Early-onset Preeclampsia Research Articles

Construction and evaluation of machine learning-based predictive models for early-onset preeclampsia.

To analyze the influencing factors of early-onset preeclampsia (EOPE). And to construct and validate the prediction model of EOPE using machine learning algorithm. Based on Python system, the data profile of 1040 pregnant women was divided into 80% training set and 20% test set. Logistic regression algorithm, XGBoost algorithm, random forest algorithm, support vector machine algorithm and artificial neural network algorithm were used to construct the EOPE prediction model, respectively, and the resulting model was validated by resampling method. Accuracy, sensitivity, specificity, F1 score, and area under the ROC curve were used to evaluate the resulting models and screen the optimal models. EOPE in pregnant women. The results of binary logistic regression showed that the influencing factors of EOPE included six indicators: pre-pregnancy BMI, number of pregnancies, mean arterial pressure, smoking, alpha-fetoprotein, and methods of conception. Among them, the prediction model of EOPE constructed based on the XGBoost algorithm performed the best in the training and test sets, with an F1 score of 0.554±0.068 and an AUC of 0.963 (95% CI: 0.943∼0.983) in the training set, and an F1 score of 0.488±0.082 and an AUC of 0.936 (95% CI: 0.887∼0.983). Our prediction model for EOPE constructed based on the XGBoost algorithm has superior disease prediction ability and can provide assistance in predicting the disease risk of EOPE.

Relationship between Age and Parity with Late Onset Severe Preeclampsia at PKU Muhammadiyah Surabaya Hospital

Maternal and fetal mortality is 31.15% due to undetected preeclampsia leading to eclampsia. Pre-occurrence of eclampsia is often characterized by severe preeclampsia symptoms such as increased blood pressure, and proteinuria, furthermore, preeclampsia is also divided into 2 types, based on the time of symptom onset, in early-onset type preeclampsia appears at <34 weeks of gestation while for late-onset appears at >34 weeks of gestation. Extreme age and multigravida parity are risk factors for severe preeclampsia. This study aims to determine the relationship between age and parity with late-onset severe preeclampsia. This study used a cross-sectional study design, sampling method used nonprobability sampling techniques with observational analysis on pregnant women diagnosed with preeclampsia at PKU Muhammadiyah Surabaya Hospital for January 2022 - November 2023. The data collection instrument used medical record data, which was analyzed using Chi-Square. In the analysis obtained for the relationship between age and preeclampsia, the large p-value is 0.16 <0.05. The relationship of parity with preeclampsia is 0.004 < 0.05, thus proving a relationship between age and parity with late-onset severe preeclampsia at PKU Muhammadiyah Surabaya Hospital. In conclusion, there is a relationship between age and parity with late-onset severe preeclampsia at PKU Muhammadiyah Surabaya Hospital.

C3AR1 as a target for preeclampsia: from bioinformatics and network pharmacology to experimental validation.

Preeclampsia, characterized by hypertension and proteinuria during pregnancy, poses significant risks to both mother and fetus. The complement system's aberrant activation, notably the C3AR1, is important to the pathogenesis of preeclampsia, although the precise mechanisms are not fully understood. Utilizing the Comparative Toxicogenomics Database (CTD) and Molecular Signatures Database (MSigDB), we identified complement system targets associated with preeclampsia and environmental pollutants. Expression validation was conducted through the Gene Expression Omnibus (GEO) database. Molecular docking predicted interactions between BPA, PFOS, and C3AR1. Immunohistochemical staining of 80 placental tissues (40 early-onset preeclampsia and 40 healthy controls) confirmed C3AR1 expression and its clinical correlation. Integrated bioinformatics analyses revealed C3AR1's role in preeclampsia's molecular mechanisms. Functional verification was assessed by knocking down C3AR1 in HTR-8/Svneo cells, including cell proliferation, invasion, and apoptosis. Network pharmacology established connections between pollutants and preeclampsia, with C3AR1 as a key target. Molecular docking confirmed BPA and PFOS binding to C3AR1. Reduced C3AR1 in preeclamptic placentas correlated with maternal blood pressure, and showed high diagnostic potential (AUC = 0.95). C3AR1's involvement in preeclampsia was linked to Jak-STAT, TGF-β, and HIF-1 pathways, and associated with NK cell and M1 macrophage activity. C3AR1 knockdown in HTR-8/Svneo cells decreased proliferation and invasion, and increased apoptosis. C3AR1 expression is diminished in preeclampsia placental tissues, correlating with disease severity, suggesting its potential as a biomarker. It is crucial for cellular functions and inflammation, with future studies aiming to leverage this for novel preeclampsia treatments. Not applicable.

