Early-onset Preeclampsia Group Research Articles

Longitudinal Assessment of Oxidative Stress Markers in Women with Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder and a major contributor to maternal and fetal morbidity and mortality. Role of oxidative stress in early pregnancy with the pathophysiology of the disorder is unclear. The current study aims to analyse maternal levels of oxidative stress markers (MDA and protein carbonyl) longitudinally across gestation and placental levels of oxidative stress markers (MDA, protein carbonyl and 8-oxo-2'-deoxyguanosine) in women with PE and compare them with non-PE women. 324 pregnant women (216 non-PE and 108 PE women) were longitudinally followed during pregnancy. Women with preeclampsia were stratified as early onset preeclampsia (EOP) and late onset preeclampsia (LOP) Maternal blood at four time points across gestation (11-14weeks, 18-22weeks, 26-28weeks, and at delivery) and placenta were collected. Maternal and placental levels of oxidative stress markers were assessed using commercially available kits. Maternal plasma MDA and protein carbonyl levels were comparable between the PE and non-PE group at all timepoints across gestation. Maternal plasma MDA were significantly higher levels at 26-28weeks in EOP women when compared to non-PE women (p < 0.05). Placental 8-oxo-dG levels were lower in the EOP group as compared to non-PE (p < 0.05). Elevated plasma MDA levels were positively associated with birth length at 18-22weeks and 26-28weeks in the PE group (p < 0.05 for both). Maternal plasma MDA levels were positively associated with systolic blood pressure at 18-22weeks. Oxidative stress in early pregnancy is not associated with risk of PE.

A new Doppler index, cerebro-placental-uterine ratio, and fetal cardiac parameters in early onset preeclampsia.

Our aim was to investigate the significance of cerebro-placento-uterine ratio CPUR, a new Doppler index, and fetal cardiac parameters (Mod MPI, EFT) in early-onset preeclampsia (EOPE) and to examine whether these parameters are related to perinatal outcome. Forty participants diagnosed with EOPE (preeclampsia cases diagnosed before 34 weeks of gestation) and 40 healthy pregnant women were included in this study. Demographic data were recorded. Doppler parameters such as middle cerebral artery (MCA), umbilical artery (UA), and uterine artery (Ut-A), and left modified myocardial performance index (Mod-MPI) and epicardial fat thickness (EFT) were measured. Cerebroplacental ratio (CPR) was determined by dividing MCA pulsatility index (PI) by UA PI. CPUR was calculated as the ratio of CPR to mean UtA-PI (CPUR = CPR/UtA-PI). All parameters were compared between the EOPE and control groups. Correlation tests were used to examine the relationship between Doppler parameters and perinatal outcome. p values less than 0.05 were considered statistically significant. The pulsatility index of the middle cerebellar artery, CPUR and CPR values were statistically lower in the EOPE group than in the control group (p = 0.002; p = <0.001; p = <0.001; respectively). No statistical differences were found between groups for isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), ejection time (ET), left mod-MPI, EFT (p = 0.117; p = 0.093; p = 0.398; p = 0.882; p = 0.202, respectively). Umbilical artery Doppler pulsatility index (PI), mean uterine artery Doppler pulsatility index (PI), were higher in the EOPE group than in the control group (p = 0.006; and p = <0.001, respectively). The CPUR value for predicting EOPE was ≤1.3652 with 74. 4% sensitivity and 94.9% specificity. Positive correlations were found between CPUR, CPR, and some neonatal parameters. CPUR, a new index combining fetal and uterine Doppler indices, may add contribution to predict adverse perinatal outcome and EOPE.

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.

