality. Objective: To establish an early-onset preeclampsia prediction model by clinical characteristics, risk factors and routine laboratory indicators from 6 to 10 gestational weeks of pregnant women. Methods: The clinical characteristics, risk factors and 38 routine laboratory indicators (6 - 10 weeks of gestation) including blood lipids, liver and kidney function, coagulation, blood count and other indicators of 91 early-onset preeclampsia patients and 709 normal controls without early-onset preeclampsia from January 2010 to May 2021 in Peking University Third Hospital (PUTH) were retrospectively analyzed. Logistic regression, Decision tree model and Support vector machine (SVM) model were applied for establishing prediction models, respectively. ROC curves were drawn, and the area under the curve (AUCROC), sensitivity and specificity was calculated and compared. Results: There were statistically significant differences in the rates of diabetes, Antiphospholipid Syndrome (APS), kidney disease, Obstructive Sleep Apnea (OSAHS), primipara, history of preeclampsia and Assisted Reproductive Technology (ART) (p &lt; 0.05). Among the 38 routine laboratory indicators, there were no significant differences in the levels of PLT/LYM, NEU/LYM, TT, D-Dimer, FDP, TBA, ALP, TP, ALB, GLB, UREA, Cr, P, Cystatin C, HDL- C, Apo-A1, and Lp(a) between the two groups (p &gt; 0.05). The levels of the rest indicators were all statistically different between the two groups (p &lt; 0.05). If only 12 risk factors of PE were analyzed by logistic regression, decision tree model, and the Support Vector Machine (SVM), the AUCROC were 0.78, 0.74 and 0.66 respectively, while 12 risk factors of PE and 38 routine laboratory indicators were analyzed by logistic regression, decision tree model and the support vector machine(SVM), the AUCROC were 0.86, 0.77 and 0.93 respectively. Conclusion: The efficacy of clinical risk factors alone in predicting early-onset preeclampsia is not high, while the efficacy increased significantly when PE risk factors were combined with routine laboratory indicators. The SVM model was better than the logistic regression model and decision tree model in the early prediction of early-onset preeclampsia incidence.

CircRNA_06354 might promote early-onset preeclampsia in humans via hsa-miR-92a-3p/vascular endothelial growth factor-A.

Early-onset preeclampsia (EOPE) is a serious pregnancy disorder with multisystem complications. Recently, circRNA was reported to participate in the progression of EOPE. However, the role and mechanism of circRNA_06354 in the pathophysiological development of EOPE remain unclear. Blood samples from patients with EOPE and healthy pregnant controls (CTRL) were analyzed by RNA-seq. functions and mechanisms of circRNA_06354 in EOPE were investigated by a series of experiments. An EOPE rat model was constructed to detect the expression levels of circRNA_06354. The level of circRNA_06354 was altered in EOPE and CTRL individuals, as well as EOPE and CTRL rats. CircRNA_06354 had a sensitivity of 88.9% and a specificity of 100% in predicting EOPE. Subcellular localization indicated that circRNA_06354 was primarily detected in the cytoplasm of HTR8-/SV-neo cells and the cytotrophoblast of EOPE placentas. In addition, circRNA_06354 transcription was markedly higher than that of its linear counterpart. RNA pull-down assays implied that hsa-miR-92a-3p might sponge circRNA_06354. Vascular endothelial growth factor-A (VEGF-A) levels were found to be increased in EOPE patients. Moreover, overexpression of circRNA_06354 suppressed the migration, invasion and tube formation of trophoblastic cells invading spiral arteries or the endometrium. CircRNA_06354 inhibits trophoblastic cell invasion, migration and tube formation toward the endometrium in the initiation of EOPE. The circRNA_06354/hsa-miR-92a-3p/VEGF-A axis might be a therapeutic target in the prevention and treatment of EOPE.

High Throughput Sequencing Analysis of Exosomal miRNA Expressions in Early-Onset Preeclampsia Patients.

