Etiology Of Preeclampsia Research Articles

Effects of Xenobiotic Compounds on Preeclampsia and Potential Mechanisms.

Preeclampsia (PE) refers to a disease with new hypertension and albuminuria or other end-organ damage after 20 weeks of pregnancy. As a major complication of pregnancy, PE can increase the morbidity and mortality of pregnant women and fetuses and cause serious social burden. Recently, it has been found that exposure to xenobiotic compounds, especially endocrine disruptors in the environment, may contribute to the development of PE. However, the underlying mechanism is still unclear. It is generally believed that PE is related to placental dysplasia, spiral artery remodelling failure, oxidative stress, etc. Therefore, in order to better prevent the occurrence of PE and reduce the damage and impact on mother and fetus, this paper reviews the role and potential mechanism of PE induced by exogenous chemicals and provides an outlook on the environmental etiology of PE.

Amalgamation of Toll-Like Receptor and Hypoxic Signaling in Etiology of Preeclampsia.

Inflammation and oxidative stress are involved in the pathogenesis of preeclampsia. Therefore, the aim of this study was to investigate the expression of Toll-like receptor (TLR) (TLR-4, HMGB1, NFκB, IκBα) and hypoxic (HIF-1α, HIF-1β, PHD, pVHL) pathway proteins in the placenta of preeclamptic pregnant women after 28 weeks of gestational period. A possible association between these 2 pathways was also explored. A total of 194 placental tissues of preeclamptic as well as healthy pregnant women were analyzed by immunohistochemistry. On the basis of gestational age, the samples were divided into 2 groups, I (28-36wk) and II (36wk onwards), with 55 and 139 samples in the respective groups. The expression of both TLR (TLR-4, HMGB1, NFκB, IκBα) and hypoxic (HIF-1α, HIF-1β, PHD, pVHL) pathway proteins were significantly modulated in the placental tissues of preeclampsia as compared with control. The 2 pathways were interlinked in preeclampsia. This study highlights the intercorrelation of both TLR and hypoxic signalling pathways that may be a causative factor for the pathophysiology of preeclampsia.

A theoretical model of dietary lipid variance as the origin of primary ciliary dysfunction in preeclampsia.

Serving as the cell's key interface in communicating with the outside world, primary cilia have emerged as an area of multidisciplinary research interest over the last 2decades. Although the term "ciliopathy" was first used to describe abnormal cilia caused by gene mutations, recent studies focus on abnormalities of cilia that are found in diseases without clear genetic antecedents, such as obesity, diabetes, cancer, and cardiovascular disease. Preeclampsia, a hypertensive disease of pregnancy, is intensely studied as a model for cardiovascular disease partially due to many shared pathophysiologic elements, but also because changes that develop over decades in cardiovascular disease arise in days with preeclampsia yet resolve rapidly after delivery, thus providing a time-lapse view of the development of cardiovascular pathology. As with genetic primary ciliopathies, preeclampsia affects multiple organ systems. While aspirin delays the onset of preeclampsia, there is no cure other than delivery. The primary etiology of preeclampsia is unknown; however, recent reviews emphasize the fundamental role of abnormal placentation. During normal embryonic development, trophoblastic cells, which arise from the outer layer of the 4-day-old blastocyst, invade the maternal endometrium and establish extensive placental vascular connections between mother and fetus. In primary cilia of trophoblasts, Hedgehog and Wnt/catenin signaling operate upstream of vascular endothelial growth factor to advance placental angiogenesis in a process that is promoted by accessible membrane cholesterol. In preeclampsia, impaired proangiogenic signaling combined with an increase in apoptotic signaling results in shallow invasion and inadequate placental function. Recent studies show primary cilia in preeclampsia to be fewer in number and shortened with functional signaling abnormalities. Presented here is a model that integrates preeclampsia lipidomics and physiology with the molecular mechanisms of liquid-liquid phase separation in model membrane studies and the known changes in human dietary lipids over the last century to explain how changes in dietary lipids might reduce accessible membrane cholesterol and give rise to shortened cilia and defects in angiogenic signaling, which underlie placental dysfunction of preeclampsia. This model offers a possible mechanism for non-genetic dysfunction in cilia and proposes a proof-of-concept study to treat preeclampsia with dietary lipids.