Investigation of serum apelin-13 and apelin-36 concentrations in pregnancies complicated by preeclampsia; a prospective case-control study

Objective We aimed to investigate the relationship between preeclampsia and maternal serum apelin-13 and apelin-36 concentrations. Methods This cross-sectional study was carried out in the Gynecology and Obstetrics Clinic of Umraniye Training and Research Hospital. The preeclampsia group consisted of 40 pregnant women diagnosed with preeclampsia, and the control group consisted of 40 healthy pregnant women matched with the preeclampsia group in terms of age and body mass index. The two groups were compared in terms of maternal serum apelin-13 and apelin-36 concentrations. Results Both groups were similar in terms of demographic characteristics and the gestational week at blood sampling. Maternal serum apelin-13 and apelin-36 concentrations were significantly lower in the preeclampsia group than in the control group (p = 0.005, p = 0.001, respectively). The optimal cutoff value for the prediction of preeclampsia in receiver operator curve analysis for apelin-13 was determined as 1781.67 pg/ml with 60% sensitivity and 60% specificity, and 885.5 pg/ml for apelin-36 with 67% sensitivity and 65% specificity. We divided the preeclampsia group into two groups mild and severe and compared the three groups in terms of maternal serum apelin-13 and apelin-36 concentrations. The lowest apelin-13 concentration was detected in the severe preeclampsia group, while the lowest apelin-36 concentration was detected in the mild preeclampsia group (p = 0.020, p = 0.003, respectively). Considering the onset of the disease, we divided the preeclampsia group into two groups early and late-onset, then compared the three groups in terms of maternal serum apelin-13 and apelin-36 concentrations. The lowest maternal serum apelin-13 and apelin-36 concentrations were detected in the early-onset preeclampsia group (p = 0.016, p = 0.001, respectively). Conclusion It was determined that serum apelin-13 and apelin-36 concentrations were significantly lower in preeclamptic pregnant women, this decrease was more significant in early-onset preeclampsia, and low maternal serum apelin-13 concentration was more associated with the severity of preeclampsia.

PLACENTAL MUTATIONAL BURDEN NEGATIVELY CORRELATES WITH GESTATIONAL AGE IN EARLY-ONSET PREECLAMPSIA

Abstract The placenta exists in a hypoxic environment during early pregnancy, making it susceptible to somatic genetic mutations caused by oxidative stress and rapid cell proliferation. Oxidative stress is one of the leading factors involved in cellular aging causing genetic mutations, cellular senescence, and mitochondria dysfunction over time. While it has been demonstrated that healthy placentas accumulate somatic mutations as they develop, we hypothesize that diseased placentas display an accelerated aging phenotype through the accumulation of somatic mutations. To address this, we analyzed RNA-seq data from 84 human placentas throughout gestation from healthy (N=33) and preeclamptic pregnancies (N=51). We identified rare single nucleotide variants, insertions and deletions using GATK Best practices Workflow for RNA-seq short variant discovery using bcbio-nextgen and annotated with VEP and LOFTEE. Mutational burden, defined as the total number of rare mutations per megabase, was calculated after strict quality control and filtering for rare (gnomADg&amp;lt; 0.05) variants using maftools in R. Linear regression models were employed to determine the association between mutational burden and gestational age. Differences in mean values were computed with a pairwise t-test . This study revealed that mutational burden in early-onset preeclampsia placentas is negatively correlated to gestational age (R^2=0.256; p-value=0.032). The early-onset preeclampsia group had a higher mutational burden relative to the other groups (p-value&amp;lt; 0.05). This study revealed a significant correlation of mutational burden with gestational age in early-onset preeclampsia, paving the way for additional investigation of accelerated aging in placentas and its contribution to the development of preeclampsia.

Altered Placental Insulin Signaling in the Absence of Systemic Insulin Resistance in Hypertensive Disorders of Pregnancy among South Indian Tamil Population

A cross sectional study was conducted to explore the possible derangements in placental insulin signaling and also to investigate the presence or absence of maternal systemic insulin resistance in different types of hypertensive disorders of pregnancy (HDP). Study Design: Healthy pregnant women (n=32) and pregnant women with gestational hypertension (GH) (n=18), late onset Pre-eclampsia (LP) (n=18) and early onset Pre-eclampsia (EP) (n=19) were recruited for the study. Maternal venous blood and placental samples were collected from the study subjects at 35±7 weeks of gestation. Insulin resistance parameters such as fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, beta cell function and insulin sensitivity and glycated hemoglobin were estimated in the maternal venous blood samples. Placental protein expressions of insulin signaling molecules were analyzed by western blotting method. Results: Maternal venous blood insulin resistance parameters were not significantly different between the study groups. However, placental content of phospho insulin receptor beta was significantly decreased in GH, LP and EP groups in comparison to controls. We also found a significant decrease in placental protein expression of phosphatidyl inositol 3-kinase p85 alpha in LP group when compared to other groups.