The goal of this study was to screen for differentially expressed exosomal miRNAs in peripheral blood samples of early-onset preeclampsia and normal pregnant patients using high-throughput sequencing methods and explore their effects on the pathogenesis of preeclampsia. Peripheral blood samples from 5 patients with early-onset preeclampsia and 5 normal pregnant women (control group) were enrolled. Then, exosomes were extracted from each sample, and the procedure was replicated three times. An Illumina HiSeq4000 sequencing platform was used to analyze exosomal miRNAs in all samples before comparison. The target genes and signaling pathway predictions and the biological function enrichments of significant and differentially expressed miRNAs were assessed using Miranda and Starbase software, as well as GO and KEGG databases. Compared with the control, patients in the early-onset preeclampsia group had 65 significantly and differentially expressed exosomal miRNAs in their peripheral blood samples. The results have shown that of the 65 differentially expressed miRNAs, 17, including has-miR-6855, has-miR-7151, and has-miR-6777, were up-regulated, and 48, including has-miR-1247, has-miR-29B2, and has-miR-941, were down-regulated (p < 0.05). The Miranda and TargetScanS algorithms predicted a total of 2,231 target genes from the differentially expressed miRNAs. The Go and KEGG analyses showed that the principal biological function of these target genes was the regulation of Ras protein signal transduction, histone modification, GTPase-mediated signal transduction, and transforming growth factor (TGF)-β. Additionally, the results also showed that the major pathways involved in the regulation of these functions were the PI3K Akt, MAPK, tumor necrosis factor, and EGFR tyrosine kinase inhibition signaling pathways. There are significant differences in the expression profiles of exosomal miRNAs between early-onset preeclampsia patients and normal pregnant women. These differentially expressed miRNAs may not only play an important regulatory role in the occurrence of early-onset preeclampsia but also participate in its pathophysiological process through genetic regulation of a variety of biological functions and signal pathways.

Clinical Comparative Analysis of Early-Onset Preeclampsia Combined with HELLP Syndrome

To explore the clinical characteristics of early-onset preeclampsia (PE) combined with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and to improve the capacity for early diagnosis and treatment. Pregnant women who received treatment at Women's Hospital, School of Medicine, Zhejiang University between March 2014 and October 2021 were retrospectively enrolled. There were two patient groups, the HELLP group consisting of 70 cases of early-onset PE combined with HELLP syndrome and the control group consisting of 140 cases of early-onset PE without HELLP syndrome. Patients in the two groups were matched by age. The general clinical data, characteristics of pathogenesis, and laboratory findings of the patients were collected and the perinatal outcomes of the two groups were compared and analyzed. 1) There was no significant difference in gravidity, pre-delivery body mass index, years from the last delivery, and family history of diabetes mellitus and hypertension between the two groups. 2) The highest systolic blood pressure, highest diastolic blood pressure during the pregnancy, and the postpartum hospital length-of-stay ( P<0.001) in the HELLP group were higher than those in the control group. The gestational age at the time of the diagnosis of PE ( P=0.001) and the gestational age at delivery ( P<0.001) in the HELLP group were significantly earlier than those in the control group. The difference between the gestational age at the time of blood pressure elevation and that at the time of delivery ( P<0.001), and the gestational age difference between the diagnosis of early-onset PE and delivery ( P=0.027) were lower than those in the control group. The incidences of eclampsia in the HELLP group, pleural effusion, and ascites were higher than those of the control group. 3) Neonates in the HELLP group had a higher probability of being admitted to NICU and developing cyanotic/pale asphyxia ( P<0.001). 4) Before the termination of pregnancy, the HELLP group had higher levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, urea, random glucose, lactate dehydrogenase, activated partial thromboplastin time, and the last 24-hour urine protein quantification than those of the control group (all P<0.05), while the platelet (PLT) counts were significantly lower than those of the control group ( P<0.001). 5) There was a significant correlation between PLT counts in the second trimester and the onset of HELLP syndrome ( P=0.006), with the area under the ROC curve reaching 0.746 (95% CI: 0.596-0.897). In comparison with early-onset PE patients without HELLP syndrome, patients with early-onset PE combined with HELLP syndrome are diagnosed for PE at an earlier gestational age, have higher blood pressure, are more prone to serious pregnancy complications, and have longer postpartum hospital length-of-stay and worse neonatal outcomes. Close monitoring of PLT counts of early-onset PE patients in the second trimester may help predict subsequent HELLP syndrome.

Increased maternal serum aquaporin-9 expression in pregnancies complicated with early-onset preeclampsia.