The Relationship between Soluble Endoglin Levels, Endothelial Nitric Oxide Synthase Levels, and Thrombocyte Count and the Onset of Preeclampsia

Background Early-onset preeclampsia, or EOP, depicts clear placental abnormalities (placental factor), whereas late-onset preeclampsia, or LOP, does not. However, previous studies found varying results on the role of proangiogenic and antiangiogenic factors, including soluble endoglin (sEng), endothelial nitric oxide synthase (eNOS), and thrombocytes in both types of preeclampsia. Objective This study aimed to determine the relationship between sEng levels, eNOS levels, and thrombocyte count with the onset of preeclampsia. Methods A cross-sectional study was conducted on subjects diagnosed with severe preeclampsia receiving treatment at Dr. M. Djamil Hospital Padang from December, 2023, until March, 2024. After meeting the inclusion and exclusion criteria, maternal plasma concentrations of sEng and eNOS were determined by ELISA, while thrombocytes were measured by a complete blood count. Results A total of 40 women with EOP and 40 with LOP participated in this study. This study found no difference between the two groups in eNOS (p = 0.303) and sEng (p = 0.468). However, thrombocyte count differed between early and late-onset PE (p = 0.001). Spearman correlation analysis found a significant correlation between eNOS and sEng (p = 0.033), eNOS and thrombocyte count (p = 0.026), and thrombocyte count and sEng (p = 0.032). Conclusion This study found no difference in proangiogenic and antiangiogenic factors between EOP and LOP, which suggests that a subset of patients with LOP also has an imbalance in the concentrations of proangiogenic and antiangiogenic factors in maternal plasma. However, lower thrombocyte counts in EOP reflect a more severe disease course. This study also found a correlation between eNOS and sEng, eNOS and thrombocyte count, and thrombocyte count and sEng in preeclampsia.

Evaluating the ability of fullPIERS calculator to predict adverse maternal outcomes in pre-eclampsia at Charlotte Maxeke Johannesburg Academic Hospital.

To evaluate the ability of the fullPIERS model to predict adverse maternal outcomes in patients diagnosed as early-onset pre-eclampsia at Charlotte Maxeke Johannesburg Academic Hospital, South Africa. Retrospective record review and analysis of 134 patients admitted with early-onset pre-eclampsia. Demographic data, symptoms, and investigation results relevant to the fullPIERS calculator present on admission were collected. Adverse maternal outcomes occurring before the end of 7 days from admission were recorded. Descriptive analysis was conducted, χ2 and Wilcoxon rank-sum tests were used to evaluate the association between fullPIERS parameters, score, and adverse outcomes. Performance of fullPIERS score was evaluated by positive and negative predictive values, sensitivity, specificity, and receiver operating curve analysis. The median age was 34 years (interquartile range [IQR] 28-37 years). A total of 131 deliveries were recorded at a median gestation of 31 weeks (IQR 29-33 weeks). Most deliveries (71; 54.2%) were due to fetal indications and 102 (77.9%) were by cesarean section. A total of 20 (15.1%) patients had adverse maternal outcomes. Three (2.6%) neonates were delivered with Apgar score less than 7 at 5 minutes and were all admitted to the neonatal intensive care unit. FullPIERS formula predicted adverse maternal outcomes with positive and negative predictive values of 100% and 94.9%, respectively, and sensitivity and specificity of 70% and 100%, respectively. The area under the receiver operating characteristic curve was 0.88 (95% confidence interval 0.75-0.95), which shows good discrimination. FullPIERS model is a useful adjunct in identifying patients at high risk of adverse outcomes from early-onset pre-eclampsia; this allows timely and appropriate management.

SerumFoxO1 and SIRT2 concentrationsin healthy pregnant women and complicated by preeclampsia.