The Risk of Persistent Hypertension and Chronic Kidney Disease in Early- and Late-Onset Preeclampsia: A Report From Developing Country.

Preeclampsia (PE) has been disproportionately prevalent in developing countries and constitutes a leading cause of maternal mortality, and also has long-term impacts, including renal consequences.This study aimed to explore the risk of persistent hypertension and kidney failure in early-onset PE (EOP) and late-onset PE (LOP) in the five years after delivery. This retrospective cohort study included women with a prior history of severe PEor normotensive pregnancy admitted to tertiary hospitals in Indonesia. The blood pressure, body mass index (BMI), urea, creatinine serum, and protein urine were analyzed, and the risk of chronic kidney disease (CKD) after five years was performed using theKidney Disease Improvement Global Outcomes (KDIGO) classification. Twenty-seven EOP, 35 LOP, and 30 normotensive cases were included. Mean blood pressure after five years was recorded as 115.6 ± 14.25 mmHg in the normotensive group, 131.82 ± 19.34 mmHg in the LOP group, and 154.96 ± 23.48 mmHg in the EOP group. According to the KDIGO classification, the normotensive group had an average 10% risk of CKD, but severe PE had a risk of CKD greater than 90%. In the severe PE group, the risk of CKD was 20.94 times higher compared to normotensive women (OR 20.94; 95% CI 2.67-163.72, p = 0.004). The risk of CKD in the EOP group was 6.75 times higher than in the LOP group (OR 6.75; 95% CI 2.19-20.76, p = 0.001), whereas persistent hypertension in the EOP group was 5.78 times higher than in the LOP group (OR 5.78; 95% CI 1.91-17.395, p = 0.002). PE women have a higher risk of CKD than normotensive women. Women with a history of EOP are more likely to develop persistent hypertension and CKD than women with a prior LOP history.

Genome-wide association study reveals HSF2, GJA1 and TRIM36 as susceptibility genes for preeclampsia: a community-based population study in Tianjin, China

ABSTRACT Background Preeclampsia (PE) mainly occurs in pregnant women and is hereditary. Several genome-wide association studies (GWAS) on Caucasian samples have reported some gene loci that are associated with preeclampsia. However, these studies have not reached consistent conclusions. No previous GWAS has examined preeclampsia in the Chinese Han population. Method This study aimed to identify common genetic variations associated with preeclampsia in the Chinese Han population through two-stage case‒control studies. The discovery cohort included 92 patients with severe preeclampsia and 187 healthy controls. The validation cohort included 52 patients with preeclampsia and 104 controls. A genome-wide association study was performed to identify putative preeclampsia genes in the discovery cohort, with validation in the validation cohort. Results In the discovery cohort, GWAS demonstrated that 19 single-nucleotide polymorphisms (SNPs) were associated with preeclampsia (P < 10−5). The pathway analysis revealed that these 19 SNP representative genes were mainly enriched in the adenylyl cyclase-inhibiting G-protein coupled receptor signaling pathway. After validation in the validation cohort, rs13176432 and rs13210237 remained closely related to preeclampsia (P<0.05). In the combined data set, the frequency of the G allele in rs13176432 was significantly higher in cases with preeclampsia than in controls (P = 5 × 10−6). The frequency of the A allele in rs13210237 was higher in the preeclampsia group (P = 8 × 10−6). The rs13210237 representative genes include HSF2 and GJA1, while the rs13176432 representative gene is TRIM36. There were no differences in genotype distribution between the early-onset and late-onset preeclampsia groups (P > 0.05). Furthermore, rs13210237 and rs13176432 were related to preeclampsia in the adjusted regression model (P < 0.000). Conclusion In this study of two independent cohorts, we found that rs13210237 and rs13176432 might be novel preeclampsia-susceptible genetic factors in the Han population in China. However, there was no association between the onset of preeclampsia and these genotypes.

Down-regulated Wnt7a and GPR124 in early-onset preeclampsia placentas reduce invasion and migration of trophoblast cells.