We aimed to evaluate maternal serum aquaporin-9 (AQP9) concentrations in patients with early-onset preeclampsia and compare them with the uncomplicated control group with normal blood pressure. This was a prospective case-control study including pregnant women who were diagnosed with early-onset preeclampsia between 200/7 -340/7 weeks of gestation. Demographic and clinical characteristics, complete blood count and biochemical parameters, and serum AQP9 concentrations were documented. A receiver operating characteristic (ROC) curve was constructed to illustrate the sensitivity and specificity performance characteristics of AQP9 and a cut-off value was estimated by using the Youden index. The mean serum concentrations of maternal AQP9 were significantly increased in the early-onset preeclampsia group (722.22 ± 211.80 pg/mL) than the control group (499.97 ± 68.89 pg/mL, p < 0.001). When we analyze the area under the ROC curve (AUC), the serum AQP9 value can be considered a statistically significant parameter for diagnosing preeclampsia. According to the Youden index, a 587.70 ng/mL cut-off value of serum AQP9 level can be used to diagnose early-onset preeclampsia with 80.0% sensitivity and 89.7% specificity. Maternal serum AQP9 concentrations were significantly increased in early-onset preeclampsia patients than healthy normotensive pregnant patients. We suggest that AQP9 might be a crucial biomarker of the inflammatory process in early-onset preeclampsia.

Clinical significance of microRNA-320a and insulin-like growth factor-1 receptor in early-onset preeclampsia patients

AimsCurrently, there is no reliable method to effectively predict and diagnose early-onset preeclampsia (EOPE). microRNAs (miRs) are promising biomarkers for EOPE. This study investigated the role of miR-320a in EOPE. MethodsExpressions of miR-320a and insulin-like growth factor-1 receptor (IGF-1R) in serum of EOPE patients and normal pregnant women were detected. The clinical diagnostic efficacy of miR-320a and IGF-1R for EOPE was analyzed using receiver operating characteristic curve. The correlation between miR-320a expression and EOPE clinical indicators [mean arterial pressure (MAP), 24-h urinary protein excretion, serum creatinine (SCR), uric acid (UA), albumin (ALB) and platelet count] was analyzed. The correlation and binding relationship between miR-320a and IGF-1R was predicted and verified. ResultsmiR-320a was upregulated, and IGF-1R was downregulated in EOPE patients with their differential expressions more obvious in severe EOPE than mild EOPE. miR-320a and IGF-1R possessed potent clinical diagnostic efficacy for EOPE. miR-320a expression showed a positive correlation with MAP, 24-h urinary protein excretion, UA and SCR levels, and a negative correlation with ALB level and platelet count in EOPE patients. Moreover, miR-320a targeted IGF-1R. ConclusionWe demonstrated that miR-320a was aberrantly elevated in EOPE and showed powerful clinical diagnostic efficacy for EOPE, which may be achieved by directly targeting IGF-1R. This study provided great reference values for EOPE early diagnosis and novel targets for EOPE treatment.

Maternal lipid levels in preeclampsia: singleton vs. twin pregnancies

Objective To compare the maternal lipid levels in preeclampsia (PE) patients between singleton and twin pregnancies. Methods In this retrospective study, pregnant women with PE were divided into singleton group (n = 702) and twin group (n = 198). Serum lipids which include total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured and the TC/HDL-C ratio, TG/HDL-C ratio, and LDL-C/HDL-C ratio were calculated and compared between the two groups. Covariance analysis was used to correct the potential factors affecting serum lipid levels such as maternal age, pre-pregnancy body mass index, gestational weight gain, etc. Results The levels of TC, TG, LDL-C, and TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio in twin PE were significantly higher than those in singleton PE group, and there was no significant difference in the level of HDL-C between the two groups. In late-onset PE patients, the lipid levels of TC, TG, LDL-C, and TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio in twin PE group were significantly higher than those in singleton PE group, with no significant difference in the level of HDL-C. However, in early-onset PE patients, there were no significant differences in the lipid levels between the two groups. Conclusions There were more obvious lipid disturbances such as higher levels of TC, TG, LDL-C, and TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio in twin PE group than singleton PE group. The differences of lipid levels appeared mainly in late-onset PE group, while the lipid levels in twin PE group were similar to those in singleton PE group during pregnancy in early-onset PE group.