Association between angiotensin converting enzyme gene polymorphism (rs4343) and susceptibility to gestational hypertension and preeclampsia in pregnant women

Hypertension is the most frequent medical complication of pregnancy, and the most severe clinical presentation of hypertensive disorders of pregnancy (HDP) is preeclampsia (PE). PE is a condition significantly associated with maternal and perinatal morbidity and mortality. The etiology of PE remains unknown. However, it has been found that genetic factors cause a defective immune adaptation, which in turn leads to inadequate trophoblast invasion and inappropriate placenta development. This study involved 30 patients with gestational hypertension (GH), 30 patients with PE and 30 normotensive pregnant women as controls. We aimed to evaluate the association between the angiotensin-converting enzyme (ACE) gene polymorphism (rs4343) and susceptibility to GH and PE. Genotyping for rs4343 polymorphism was performed by real-time polymerase chain reaction. The differences of genotypes and allele frequencies were analyzed as well as the relationship between ACE polymorphism and susceptibility to PE. The GG genotype of ACE gene rs4343 and G allele frequency were significantly associated with increased risk of PE [OR (95% CI) 10.3125 (2.1043 to 50.5388), p=0.004 and OR (95% CI) 3.4714 (1.6352 to 7.3697), p = 0.001, respectively]. Also, G allele frequency was significantly associated with severity of PE [OR (95% CI) 15.5455 (1.8938 to 127.6075), p = 0.011]. However, the GG genotype and G allele frequency were not associated with GH. In conclusion, ACE rs4343 polymorphism may be associated with PE susceptibility and severity but not with GH.

16 Cross-ancestry analysis of preeclampsia identifies novel maternal susceptibility loci

OBJECTIVES/GOALS: Preeclampsia (PE) is a hypertensive disorder of pregnancy, affecting 5 - 7% of pregnancies worldwide. A major cause of morbidity and mortality, PE is also associated with subsequent adverse health outcomes, including long-term increased risk of cardiovascular disease. The genetics conferring increased risk for PE are incompletely understood. METHODS/STUDY POPULATION: We performed a cross-ancestry, fixed-effects meta-analysis, incorporating both published and unpublished genome-wide association study (GWAS) summary statistics. In addition to publicly available summary statistics from two prior studies, we generated GWAS data from three electronic health record biobanks (BioVU, eMERGE, and PMBB). In total, we utilized data from 359,378 individuals (4,411 cases and 354,967 controls). Leveraging this large-scale biobank data importantly allows for detection of complex factors contributing to the diverse etiology of PE. Cases across cohorts were defined using PE-specific ICD-9/ICD-10 codes and phecodes. Cohorts included pregnant individuals of self-identified non-Hispanic Black, non-Hispanic White, and East Asian ancestry. RESULTS/ANTICIPATED RESULTS: 2 of 20,204,625 loci achieved genome-wide significance (p < 5 × 10–8) when minor allele frequency was limited to common variants (>0.01). The most significant locus was rs138180605 (p = 1.77 × 10–8), located in an intergenic region between FGFR2 and ATE1, both previously associated with breast cancer. The other significant locus was rs137895377 (p = 2.33 × 10–8), located in an intronic region of PLEKHO1. Another 225 loci achieved suggestive significance (p < 1 × 10–5). 203 loci could be mapped to 109 unique genes, some previously associated with related phenotypes such as hypertension. Next steps will focus on functional analyses, including genetically predicted gene expression incorporating placental tissue, followed by construction of a PE polygenic risk score to demonstrate predictive utility of results. DISCUSSION/SIGNIFICANCE: This work has contributed to the limited body of knowledge surrounding maternal genetic susceptibility to PE by identifying several loci warranting further investigation. Further work will expand on these results to improve understanding of genetic factors and clarify clinical risk of disease.

A mathematical model of vascular and hemodynamics changes in early and late forms of preeclampsia.