Preeclampsia (PE) is a disease specific to pregnancy that causes 9-10 % of maternal deaths. Early-onset PE (<34 weeks' gestation) is the most dangerous category of PE. Wnt7a and GPR124 (G protein-coupled receptor 124) are widely expressed in the human reproductive process. Especially during embryogenesis and tumorigenesis, Wnt7a plays a crucial role. However, few studies have examined the association between Wnt7a-GPR124 and early-onset PE. The aim of this study was to examine the significance of Wnt7a and GPR124 in early-onset PE as well as Wnt7a's role in trophoblast cells. Immunohistochemistry (IHC), real-time PCR, and western blotting (WB) were used to investigate Wnt7a and GPR124 expression in normal and early-onset PE placentas. Additionally, FACS, Transwell, and CCK-8 assays were used to diagnose Wnt7a involvement in migration, invasion, and proliferation. In the early-onset PE group, Wnt7a and GPR124 expression was significantly lower than in the normal group, especially in the area of syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). A negative correlation was found between Wnt7a RNA and GPR124 expression (r=-0.42, p<0.01). However, the Wnt7a RNA expression level was positive correlated with PE severity. In further cellular functional experiments, knockdown of Wnt7a inhibits HTR8/SVeno cells invasion and migration but has little effect on proliferation and apoptosis. Through the Wnt pathway, Wnt7a regulates trophoblast cell invasion and migration, and may contribute to early-onset preeclampsia pathogenesis. A molecular level study of Wnt7a will be needed to find downstream proteins and mechanisms of interaction.

Bax mRNA Expression as A Potential Biomarker of Placental Apoptosis in Early-onset Preeclampsia

BACKGROUND: Early-onset preeclampsia is characterized by higher oxidative stress and apoptosis level than late-onset one. Studies comparing the expression of the Bcl-2 family protein in early and late-onset preeclampsia are still lacking and show inconclusive evidence. This study aimed to compare the expression of Bax and Bcl-2 messenger RNA (mRNA) as a biomarker of placental apoptosis between early-onset and late-onset preeclampsia.METHODS: A cross-sectional study was conducted using formalin-fixed, paraffin-embedded preeclamptic placental samples and dividing them into early-onset and late-onset preeclampsia groups. Bax and Bcl-2 mRNA expressions were assessed using the quantitative real-time polymerase chain reaction method. Apoptosis was assessed through DNA fragmentation examination by the ligation-mediated real-time polymerase chain reaction method.RESULTS: Thirty early-onset and 30 late-onset preeclamptic placental samples were included. The mean fold change Bax mRNA in early-onset was higher than in late-onset preeclampsia (6.02±3.59 vs. 2.82±1.97; p=0.00). The mean fold change Bcl-2 mRNA early-onset was not different from late-onset preeclampsia (31.20±17.94 vs. 31.01±27.60; p=0.98). The mean DNA fragmentation cycle threshold in early-onset preeclampsia was lower than in late-onset preeclampsia (28.07±0.64 vs. 30.63±0.96; p=0.00). A weak negative correlation exists between fold change Bax mRNA and DNA fragmentation cycle threshold (r=-0.30; p=0.02).CONCLUSION: Bax mRNA showed significant correlation in DNA fragmentation compared to Bcl-2 mRNA; hence, might show more role in apoptotic pathway. Early-onset preeclampsia has higher Bax mRNA relative expression and apoptosis than late-onset preeclampsia. Therefore, Bax mRNA can be potential biomarker in early-onset preeclampsia.KEYWORDS: mRNA, Bax, Bcl-2, apoptosis, DNA fragmentation, early-onset, preeclampsia

Evaluation of first- and third-trimester afamin levels in preeclampsia.