Sirtuins and FoxO1 are reported to be important in the pathophysiology of preeclampsia. This study aimed to investigate whether serum FoxO1 and SIRT2 concentrations differ between preeclampsia and normal pregnancy and also to compare these markers in early- and late-onset preeclampsia. This cross-sectional study was conducted on 27 women with early-onset preeclampsia, 27 women with late-onset preeclampsia, and 26 healthy normotensive pregnant controls. Maternal serum levels of FoxO1 and SIRT2 were measured with the use of an enzyme-linked immunosorbent assay kit. The mean maternal serum FoxO1 levels were significantly lower both in early-onset (9.1 ± 3.8 vs. 29.1 ± 3.2, p < 0.001) and late-onset preeclampsia (2.6 ± 1.6 vs. 29.1 ± 3.2, p < 0.001) than the normotensive pregnancies. The mean maternal serum FoxO1 level of late-onset preeclampsia was significantly lower than the early-onset preeclampsia group (2.6 ± 1.6 vs. 9.1 ± 3.8, p < 0.001). The mean maternal serum SIRT2 levels were significantly lower both in early-onset (4.5 ± 2.1 vs. 6.3 ± 0.9, p < 0.001) and late-onset preeclampsia (2.1 ± 0.6 vs. 6.3 ± 0.9, p < 0.001) than the healthy pregnancies. FoxO1 and SIRT2 may be biomarkers for early detection of preeclampsia and potential therapeutic targets in the pathophysiology of preeclampsia.

Predictive value of platelet parameters for early-onset pre-eclampsia: A prospective cohort study in a teaching institution in Gujarat, India

ABSTRACT Background: Early-onset pre-eclampsia is associated with severe maternal and perinatal complications. Identifying novel biomarkers for early prediction is crucial for timely intervention and improved outcomes. This study aimed to evaluate the predictive value of platelet parameters, namely mean platelet volume (MPV), platelet distribution width (PDW), and platelet count (PC), for early-onset pre-eclampsia. Methods: A prospective cohort study was conducted at a tertiary care hospital in Gujarat, India. Pregnant women (n = 712) between 14 and 18 weeks of gestation were enrolled and followed up until delivery. MPV, PDW, and PC were measured at enrollment. The primary outcome was the development of early-onset pre-eclampsia (&lt;34 weeks). Receiver operating characteristic (ROC) curves were used to evaluate the predictive value of platelet parameters. Results: The prevalence of early-onset pre-eclampsia was 5.3%. Women who developed early-onset pre-eclampsia had significantly higher MPV and PDW and lower PC at 14–18 weeks compared to those who remained normotensive. The combination of MPV &gt; 10.2 fL, PDW &gt; 16.5 fL, and PC &lt; 180 × 103/µL had the highest predictive value (AUC: 0.951, sensitivity: 71.1%, specificity: 99.1%). Individual platelet parameters also demonstrated good predictive ability. Conclusion: Platelet parameters, particularly MPV, PDW, and PC, measured at 14–18 weeks of gestation, have good predictive value for early-onset pre-eclampsia. Incorporating these parameters into routine antenatal screening could improve the early identification of at-risk women. Further research is needed to validate these findings and evaluate the cost-effectiveness of implementation.

Single-nuclei RNA-sequencing fails to detect molecular dysregulation in the preeclamptic placenta.

Single-cell RNA-seq (scRNA-seq) revolutionized our understanding of tissue complexity in health and disease and revealed massive transcriptional dysregulation across placental cell classes in early-onset, but not late-onset preeclampsia (PE). However, the multinucleated syncytium is largely inaccessible to cell dissociation. Nuclei isolation and single-nuclei RNA-seq may be preferable in the placenta; not least considering compatibility with long-term tissue storage. Yet, nuclei contain a subsample of the cells' transcriptional profile. Mature transcripts critical to cellular function and disease may be missed. We analyzed placenta from pregnancies using single-cell and single-nuclei RNA-seq. The datasets comprise 45,836cells and 27,078 nuclei, from 10 to 7 early-onset preeclampsia (EPE) cases and 3 and 2 early idiopathic controls (ECT), respectively. We compared the methods' sensitivities, cell type detection, differential gene expression in PE, and performed histological validations. Mature syncytiotrophoblast were sampled ∼50x more efficiently after nuclei extraction. Yet, scRNA-seq was more sensitive in detection of genes, molecules and mature transcripts. In snRNA-seq, nuclei of all placental cell classes suffered ambient trophoblast contamination. Transcripts from extravillous trophoblast, stroma, vasculature and immune cells were profiled less comprehensively by single-nuclei RNA-seq (snRNA-seq), restricting cell-type detection. In EPE, we found dysregulation of angiogenic actors FLT1/PGF both in prefused syncytiotrophoblast after cell extraction, and mature syncytiotrophoblast after nuclei isolation. Disease-related stress and inflammation were undetected from nuclei. scRNA-seq has important advantages over snRNA-seq for comprehensive transcriptomics studies of the placenta, especially to understand cell-type resolved dysregulation in pathologies. Yet, to address the dilemma of an underrepresented syncytium, studies benefit from complementary nuclei extraction.