Preeclampsia-eclampsia syndrome is a leading cause of maternal mortality. The precise etiology of preeclampsia is still not well-defined and different forms exist, including early and late forms or preeclampsia, which may arise via distinctly different mechanisms. Low-dose aspirin administered at the end of the first trimester in women identified as high risk has been shown to reduce the incidence of early, but not late, preeclampsia; however, current risk factors show only fair predictive capability. There is a pressing need to develop accurate descriptions for the different forms of preeclampsia. This paper presents 1D fluid, solid, growth, and remodeling models for pregnancies complicated with early and late forms of preeclampsia. Simulations affirm a broad set of literature results that early forms of preeclampsia are characterized by elevated uterine artery pulsatility index (UA-PI) and total peripheral resistance (TPR) and lower cardiac output (CO), with modestly increased mean arterial blood pressure (MAP) in the first half of pregnancy, with elevation of TPR and MAP beginning at 20 weeks. Conversely, late forms of preeclampsia are characterized by only slightly elevated UA-PI and normal pre-term TPR, and slightly elevated MAP and CO throughout pregnancy, with increased TPR and MAP beginning after 34 weeks. Results suggest that preexisting arterial stiffness may be elevated in women that develop both early forms and late forms of preeclampsia; however, data that verify these results are lacking in the literature. Pulse wave velocity increases in early- and late-preeclampsia, coincident with increases in blood pressure; however, these increases are mainly due to the strain-stiffening response of larger arteries, rather than arterial remodeling-derived changes in material properties. These simulations affirm that early forms of preeclampsia may be associated with abnormal placentation, whereas late forms may be more closely associated with preexisting maternal cardiovascular factors; simulations also highlight several critical gaps in available data.

Pre-eclampsia.

Pre-eclampsia is a life-threatening disease of pregnancy unique to humans and a leading cause of maternal and neonatal morbidity and mortality. Women who survive pre-eclampsia have reduced life expectancy, with increased risks of stroke, cardiovascular disease and diabetes, while babies from a pre-eclamptic pregnancy have increased risks of preterm birth, perinatal death and neurodevelopmental disabilityand cardiovascular and metabolic disease later in life. Pre-eclampsia is a complex multisystem disease, diagnosed by sudden-onset hypertension (>20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction or uteroplacental dysfunction. Pre-eclampsia is found only when a placenta is or was recently present and is classified as preterm (delivery <37 weeks of gestation), term (delivery ≥37 weeks of gestation) and postpartum pre-eclampsia. The maternal syndrome of pre-eclampsia is driven by a dysfunctional placenta, which releases factors into maternal blood causing systemic inflammation and widespread maternal endothelial dysfunction. Available treatments target maternal hypertension and seizures, but the only 'cure' for pre-eclampsia is delivery of the dysfunctional placenta and baby, often prematurely. Despite decades of research, the aetiology of pre-eclampsia, particularly of term and postpartum pre-eclampsia, remains poorly defined. Significant advances have been made in the prediction and prevention of preterm pre-eclampsia, which is predicted in early pregnancy through combined screening and is prevented with daily low-dose aspirin, starting before 16 weeks of gestation. By contrast, the prediction of term and postpartum pre-eclampsia is limited and there are no preventive treatments. Future research must investigate the pathogenesis of pre-eclampsia, in particular of term and postpartum pre-eclampsia, and evaluate new prognostic tests and treatments in adequately powered clinical trials.

The central role of natural killer cells in preeclampsia.

Preeclampsia (PE) is a disease that is unique to pregnancy and affects multiple systems. It can lead to maternal and perinatal mortality. The precise etiology of PE is unclear. Patients with PE may have systemic or local immune abnormalities. A group of researchers has proposed that the immune communication between the fetus and mother is primarily moderated by natural killer (NK) cells as opposed to T cells, since NK cells are the most abundant immune cells in the uterus. This review examines the immunological roles of NK cells in the pathogenesis of PE. Our aim is to provide obstetricians with a comprehensive and updated research progress report on NK cells in PE patients. It has been reported that decidual NK (dNK) cells contribute to the process of uterine spiral artery remodeling and can modulate trophoblast invasion. Additionally, dNK cells can stimulate fetal growth and regulate delivery. It appears that the count or proportion of circulating NK cells is elevated in patients with or at risk for PE. Changes in the number or function of dNK cells may be the cause of PE. The Th1/Th2 equilibrium in PE has gradually shifted to an NK1/NK2 equilibrium based on cytokine production. An improper combination of killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA)-C may lead to insufficient activation of dNK cells, thereby causing PE. In the etiology of PE, NK cells appear to exert a central effect in both peripheral blood and the maternal-fetal interface. To maintain immune equilibrium both locally and systemically, it is necessary to take therapeutic measures directed at NK cells.