The aim of this study was to investigate serum afamin levels in the first and third trimesters in preeclampsia. Serum samples from 118 patients in the first and third trimesters were analyzed. Serum samples were collected from pregnant women who had enrolled in the first trimester. Blood was then collected from pregnant women who had developed preeclampsia and from healthy controls in the third trimester. The collected blood samples were resolved for analysis, and serum afamin concentrations were measured in the first and third trimesters. Preeclampsia and healthy controls were compared. There was no significant difference between the control and preeclampsia groups in terms of age, body mass index, and smoking. Afamin levels in the first and third trimesters were higher in the preeclampsia group than in the control group (p<0.05). In the subgroup analysis of the preeclampsia group, afamin levels were higher in the early-onset preeclampsia group than in the late-onset preeclampsia group in the first and third trimesters (p<0.05). In the receiver operating characteristic analysis afamin levels were 96.23 ng/mL in the first trimester and 123.57 ng/mL in the third trimester as cut-off values for preeclampsia. Serum afamin levels are useful for predicting preeclampsia in the first trimester in pregnant women and can be used in clinical practice as a supportive biomarker for the diagnosis of preeclampsia in the third trimester. Meta-analyzes are needed to investigate the effect of afamin levels in the prediction and diagnosis of preeclampsia and to determine the cut-off value.

Assessment of maternal serum SERPINC1, E-selectin, P-selectin, and RBP4 levels in pregnancies with early- and late-onset preeclampsia.

To investigate whether the SERPINC1, E-selectin, P-selectin, and RBP4 levels in first trimester maternal serum was associated with the presence of preeclampsia (PE). This cross-sectional study was conducted on 26 women with early-onset preeclampsia (EO-PE), 27 women with late-onset preeclampsia (LO-PE), and 27 women with uncomplicated pregnancies. Levels of serum SERPINC1, E-selectin, P-selectin, and RBP4 were measured with the use of an enzyme-linked immunosorbent assay (ELISA) kit. E-Selectin levels in patients with EO-PE were higher than those with LO-PE and control patients (pE-L =0.025; pE-C =0.000; p < 0.05). There was no significant intergroup difference in terms of P-selectin and RBP4 levels (p > 0.05). SERPINC1 levels were lower in the patients in the with EO-PE group than in those in the LO-PE and the control groups (pE-L =0.000; pE-C =0.000; p < 0.05). In the PE group, there was a negative, moderate (41.7%) correlation between E-selectin level and SERPINC1 (p=0.002; p < 0.05). The receiver operating characteristic (ROC) curve showed that the best cut-off values for E-selectin were 23.14 ng/ml > with 100% sensitivity and 100% specificity. The ROC curve showed that the best cut-off values for SERPINC1 were ≤87.76 ng/ml with 98.1% sensitivity and 96.3% specificity. Of the endothelial damage parameters, E-selectin and SERPINC1 are especially associated with EO-PE. Furthermore, they can be used as potential early diagnosis markers in the prediction of PE.

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.

Integrated Proteomic and N-Glycoproteomic Profiling of Placental Tissues of Patients with Preeclampsia.

Preeclampsia (PE) is a multi-system disorder of pregnancy that poses a serious threat to maternal and perinatal health worldwide. This study aims to evaluate the global alterations of protein expression and N-glycosylations that are crucial for PE pathogenesis. Here, tandem mass tag labeling combined with LC-MS/MS was employed to determine the global expression of all proteins and intact glycopeptide in placentas from three healthy pregnant women, three patients with early-onset severe PE, and three patients with late-onset severe PE. A total of 2260 proteins were quantified across 9 placental tissues, of which 37 and 23 were differentially expressed in the early-onset and late-onset PE groups, compared to the controls. A total of 789 glycopeptides were accurately quantified, which were derived from 204 glycosylated sites in 159 glycoproteins and were modified by 59 N-Linked glycans. A total of 123 differently expressed glycopeptides, which were from 47 glycoproteins were identified among three groups. Through a combined analysis of proteomic and glycoproteomic data, it was found that the changes in 10 glycoproteins were caused by the difference in glycosylation level but not in the protein abundance level. This is the first study to conduct an integrated proteomic and glycoproteomic characterization of placental tissues of PE patients. Our findings suggest that glycosylation modification may affect the molecular function of proteins through changes in the glycosylation structure or the occupancy of glycosylation, which will provide new insights to help elucidating the pathogenic mechanism of PE.