The potential of repeated mean arterial pressure measurements for predicting early- and late-onset pre-eclampsia in twin pregnancies: Prediction model study.

To investigate the contribution of longitudinal mean arterial pressure (MAP) measurement during the first, second, and third trimesters of twin pregnancies to the prediction of pre-eclampsia. A retrospective cohort study was conducted on women with twin pregnancies. Historical data between 2019 and 2021 were analyzed, including maternal characteristics and mean artery pressure measurements were obtained at 11-13, 22-24, and 28-33 weeks of gestation. The outcome measures included pre-eclampsia with delivery <34 and ≥34 weeks of gestation. Models were developed using logistic regression, and predictive performance was evaluated using the area under the curve, detection rate at a given false-positive rate of 10%, and calibration plots. Internal validation was conducted via bootstrapping. A total of 943 twin pregnancies, including 36 (3.82%) women who experienced early-onset pre-eclampsia and 93 (9.86%) who developed late-onset pre-eclampsia, were included in this study. To forecast pre-eclampsia during the third trimester, the most accurate prediction for early-onset pre-eclampsia resulted from a combination of maternal factors and MAP measured during this trimester. The optimal predictive model for late-onset pre-eclampsia includes maternal factors and MAP data collected during the second and third trimesters. The areas under the curve were 0.937 (95% confidence interval [CI] 0.894-0.981) and 0.887 (95% CI 0.852-0.921), respectively. The corresponding detection rates were 83.33% (95% CI 66.53%-93.04%) for early-onset pre-eclampsia and 68.82% (95% CI 58.26%-77.80%) for late-onset pre-eclampsia. Repeated measurements of MAP during pregnancy significantly improved the accuracy of late-onset pre-eclampsia prediction in twin pregnancies. The integration of longitudinal data into pre-eclampsia screening may be an effective and valuable strategy.

Prediction of perinatal mortality in early-onset fetal growth restriction: A post hoc analysis of the Dutch STRIDER trial to predict perinatal mortality in early-onset fetal growth restriction

ObjectiveEarly-onset fetal growth restriction affects about 0.3% of pregnancies, posing high perinatal risks due to placental insufficiency. Early-onset fetal growth restriction often coincides with early-onset pre-eclampsia, associated with significant mortality and morbidity. Clinical management varies among clinicians, with emphasis on intensive monitoring and timely delivery. Our objective was to improve clinical prediction of perinatal mortality in early-onset fetal growth restriction for parental counseling. Study designThis was a secondary analysis of prospective cohort data from the Dutch STRIDER trial. The study included 215 pregnant women diagnosed with severe early-onset fetal growth restriction between 20 + 0 and 29 + 6 weeks of gestation, from tertiary and secondary antenatal care centers in The Netherlands. Maternal and fetal characteristics were collected at inclusion, including sonographic and laboratory measurements. Analysis was performed using univariable and multivariable binary logistic regression to create a prediction model for perinatal mortality. The main outcome measures were fetal demise and neonatal mortality up to discharge. Results215 Participants were included for this analysis. Perinatal mortality occurred in 84 (39 %) cases; 51 (24 %) were fetal and 33 (15 %) neonatal. Fetal abdominal circumference, gestational age at diagnosis, estimated fetal weight Multiple of Median, absent or reversed end-diastolic flow of the umbilical artery, umbilical artery pulsatility index Multiple of Median, non-Caucasian ethnicity, male sex, placental growth factor level and uterine artery pulsatility index were independent predictors of perinatal mortality. Randomization allocation (sildenafil or placebo) had no predictive value for mortality. The prediction model including gestational age at diagnosis, estimated fetal weight Multiple of Median and umbilical artery pulsatility index Multiple of Median showed an area under the receiver operating characteristic curve of 0.840 (P < 0.01). Placental growth factor was measured in a subset of patients and was an independent prognostic factor and performed significantly better within the predictive model, however it did not improve the predictive value of the model. ConclusionsPrediction of perinatal mortality in early-onset fetal growth restriction is feasible with commonly available tests and measurements and could support decision making in management of pregnancy. However, implementation in practice requires further studies.