Analysis of serum calcium, sodium, potassium, zinc, and iron in patients with pre-eclampsia in Bangladesh: A case-control study.

Pre-eclampsia is a particular type of pregnancy condition. Although the primary etiology of pre-eclampsia is unclear, it hypothesizes that the alteration of trace elements and macro-minerals may play a crucial function in the pathogenesis of Pre-eclampsia. Therefore, our research sought to ascertain the serum level of trace elements (zinc, iron) and macro-minerals (sodium, calcium, potassium) and their possible association with pre-eclampsia. The present study was conducted with 74 pre-eclampsia pregnant women (case) and 118 pregnant women having normal blood pressure (controls). Atomic Absorption Spectroscopy determined the serum level of trace components and electrolytes. The researchers discovered notable differences in maternal age, gestational period, body mass index, systolic and diastolic blood pressure, hemoglobin, and creatinine level. Results of serum analysis revealed that calcium (52.06 ± 3.71 mg/L vs. 65.93 ± 2.57 mg/L, p < 0.05) and potassium (63.44 ± 5.33 mg/L vs. 102.54 ± 4.25 mg/L, p < 0.001) concentrations were substantially lower in the patient group than in control. Serum zinc (0.34 ± 0.02 mg/L vs. 0.52 ± 0.02 mg/L, p < 0.001) and iron (0.38 ± 0.03 mg/L vs. 0.46 ± 0.02 mg/L, p < 0.05) concentration were also considerably decreased in pre-eclampsia participants compared with a pregnant normotensive group. Pearson's correlation research results in the patient group revealed a connection between trace elements or macro minerals. In addition, the systolic blood pressure was positively correlated with sodium (r = 0.392, p < 0.01) and negatively correlated with potassium (r = -0.257, p < 0.05) in the control group. This study concludes that calcium, potassium, iron, and zinc levels were lower, whereas sodium levels were higher in Bangladeshi pre-eclampsia patients compared to controls. These findings with Pearson's correlation and the inter-element relationship between the patient and a control subject results can act as critical indication factors for patients with pre-eclampsia in Bangladesh and, as a result, may require a higher intake of calcium, potassium, iron, and zinc for effective therapeutic intervention and reduce the intake of sodium.

Morphometry of Placentae of Anaemic and Non-anaemic Preeclamptic Patients

Background&#x0D; The etiology of preeclampsia (PE) still remains elusive. Nevertheless, early onset PE has been hypothesized to develop following defective implantation of the conceptus into the endometrium and subsequent placentation. Defective placentation leads to insufficient remodeling of spiral arteries thus hypoperfusion of the placenta and clinical manifestations. Anaemia is highly prevalent amongst pregnant women. It is postulated that hypoxia is one of the mechanisms by which PE develops. The severity of symptoms seen in patients with coexisting preeclampsia and anaemia has been linked to uteroplacental insufficiency. Few studies however, have defined the placental morphometry when the two conditions occur concurrently.&#x0D; &#x0D; Methods&#x0D; This unmatched case-control study was carried out at the Kenyatta National Hospital where 42 placentae were obtained; 21 from preeclamptic mothers who had anaemia in the first and third trimesters of pregnancy (cases) and 21 from preeclamptic mothers without a history of anaemia in pregnancy (controls). The tissues were obtained and macroscopically and microscopically examined to determine relative differences. Photographs of the placentae were taken using a 12 MP (f/1.8, 26mm wide, 1/2.55", 1.4μm, dual pixel PDAF, OIS) camera. Photomicrographs were taken using a ZeissTM digital photomicroscope at ×400 magnification for stereological analysis. SPSS (Version 25.0) was used to input data where median values, interquartile ranges and frequency tables were obtained. Mann-Whitney U tests were run to compare differences in medians of the clinical, gross and histological features between the 2 groups. A p-value of ≤ _0.05 was considered statistically significant.&#x0D; &#x0D; Results&#x0D; Hemoglobin levels in the anemic group ranged between 7.0-10.5 g/dl in the 1st trimesters and 7.6-10.9g/dl in the 3rd trimester with patients being mild to moderately anemic. Gross placental infarction was observed in 17/21 (81.0%) of the cases and 15/21 (71.4%) of the controls. The gross morphometric parameters that were lower in cases were the placental weight and volume (p-values of &lt;0.001, 0.001 respectively). The histopathological features observed were extensive perivillous and intervillous fibrin deposition and larger volumes of syncytial knots in the case group. The harmonic mean thickness of the interhaemal membrane was higher in the cases when compared to controls (p -value: &lt;0.001). The estimated mean morphometric diffusing capacity was higher in cases when compared to controls (p-value: 0.001).&#x0D; &#x0D; Conclusion&#x0D; The frequency of gross and histopathological lesions seen in the PE placentae was increased when the patients had both preeclampsia and anaemia. Anaemia may thus exacerbate the pathology caused by preeclampsia. This may be the structural basis for the uteroplacental insufficiency observed when the two morbidities co-exist. It may therefore be prudent for clinicians to monitor maternal hemoglobin levels, in order to reduce the severity of preeclampsia when the two conditions co-exist.&#x0D;