Ghrelin promotes angiogenesis by activating the Jagged1/Notch2/VEGF pathway in preeclampsia.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), has been found to be involved in the regulation of blood pressure; however, its effects in preeclampsia (PE) and the potential underlying mechanism remain poorly understood. In this study, we aimed to investigate the correlation between ghrelin and PE and reveal the possible mechanism underlying any relationship. The levels of ghrelin and VEGF in the plasma of 6 early-onset PE (EOPE), 6 late-onset PE (LOPE) and 12 healthy pregnant (HP) women were detected using enzyme-linked immunosorbent assay (ELISA). The recombinant plasmid, pCDH-ghrelin, was designed to overexpress ghrelin in human umbilical vein endothelial cells (HUVECs). We analyzed angiogenesis in vitro and investigated the mechanism using MTT assay, colony formation assay, transwell migration assay, Matrigel-induced tube formation assay and western blotting. Ghrelin was significantly decreased in EOPE patients (P < 0.05) but elevated in LOPE patients compared to HP groups (P > 0.05). There was a significant decrease in plasma level of VEGF in EOPE and LOPE patients compared to the controls (P < 0.05). The proliferation, migration and tube formation ability of HUVECs were enhanced after transfection with pCDH-ghrelin. Ghrelin increased VEGF by activating the Jagged1/Notch2 pathway. Our study uncovered that ghrelin has the potential to improve endothelial function by promoting angiogenesis through Jagged1/Notch2/VEGF pathway.

Serum ischemia modified albumin and dynamic thiol/disulfide homeostasis in early- and late-onset preeclampsia

Aim: In the present study, we aimed to evaluate serum IMA, IMA/albumin ratio, and DTDH levels in patients with early- and late-onset PE compared to healthy controls.Impaired homeostasis between oxidant and antioxidant mechanisms, inflammatory processes, and endothelial dysfunction play a key role in the pathogenesis of preeclampsia (PE). Serum ischemia modified albumin (IMA) and dynamic thiol/disulfide homeostasis (DTDH) levels are elevated in the presence of inflammation, oxidative stress, and endothelial dysfunction. Material and Methods: A total of 24 patients with early-onset PE and 62 patients with late-onset PE were included.The control group consisted of 46 healthy controls with similar gestational weeks. Serum samples were collected and IMA, albumin, and native, total, and disulfide thiol levels analyzed. Corrected IMA/albumin ratios were also calculated.Results: Disulfide levels, disulfide/native and disulfide/total thiol levels were higher in patients with early-onset PE compared to late-onset patients(p=0.008, p=0.022, and p=0.021, respectively). However, there was no significant difference between the late-onset PE patients and late-onset PE controls. Although there was no significant difference in the IMA levels between the patient and control groups, the IMA/albumin ratio was higher in the early-onset and late-onset PE patients, compared to the control group. However, there was no significant difference between the early-onset and late-onset PE patients.Conclusion: Our study results showed increased disulfide levels, disulfide/native thiol, disulfide/total thiol and IMA/albumin ratio in the early-onset PE patients, indicating increased oxidative stress in the pathogenesis of PE. In the late-onset PE patients, there was an increase only in the IMA/albumin ratio. However, further large-scale, prospective studies are needed to confirm the diagnostic value of these markers in the clinical practice.

RITA Is Expressed in Trophoblastic Cells and Is Involved in Differentiation Processes of the Placenta.

Preeclampsia (PE) remains a leading cause of maternal and perinatal mortality and morbidity worldwide. Its pathogenesis has not been fully elucidated and no causal therapy is currently available. It is of clinical relevance to decipher novel molecular biomarkers. RITA (RBP-J (recombination signal binding protein J)-interacting and tubulin-associated protein) has been identified as a negative modulator of the Notch pathway and as a microtubule-associated protein important for cell migration and invasion. In the present work, we have systematically studied RITA’s expression in primary placental tissues from patients with early- and late-onset PE as well as in various trophoblastic cell lines. RITA is expressed in primary placental tissues throughout gestation, especially in proliferative villous cytotrophoblasts, in the terminally differentiated syncytiotrophoblast, and in migrating extravillous trophoblasts. RITA’s messenger RNA (mRNA) level is decreased in primary tissue samples from early-onset PE patients. The deficiency of RITA impairs the motility and invasion capacity of trophoblastic cell lines, and compromises the fusion ability of trophoblast-derived choriocarcinoma cells. These data suggest that RITA may play important roles in the development of the placenta and possibly in the pathogenesis of PE.

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.