An observational study of pro- and anti-angiogenic factors in hypertensive disorders of pregnancy in women of African ancestry

Hypertensive disorders in pregnancy (HDPs) are the leading cause of maternal and perinatal deaths worldwide. Despite the widely reported multisystemic pathophysiology of pre-eclampsia and other HDPs, it is unknown whether these disorders represent a continuum or separate entities making clinical diagnosis a challenge. This study aimed to investigate angiogenic, metabolic and immunoregulatory specific profiles of hypertensive and gestationally matched normotensive pregnancies. A total of 200 pregnancies from a regional hospital in South Africa, via convenience sampling, were quantitatively analysed for circulating sFlt-1; PlGF; VEGF; sENG; PAPP-A; PP13; ADAMTS 12; TGF-β1 in maternal serum samples using ELISA technique. Serum protein markers TGF-β1, sENG and PAPP-A were significantly increased (p < .05) in early-onset pre-eclampsia vs. NG1 groups. sFlt-1 was significantly higher in late-onset pre-eclampsia vs NG2 groups. The GH group showed a significant increase in TGF-β1 and PAPP-A vs. NG1 counterpart. ADAMTS12 and sENG were significantly lower in gestational hypertension vs. early-onset pre-eclampsia. No significant differences were seen in PlGF, VEGF and PP13 levels across the groups. These changes show the HDP spectrum has distinct characteristics on the angiogenic profile. Based on these results, further validation of diagnostic and prognostic biomarkers of pre-eclampsia and gestational hypertension is warranted. Impact statement What is already known on this subject? Hypertensive pregnancy disorders are a public health problem with adverse effects on both mother and neonate. The elusive pathogenesis of this syndrome combined with the late prevalence of symptoms leaves clinicians with a myriad of theories and indefinite treatments. The investigation into conventional anti-/angiogenic factors has been extensively studied in pre-eclampsia patients only. The overlapping clinical presentation of pre-eclampsia and gestational hypertension further complicates the diagnosis of disorders. What do the results of this study add? The investigation of novel angiogenic, metabolic and inflammatory markers will firstly contribute to generating a database for researchers both nationally and internationally. This combinatory triad of markers will assist in elucidating and differentiating between early- and late-onset preeclampsia versus gestational hypertension. The results of our cohort study suggest possible early diagnostic markers for pre-eclampsia and gestational hypertension. What are the implications of these findings for clinical practice and/or further research? Research in this area will contribute to an improvement in early disease management which will ultimately lead to a reduction in health care costs and mortality rate locally and globally. It will also enforce diagnostic and prognostic markers for hypertensive pregnancy diseases and warrant further investigation into the proteins primarily involved in the trophoblastic invasion. This will then clarify whether these two closely related hypertensive disorders represent a continuum or two separate entities.

Relationship between serum cadherin 6 and 11 levels and severe and early-onset preeclampsia: A pilot study.

Objective:Preeclampsia is a highly morbid disease of placental origin, life-threatening condition for both a pregnant woman and her fetus. Cadherin 6 and 11 are adhesion molecules that play an important role in trophoblastic development and placentation. In our study, we investigated the change in serum cadherin 6 and 11 levels in pregnant women with preeclampsia.Materials and Methods:Pregnant women with preeclampsia were selected and compared with healthy women (as a control group) for a one-year study. The serum alanine aminotransferase, aspartate aminotransferase, and cadherin levels 6 and 11 of participants were analyzed and compared.Results:A total of 189 pregnant women were subdivided into 2 groups as preeclamptic (n=94) and women with healthy pregnancy (n=95). The cadherin 6 and cadherin 11 levels of the preeclamptic patients were significantly higher than those in the control group (p=0.001), and they were found to be significantly higher mainly in patients with early-onset and severe preeclampsia group (p=0.001). The cut-off cadherin 6 and 11 values for severe preeclampsia were found as 98.174 ng/mL and 1.92 ng/mL; with sensitivity of 88.3% and 84% respectively (p=0.001).Conclusion:The data analysis showed elevated serum cadherin 6 and 11 levels associated with the severity and early onset of pre-eclampsia. Serum cadherin 6 and 11 levels can be a candidate marker for the prediction of preeclampsia.

Evaluation of placental growth potential and placental bed perfusion by 3D ultrasound for early second-trimester prediction of preeclampsia.