Evaluation of Uterine Artery Impedance at Gestational Age 16 to 20 weeks and its Relationship with Early-Onset Preeclampsia

Evaluation of Uterine Artery Impedance at Gestational Age 16 to 20 weeks and its Relationship with Early-Onset Preeclampsia

Allostatic Load and Oxidative Stress Markers in Women With Early- and Late-Onset Preeclampsia.

Allostatic load and oxidative stress (OS) markers differ in women with and without preeclampsia. However, there is no difference in allostatic load and OS markers between late-onset preeclampsia (L-OP) and early-onset preeclampsia (E-OP). This study aimed to compare the concentrations of allostatic load and OS markers in pregnant women with L-OP and E-OP. This was a comparative cross-sectional study. Women with single pregnancy and a diagnosis of preeclampsia were included. Women with multiple pregnancies and/or chronic hypertension were excluded. Group 1 included women with E-OP (n=16), Group 2 included women with L-OP (n=45), and Group 3 included women without preeclampsia (n=40). No statistical differences were found in maternal age, body mass index, or number of gestations. Arginase levels were higher in Group 1 compared to Group 2 (p = 0.04) and Group 1 compared to Group 3 (p = 0.01). Total antioxidative capacity was higher in Group 1 compared to Group 2 (p = 0.03) and Group 1 compared to Group 3 (p = 0.001). Malondialdehyde levels were higher in Group 1 compared to Group 2 (p = 0.001) and Group 1 compared to Group 3 (p = 0.001). Total sulfhydryl compounds were lower in Group 1 compared to Group 2 (p = 0.01) and Group 1 compared to Group 3 (p = 0.001). No differences were observed between study groups in allostatic load markers. Higher levels of OS markers were found in women with E-OP compared to women with L-OP and controls.

Genetic thrombophilia and antiphospholipid antibodies in women with early and late preeclampsia: a retrospective cohort study

Aim: to study a pattern of genetic and acquired thrombophilia in pregnant women with severe early-onset (eoPЕ) and severe late-onset PE (loPЕ) preeclampsia (PE).Materials and Methods. A retrospective cohort study was conducted from January 2022 to May 2024. A total of 109 pregnant women were examined: group 1 – 45 women with eoPЕ (&lt; 34 weeks of pregnancy), group 2 – 24 women with loPЕ (≥ 34 weeks of pregnancy), group 3 (control) – 40 women with physiologically uncomplicated pregnancy. All pregnant women were examined for lupus anticoagulant (LA) and antiphospholipid antibodies (aPL). The screening test for aPL included the quantitation of IgG/IgM antibodies against cardiolipin, phosphatidylserine, phosphatidylinositol, phosphatidic acid, and β2-glycoprotein 1 in serum or plasma using an enzyme immunoassay. Genetic thrombophilia, homocysteine, and ADAMTS-13 metalloproteinase (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) levels were also determined.Results. Pregnant women with severe PE more often had genetic forms of thrombophilia (mutations in factor (F) V Leiden gene, prothrombin G20210A, and Thr165Met) and a deficiency of natural anticoagulants (antithrombin and protein S) compared to pregnant women in control group. Women in eoPE vs. loPE group were more often found to carry genetic polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) and fibrinogen genes. Also, in the group of pregnant women with eoPE, the circulation of aPL, ADAMTS-13 inhibitor, and elevated homocysteine levels were more common. Pregnant women with loPE were older and more often suffered from hypertension, diabetes mellitus, and excess body weight. No significant differences between eoPЕ and loPЕ groups were found while comparing prevalence of autoimmune diseases, thrombosis in familial history, mutations in FV Leiden gene (heterozygous form), FII prothrombin gene G20210A (homozygous form), FII prothrombin gene Thr165Met (heterozygous form), antithrombin III deficiency, protein S deficiency.Conclusion. Precise causes underlying PE remain unknown, and we are still far from understanding all the molecular, immunological, genetic, and environmental mechanisms that lead to the various clinical manifestations of placental syndromes including PE. However, the study results suggest that the presence of thrombophilic disorders, especially in the fibrinolytic system, and aPL circulation contribute to eoPE pathophysiology or progression.

Exploring the Lifeline: Unpacking the Complexities of Placental Vascular Function in Normal and Preeclamptic Pregnancies.