Downregulation of indoleamine 2, 3-dioxygenase expression in the villous stromal endothelial cells of placentas with preeclampsia

IntroductionPrevious studies have shown that indoleamine 2, 3-dioxygenase (IDO), an immunosuppressive enzyme that converts tryptophan to kynurenine, is expressed in the placenta and might play a role in the maintenance of pregnancy, although its associations with the pathogeneses of preeclampsia (PE) and fetal growth restriction (FGR) remain unclear. The objective of this study was to investigate the differences in IDO expression among normal, PE, and FGR placentas, and the associations between IDO expression and clinical symptoms, or the expression of fms-like tyrosine kinase receptor-1 (Flt-1). MethodsImmunohistochemical studies of IDO and Flt-1 expression were performed in human placentas that were complicated with FGR alone (n=19), PE alone (n=20), or both PE and FGR (n=39), and gestational age-matched controls (n=23). ResultsIt was found that IDO was expressed on endothelial cells in the villous stroma, while Flt-1 was located on trophoblast cells. The IDO expression level of the PE alone group was significantly lower than those of the FGR alone and control groups. The IDO expression of the PE+FGR group was significantly lower than that of the FGR alone group. Lower IDO expression was significantly correlated with more severe maternal hypertension or proteinuria in PE patients, who exhibited higher Flt-1 expression. The late onset PE patients exhibited significantly lower IDO expression than the early onset PE patients. ConclusionThis study demonstrated that the downregulation of IDO expression on the endothelial cells of the villous stroma was associated with PE, but not FGR, suggesting that IDO might be involved in the pathophysiology of PE.

Association between Val158Met COMT, TNF-α -857 C>T, TNFR1 36 A>G, IL-1α 4845 G>T and IL-10 -1082 A>G polymorphisms and risk of early-onset preeclampsia and its complications

Background/Aim. Preeclampsia (PE) belongs to the group of hypertensive disorders in pregnancy with the global average incidence of 2.16%. It is considered as one of the leading causes of maternal and neonatal morbidity and mortality worldwide. The goal of this study was to assess the potential association between Val158Met catechol-o-methyltransferase (COMT), tumor necrosis factor-alpha (TNF-α) -857 C>T, tumor necrosis factor receptor 1 (TNFR1) 36 A>G, interleukin-1alpha (IL-1α) 4845 G>T and interleukin-10 (IL-10) -1082 A>G polymorphisms and risk of early-onset preeclampsia (PE) and its complications. Methods. The study included 47 early-onset PE patients, which were grouped by disease severity and by size for gestational age and 47 control cases. The Val158Met polymorphism was genotyped by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) analysis and inflammatory cytokine polymorphisms by the Sanger sequencing method. Results. The COMT Met allele as well as IL-1α T showed a protective role, decreasing the risk of early-onset PE after age and body mass index (BMI) adjustments. The detected interactions between the COMT Met and IL-10 A alleles, as well as between the COMT Met and TNF-α T alleles were insignificant after age and BMI adjustments. Conclusion. COMT and IL-1α may be used as candidate genes for early-onset PE and its severe form and small for gestational age (SGA) complications.

Tissue Factor Pathway Inhibitor Mediates Attenuation of Tissue Factor-Stimulated Thrombin Generation in Early Onset Preeclampsia