More Tools for Evaluating Decidual Artery Disease.

Introduction: Hypertensive disorders of pregnancy continue to pose the most important risks for adverse maternal and neonatal outcome. Among histological findings, decidual artery disease is one of the most common, one that has both good reproducibility among observers and whose abnormal vascular remodeling is the sole aspect of preeclampsia pathophysiology on which experts agree. Nevertheless, some aspects of arterial remodeling alterations are still under investigation. Methods: We selected 720 routine and consecutive placenta case studies, concordant with the Amsterdam consensus. From these studies, we collected maternal and neonatal clinical data and specific placental findings on spiral artery abnormalities. We took into account all criteria for decidual arteriopathy. Two hundred and fifteen (215) cases out of this population presented hypertensive disorders of pregnancy. Additional to expected arterial findings, we noted frequent persistent parietal trophoblast lining. Results: A large proportion of our population developed hypertensive disorders of pregnancy (30%). Among the histologic findings reported for preeclampsia, we paid particular attention to spiral artery abnormalities, and this interpretive analysis revealed high frequency of arterial remodeling abnormalities. We examined two additional aspects in our routine analysis: first, the novel one of parietal trophoblast persistence, and second, the established problem of associated acute inflammation, as a possible pitfall. Conclusion: In order to better understood, spiral maternal artery remodeling merits further study. The abnormalities in this process provide an objective tool in the study and diagnosis of important pregnancy complications; furthermore, abnormal remodeling is an expression of early pregnancy alteration, and subsequently related to preeclampsia etiology.

Decreased expression of caveolin-1 have relevance to promoted senescence in preeclamptic placenta.

To assess the association between altered expression of caveolin-1 and p53/p21, as indicatives of cellular senescence, in preeclamptic placenta. Placental tissues and serum were collected from rats (Sham and reduced uterine perfusion pressure group) at 18.5days post coitum and humans (normotensive pregnant and preeclampsia groups). The concentration and expression of caveolin-1 were measured in the collected tissues, and the correlation between p53 and p21 expression was evaluation. Placental mRNA expression and serum concentration of caveolin-1 were measured using qRT-PCR and ELISA, respectively. Altered expressions of caveolin-1 and p53/p21 were revealed and quantified by immunohistochemistry. The association between these changes was investigated using correlation analysis. Placental mRNA expressions and serum concentrations of caveolin-1 were significantly decreased in reduced uterine perfusion pressure and preeclampsia groups. The expressions of caveolin-1 and p53/ p21 were significantly altered in placenta complicated with preeclampsia. Correlation analysis revealed a significant inverse association between changes in caveolin-1 and p53/p21. Subsequently, these results were obtained by investigating the preeclampsia onset time. These results revealed that the expression of caveolin-1 profoundly decreases in the placenta and serum of preeclampsia. These factors contribute to the mechanism of accelerated cellular senescence in placenta, which is one of the various etiologies of preeclampsia.