The proper development and function of the placenta are essential for the success of pregnancy and the well-being of both the fetus and the mother. Placental vascular function facilitates efficient fetal development during pregnancy by ensuring adequate gas exchange with low vascular resistance. This review focuses on how placental vascular function can be compromised in the pregnancy pathology preeclampsia, and conversely, how placental vascular dysfunction might contribute to this condition. While the maternal endothelium is widely recognized as a key focus in preeclampsia research, this review emphasizes the importance of understanding how this condition affects the development and function of the fetal placental vasculature. The placental vascular bed, consisting of microvasculature and macrovasculature, is discussed in detail, as well as structural and functional changes associated with preeclampsia. The complexity of placental vascular reactivity and function, its mediators, its impact on placental exchange and blood distribution, and how these factors are most affected in early-onset preeclampsia are further explored. These factors include foremost lipoproteins and their cargo, oxygen levels and oxidative stress, biomechanics, and shear stress. Challenges in studying placental pathophysiology are discussed, highlighting the necessity of innovative research methodologies, including ex vivo experiments, in vivo imaging tools, and computational modeling. Finally, an outlook on the potential of drug interventions targeting the placental endothelium to improve placental vascular function in preeclampsia is provided. Overall, this review highlights the need for further research and the development of models and tools to better understand and address the challenges posed by preeclampsia and its effects on placental vascular function to improve short- and long-term outcomes for the offspring of preeclamptic pregnancies. © 2024 American Physiological Society. Compr Physiol 14:5763-5787, 2024.

Stem Cell Markers LGR5, LGR4 and Their Immediate Signalling Partners are Dysregulated in Preeclampsia.

Leucine-rich repeat-containing G protein-coupled receptors 5/4 (LGR5/LGR4) are critical stem cell markers in epithelial tissues including intestine. They agonise wingless-related integration site (WNT) signalling. Until now, LGR5/LGR4 were uncharacterised in placenta, where analogous functions may exist. We characterised LGR5/LGR4, their ligands/targets in human placenta, with further assessments on dysregulation in preeclampsia/fetal growth restriction (FGR). LGR5 mRNA was unaltered in first trimester (n = 11), preterm (n = 9) and term (n = 11) placental lysate. LGR5 was enriched in human trophoblast stem cells (hTSCs) and downregulated with differentiation to extravillous trophoblasts (p < 0.0215) and syncytiotrophoblasts (p < 0.0350). In situ hybridisation localised LGR5 to unique, proliferative MKI67 + mononuclear trophoblasts underlying syncytium which concurred with proposed progenitor identities in single-cell transcriptomics. LGR5 expression was significantly reduced in placentas from early-onset preeclampsia (p < 0.0001, n = 81 versus n = 19 controls), late-onset preeclampsia (p = 0.0046, n = 20 versus n = 33 controls) and FGR (p = 0.0031, n = 34 versus n = 17 controls). LGR4 was elevated in first trimester versus preterm and term placentas (p = 0.0412), in placentas with early-onset preeclampsia (p = 0.0148) and in FGR (p = 0.0417). Transcriptomic analysis and in vitro hTSC differentiation to both trophoblast lineages suggested LGR4 increases with differentiation. Single-nucleus RNA sequencing of placental villous samples supported LGR5 and LGR4 localisation findings. Hypoxia/proinflammatory cytokine treatment modelling elements experienced by the placenta in placental insufficiency pathogenesis did not significantly alter LGR5/LGR4. Ligands R-spondins 1/3/4, and neutralising targets ring finger protein 43 (RNF43) and zinc and ring finger 3 (ZNRF3) were also reduced in placentas from preeclamptic pregnancies. This study is the first to describe LGR5/LGR4 and their signalling partner expression in human placenta. Their dysregulations in the preeclamptic placenta allude to disruptions to integral trophoblast stem cell function/differentiation that may occur during placental development related to WNT signalling.

Maternal serum apelin-13 levels in early- and late-onset preeclampsia.