IntroductionPregnancy increases the risk of venous thromboembolism (VTE) in women. Interestingly, preeclampsia, an extremely pro-inflammatory disorder specific to pregnancy is associated with a lower than expected increase in thrombotic risk compared to other proinflammatory disorders. The mechanism underling this lower thrombotic risk is unknown. The aim of this study was to investigate the coagulation balance, a major determinant of VTE risk, in early onset preeclampsia (EOP) patients. EOP is the most inflammatory form of preeclampsia, characterised by the development of hypertension and proteinuria prior to 34 weeks gestation.MethodsPlatelet-poor plasma was collected from patients with early onset preeclampsia (EOP n=26), matched pregnant (n=20) and non pregnant controls (n=16). Calibrated automated thrombography, an assay of thrombin generation and TFPI assays were performed. Data are expressed as mean ± standard deviation.ResultsDuring the study period, 15,299 women delivered and 40 patients developed EOP, of whom 26 were successfully recruited with consent. For comparison, 16 non pregnant controls and 20 pregnant controls were also recruited. When artefactual contact activation was inhibited by using corn trypsin inhibitor as anticoagulant, EOP patients were characterised by a decrease in the rate and extent of Tissue Factor (TF) thrombin generation compared to pregnant controls. There was a prolongation of the time to peak thrombin generation (16 ± 4 minutes vs. 13 ± 2 minutes, p < 0.05), a decrease in the velocity index (25 ± 17nM/minute vs. 41 ± 27nM/minute, p < 0.05), and a decrease in peak thrombin generation (150 ± 80 nM IIa vs. 210 ± 70 nM IIa, p < 0.05 ) in EOP compared to pregnant controls. This reduction in the rate and extent of thrombin generation was most amplified in patients with severe EOP (multi-organ involvement) compared with moderate EOP. This lower overall procoagulant state seen was further emphasised by the increase in sensitivity to the anticoagulant activity of exogenously added activated protein C and thrombomodulin observed in EOP. Again, the increased sensitivity to APC and thrombomodulin was most apparent in severe EOP cases. Previous studies have shown that preeclampsia is characterised by a increase in plasma TFPI activity. As such, we investigated whether increases in plasma TFPI activity explained the reduction in TF-dependent thrombin generation. Consistent with previous studies, plasma tissue factor pathway inhibitor (TFPI) levels and plasma TFPI activity significantly increased in EOP, most notably in severe EOP cases. There was a significant inverse correlation between total TFPI levels and peak thrombin generation (r2 = -0.64, p < 0.05) and TFPI activity and peak thrombin generation (r2= -0.52, p < 0.05). The inhibition of TFPI with a polyclonal anti-TFPI antibody abolished the attenuation in thrombin generation seen in severe EOP.ConclusionIn conclusion, TF-dependent thrombin generation is reduced in patients with early onset preeclampsia due to increases in plasma TFPI activity. These findings may partially explain the lower thrombosis risk observed in patients with early onset preeclampsia relative to comparable systemic proinflammatory conditions. These data also have future potential in helping clinicians to manage competing bleeding and thrombotic risks in these very high-risk patients. DisclosuresMaguire:Actelion UK: Research Funding. Ní Áinle:Actelion UK: Research Funding.

Distinct expression profiles of lncRNAs between early-onset preeclampsia and preterm controls

Early-onset preeclampsia (EOPE), which is the most severe form of the syndrome, confers a high risk of neonatal morbidity and perinatal death. We aim to study the roles of long non-coding RNAs (lncRNAs) in the pathogenesis of early-onset preeclampsia (EOPE). Therefore, we examined the expression profiles of lncRNAs between early-onset preeclampsia and preterm controls using microarray analysis. Quantitative real-time PCR (qRT-PCR) was performed to verify the selected differentially expressed lncRNAs. In total, we identified 15,646 upregulated and 13,178 downregulated lncRNAs in the placenta of EOPE patients compared to the preterm controls. Gene ontology and pathway analysis revealed that compared to the preterm controls, many of the processes over-represented in the EOPE patients were related to cell migration and cell motility. A selection of the differentially expressed lncRNA transcripts was confirmed using qRT-PCR, particularly RP11-465L10.10, which is associated with the MMP9 gene. These data may offer a background/reference resource for future functional studies of lncRNAs related to EOPE.

Protective Role of Maternal P.VAL158MET Catechol-O-Methyltransferase Polymorphism against Early-Onset Preeclampsia and its Complications.

SummaryBackgroundUp until now there have been contradictory data about the association between p.Val158Met catechol-O-methyltransferase (COMT) polymorphism and risk of preeclampsia (PE). The goal of this study was to assess the potential correlation between p.Val158Met COMT polymorphism and risk of early-onset PE, risk of a severe form of early-onset PE, as well as risk of small-for-gestational-age (SGA) complicating PE.MethodsThe study included 47 early-onset PE patients and 47 control cases. Forty-seven early-onset PE patients were grouped by disease severity (33 patients with a severe form and 14 patients without severe features) and secondly by size for gestational age (12 patients with appropriate-for-gestational-age (AGA) and 35 patients with SGA size). p.Val158Met polymorphism was genotyped by PCR-RFLP analysis.ResultsAllele analysis showed significant difference in COMT allele distribution between early-onset PE and control group as well as early-onset PE SGA and controls (p=0.04057 and p=0.0411 respectively). A statistically significant distribution difference between the severe form and form without severe features of early-onset PE patients was not observed (p>0.05). The highest difference observed was in the allele recessive model where COMT MetMet genotype was associated with decreased risk of early-onset PE (OR=0.281; 95%CI = 0.092–0.7836) and PE complications including severe early-onset PE (OR= 0.304; 95%CI=0.086–0.944) and SGA early-onset PE (OR=0.284; 95%CI=0.081–0.874).ConclusionsCOMT may be used as a candidate gene for early-onset PE and its severe form and SGA complications.