This study aimed to investigate whether placental parameters measured by three-dimensional ultrasound are associated with preeclampsia (PE) and small-for-gestational-age (SGA). In total, 1163 pregnancies at 11-14weeks of gestation were recruited between October 8, 2020, and April 30, 2021. Placenta volume (PV), placental bed vascularization flow index (PBVFI), and uterine arteries pulse index (UtA-PI) were measured. Placental quotient (PQ = PV/weeks of gestation) was calculated. All participants were re-examined 4weeks later. The placental volume growth rate (PVGR = placental volume difference between the two examinations/interval days) was also calculated. Patients were divided into four groups by the gestational age at the onset of PE and birth weight: early-onset PE (E-PE, n = 18), late-onset PE (L-PE, n = 36), isolated SGA5 (birth weight less than the fifth percentile for gestational age without PE, n = 9), and unaffected (n = 1100) groups. A predictive model for E-PE was established, which consisted of unnatural conception, chronic hypertension, PBVFI (of second examination), and PVGR for E-PE; 94.4% sensitivity and 96.7% specificity by receiver operating characteristic curve analysis. Overall, decreased placental growth potential and low placental bed perfusion in the early second trimester have potential in predicting E-PE.

The role of serum netrin-1 level in the detection of early-onset preeclampsia

ObjectiveTo investigate whether serum netrin-1 levels measured in hypertensive pregnant women could predict the development of early-onset preeclampsia (EOP). MethodsThis prospective observational study was conducted at a single academic medical center between August 1, 2019, and July 31, 2021. The study included patients aged >18 years who presented to our clinic because of gestational hypertension at gestational weeks 20–24 and underwent serum netrin-1 level measurements. All the patients were followed up until delivery for the development of preeclampsia. The patients were divided into two subgroups: those who developed EOP and those who developed late-onset preeclampsia (LOP). ResultsNinety-seven patients and 45 healthy controls were included in the study. EOP and LOP developed in 43 (44.3%) and 54 (55.7%) of the patients, respectively. The mean serum netrin-1 level at the time of presentation was significantly higher in the EOP group than in the control group (916.8 ± 370.5 pg/mL vs 487.7 ± 220.4 pg/mL; p < 0.001). A multivariate logistic regression analysis revealed that high serum netrin-1 level (odds ratio: 6.02, 95% confidence interval [CI]: 2.45–18.20, p = 0.001) was an independent predictor of EOP. Serum netrin-1 levels >784.9 pg/mL predicted the development of EOP with a sensitivity of 72.0% (95% CI: 56.3–84.7%) and specificity of 88.8% (95% CI: 75.9–96.3%). ConclusionHigh serum netrin-1 levels were significantly associated with the development of EOP. The initial serum netrin-1 level may be useful for determining the risk of developing EOP in women with gestational hypertensive disorder.

Correlation between malondialdehyde level and FOXO3 and CASP3 mRNA expression changed in early-onset preeclampsia placenta

Background: Preeclampsia is one of the factors causing the high maternal mortality rate. The risk of morbidity and mortality is higher in Early Onset Preeclampsia (EOPE). Failure of spiral artery remodeling can cause oxidative stress that can inhibit placental development and increase trophoblast apoptosis.&#x0D; Objective: This study aims to analyze the oxidative stress and apoptosis of EOPE placentas.&#x0D; Methods: This study is an observational study with a cross-sectional design. A total of 31 EOPE placentas and 31 normal term placentas were used to measure the concentration of malondialdehyde (MDA) and the relative mRNA expression of FOXO3 and CASP3 using the spectrophotometric and RT-qPCR methods.&#x0D; Results: There was no difference in MDA concentration (p = 0.580) and FOXO3 (p = 0.467) and CASP3 (p = 0.243) mRNA expression in the normal and EOPE groups. There was a strong positive correlation between FOXO3 and CASP3 mRNA expression in the normal (p= 0.0001; r = 0.938) and EOPE groups (p = 0.0001; r = 0.855). There was no correlation between MDA concentration to FOXO3 (p = 0.124; r = 0.282) and CASP3 (p = 0.569; r = 0.106) mRNA expression in normal placenta. There was positive correlation between MDA concentration to FOXO3 (p = 0.016; r = 0.429) and CASP3 mRNA expression in EOPE placenta (p = 0.028; r = 0.395).&#x0D; Conclusion: These results indicate that cell integrity is still maintained through the autophagy process and the level of apoptosis in the EOPE placenta is regulated by ROS through FOXO3.

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.