To assess whether alterations in maternal serum apelin-13 levels differ between early-onset preeclampsia (EO-PE) and late-onset preeclampsia (LO-PE). A prospective case-control study included 90 preeclamptic cases and 90 normotensive healthy pregnant women as controls. Preeclampsia cases were subclassified as EO-PE and LO-PE. Blood samples were collected, centrifuged, and the separated serum was stored at -80°C for further testing. Ethylenediamine tetraacetic acid blood was used for complete blood count. Serum sample was used for analysis of biochemical parameters. Maternal serum apelin-13 concentrations were measured using ELISA. Demographic details and fetal outcomes were recorded. Results indicated significantly lower gestational age at sampling and delivery in preeclampsia cases. Blood pressure (systolic, diastolic, and mean arterial pressure) was elevated in preeclampsia. Maternal serum apelin-13 levels (261.7±110.6 pg/mL) were significantly reduced in preeclamptic cases compared to controls (575.3±164.7 pg/mL). Adverse fetal outcomes were more prevalent in preeclampsia. Regarding EO-PE and LO-PE, gestational age at sampling and delivery was lower in EO-PE compared to LO-PE. Maternal serum apelin-13 levels (371.3±116.0 pg/mL) were higher in EO-PE. A 40.9% reduction in apelin-13 levels was observed in LO-PE compared to EO-PE, indicating a gradual reduction in apelin-13 levels in preeclampsia. Adverse fetal outcomes, such as birth weight (1.8±0.5 kg), were lower, and other adverse outcomes were higher in EO-PE compared to LO-PE. Circulating serum apelin-13 concentration was reduced in preeclampsia and was higher in EO-PE than in LO-PE. Apelin-13 serves as a potential indicator for discriminating early-onset preeclampsia.

In vitro examination of Piezo1-TRPV4 dynamics: implications for placental endothelial function in normal and preeclamptic pregnancies.

Mechanosensation is essential for endothelial cell (EC) function, which is compromised in early-onset preeclampsia (EPE), impacting offspring health. The ion channels Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) are coregulated mechanosensors in ECs. Current evidence suggests that both channels could mediate aberrant placental endothelial function in EPE. Using isolated fetoplacental ECs (fpECs) from early control (EC) and EPE pregnancies, we show functional coexpression of both channels and that Ca2+ influx and membrane depolarization in response to chemical channel activation is reduced in EPE fpECs. Downstream of channel activation, Piezo1 alone can induce phosphorylation of endothelial nitric oxide synthase (eNOS) in fpECs, while combined activation of Piezo1 and TRPV4 only affects eNOS phosphorylation in EPE fpECs. Additionally, combined activation reduces the barrier integrity of fpECs and has a stronger effect on EPE fpECs. This implies altered Piezo1-TRPV4 coregulation in EPE. Mechanistically, we suggest this to be driven by changes in the arachidonic acid metabolism in EPE fpECs as identified by RNA sequencing. Targeting of Piezo1 and TRPV4 might hold potential for EPE treatment options in the future.NEW & NOTEWORTHY This study shows Piezo-type mechanosensitive ion channel component 1 (Piezo1) and transient receptor potential cation channel subfamily V member 4 (TRPV4) coexpression and functionality within primary human fetoplacental endothelial cells (fpECs), mediating nitric oxide (NO) production and barrier integrity. In early-onset preeclampsia (EPE), fpEC channel functionality and coregulation are impaired, affecting Ca2+ signaling and endothelial barrier function. Combined channel activation significantly reduces endothelial barrier integrity and increases NO production in EPE. Changes in arachidonic acid metabolism are suggested as a key underlying factor mediating impaired channel functionality in EPE fpECs.

Role of routine uterine artery Doppler at 18-22 and 24-28 weeks' gestation following routine first-trimester screening for pre-eclampsia.

To assess the performance of mean uterine artery pulsatility index (UtA-PI) at 18-22 and 24-28 weeks of gestation in the prediction of pre-eclampsia (PE) and small-for-gestational age (SGA), and its role in reassessing the risk of PE and SGA in pregnancies screened for PE in the first trimester. This was a retrospective observational cohort study of 4464 women with singleton pregnancy screened routinely for PE in the first trimester, using the Gaussian algorithm, from March 2019 to May 2021, and who underwent UtA-PI assessment at 18-22 gestational weeks. Women were categorized as low risk or high risk based on the risk index obtained after first-trimester screening for PE. In high-risk patients, UtA-PI was also assessed at 24-28 weeks of gestation. Sensitivity, specificity, positive predictive value, negative predictive value (NPV), positive likelihood ratio, negative likelihood ratio and area under the receiver-operating-characteristics curve were calculated to assess the performance of UtA-PI at 18-22 and 24-28 weeks in predicting PE and SGA in the high-risk group. In all participants, different UtA-PI percentiles at 18-22 or 24-28 weeks, or their combination, were analyzed to explore their role in reassessing the risk of PE and SGA following first-trimester PE screening. The performance of UtA-PI at 18-22 and 24-28 weeks in the high-risk group was good for predicting preterm PE and preterm SGA, and excellent for predicting early-onset PE and early-onset SGA, with an NPV of > 97% for all outcomes. In the low-risk group, UtA-PI ≥ 95th percentile at 18-22 weeks' gestation identified a subgroup of pregnancies with a significantly higher risk of preterm SGA compared to the low-risk group. In the high-risk group, UtA-PI < 60th percentile at 18-22 weeks' gestation, UtA-PI < 85th percentile at 24-28 weeks' gestation, and UtA-PI < 85th percentile at 24-28 weeks' gestation in women with UtA-PI ≥ 60th percentile at 18-22 weeks, identified subgroups of pregnancies with a risk of PE and SGA comparable to that of the low-risk group. The performance of UtA-PI at 18-22 and 24-28 gestational weeks in high-risk pregnancies identified during first-trimester screening for PE is similar to that in the general population. The risk of PE and SGA in a high-risk cohort can be reassessed by measuring UtA-PI at 18-22 weeks, 24-28 weeks or both, allowing adjustment of follow-up, particularly de-escalation of care. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Impact of inter-twin growth discordance on preeclampsia: based on ultrasonic estimated fetal weight.

A retrospective cohort study with 4396 twins who registered before 13 gestational weeks and delivered between January 2013 and December 2020 at Shanghai First Maternity and Infant Hospital, China, was conducted to clarify causal associations between inter-twin estimated fetal weight discordance and preeclampsia. Ultrasound measurements of fetal biometry were collected until the confirmation of preeclampsia diagnosis or the termination of pregnancy (when preeclampsia did not occur). Inter-twin discordance was divided into binary variables using cut-offs of 10%, 15%, and 20%. The associations between inter-twin discordance and preeclampsia were analyzed using generalized estimating equations and group-based trajectory modeling methods. The incidence of preeclampsia was 13.9%, among which 21.8% of cases were diagnosed at early onset and 55.3% at a severe stage. Inter-twin discordance based on estimated fetal weight during pregnancy was positively associated with preeclampsia. The associations were robust and constant by treating the discordance as continuous and binary. Two groups, the stable trajectory group, including 92% of participants, and the changing trajectory group, including 8% of participants, were divided according to the group-based trajectory models. Compared with the stable trajectory group, the risk of developing preeclampsia in the changing trajectory group increased by 50.3% (OR = 1.502, 95%CI: 1.073, 2.105). Subgroup analysis showed positive association primarily in early-onset preeclampsia (OR: 3.859, CI: 2.293, 6.494) and severe preeclampsia (OR: 1.896, CI: 1.264, 2.844) subgroups. These findings can provide a direction to reduce the incidence of preeclampsia in twin pregnancies, considering growth discordance as a high-risk factor in clinical practice.

Methylation and expression of imprinted genes in circulating extracellular vesicles from women experiencing early onset preeclampsia

Preeclampsia (PE) is a pregnancy complication marked by high blood pressure, posing risk to maternal and fetal health. "Genomic imprinting", an epigenetic phenomenon regulated by DNA methylation at Differently Methylated Regions (DMR's), influences placental development. Research on circulating extracellular vesicles (EVs) in PE suggests them as potential source for early biomarkers, but methylation status of EV-DNA in Preeclampsia is not reported yet. This study examines the methylation and expression profile of imprinted genes - PEG10, PEG3, MEST, and DLK1 in circulating EVs of 1st and 3rd trimester control and early onset preeclampsia (EOPE) pregnant women (n=15) using pyrosequencing and qRT-PCR respectively. In 1st trimester, PEG3 was significantly hypermethylated, whereas no significant methylation changes were noted in PEG10 and MEST in EOPE. In 3rd trimester, significant hypomethylation in PEG10, PEG3 and IGDMR was observed whereas significant hypermethyaltion noted in MEST. mRNA expression of PEG10, PEG3 and DLK1 was not affected in circulating EVs of 1st trimester EOPE. However, in 3rd trimester significant increased expression in PEG10, PEG3 and DLK1 noted. MEST expression was reduced in 3rd trimester EOPE. No correlation was observed between average DNA methylation and gene expression in PEG10 and PEG3 in 1st trimester. However, in 3rd trimester, significant negative correlation was noted in PEG10 (r=-0.426, p=0.04), PEG3 (r=-0.496, p=0.01), MEST (r=-0.398, p=0.03) and DLK1 (r=-0.403, p=0.03). The results of our study strengthen the potential of circulating EVs from maternal serum as non-invasive indicators of placental pathophysiology, including preeclampsia.