Upregulation of hnRNPC1/C2 expression in preeclampsia: a potential rationale for vitamin D insensitivity

Upregulation of hnRNPC1/C2 expression in preeclampsia: a potential rationale for vitamin D insensitivity Preeclampsia, a pregnancy-specific disorder in humans, is characterized by newly-onset maternal hypertension and proteinuria after 20 weeks of gestation. This pregnancy disorder complicates 5-8% of all pregnancies and is a leading cause of maternal and fetal morbidity and mortality worldwide. Preeclampsia is also a predisposing factor for cardiovascular and kidney diseases in women later in life. Although the etiology of preeclampsia is heterogenous, epidemiological studies revealed that vitamin D deficiency is a risk factor for preeclampsia development. Here, Drs Yuping Wang and David F. Lewis from Louisiana State University Health Sciences Center – Shreveport discuss hnRNPC1/C2 upregulation, a potential rationale for vitamin D insensitivity.

A comprehensive analysis of metabolomics and transcriptomics to reveal major metabolic pathways and potential biomarkers of human preeclampsia placenta.

Background: The etiology of preeclampsia (PE) remains unclear. With the utilization of metabolomics, dysregulated production of several metabolic components in human plasma, such as lipids, amino acids, androgens and estrogens, was found to be important in the pathogenesis of PE. Transcriptomics adds more in-depth information, and the integration of transcriptomics and metabolomics may yield further insight into PE pathogenesis than either one alone. Objectives: We investigated the placental metabolomics and transcriptomics of PE patients to identify affected metabolic pathways and potential biological targets for exploring the disease pathogenesis. Methods: Integrated transcriptomics and metabolomics were used to analyze five paired human placentas from patients with severe PE and normal pregnancies. This was followed by further validation of our findings in a publicly available dataset of 173 PE vs. 157 control placentas. In addition, weighted gene coexpression network construction was performed to assess the correlation between genetic alterations and diseases. Results: We identified 66 and 41 differentially altered metabolites in negative and positive ion modes, respectively, in the PE group compared to the control group, and found 2,560 differentially expressed genes. Several pathways were aberrantly altered in the PE placenta at both the metabolic and transcriptional levels, including steroid hormone biosynthesis, the cAMP signaling pathway, neuroactive ligand–receptor interactions, taste transduction and prion diseases. Additionally, we found 11 differential metabolites and 11 differentially expressed genes involved in the steroid hormone biosynthesis pathway, indicating impaired metabolism of steroid hormones in the PE placenta. Furthermore, we found that CYP11A1, HSD3B2, and HSD17B6 are highly correlated with diseases. Conclusion: Our findings provide a profile of the dysregulated steroid hormone biosynthesis in PE placenta, we observed a dysregulated cortisol-to-cortisone ratio, testosterone accumulation, decreased testosterone downstream metabolites, impaired production of estrone and estriol, and aberrant hydroxylation and methylation of estradiol. Disorders of placental steroid hormone metabolism might be a consequence or a compensatory change in pathological placentation in PE, which underscores the need to investigate the physiology of steroid hormone metabolites in the etiology of PE.

Diagnostic Value of IGFBP-2 in Predicting Preeclampsia before 20 Weeks of Pregnancy: A Prospective Nested Case-Control Study.

Purpose To identify novel biomarker insulin-like growth factor binding protein-2 (IGFBP-2) associated with preeclampsia (PE) before 20 weeks of gestation and to explore the predictive value of plasma IGFBP-2 in PE. Methods A prospective nested case-control investigation involving 122 PE patients and 122 normal controls (NC) that were matched 1 : 1 in terms of age and week of pregnancy was carried out in Guangzhou Women and Children's Medical Center (Guangzhou, China, 2018030306) from April 2016 to December 2019. At 8 to 20 weeks, blood samples from the mother were taken. To calculate the correlations, univariate conditional logistic regression was employed. Results Herein, 12 clinical indices were significantly different between the PE and NC groups (uric acid (UA), cystatin C (Cys C), aspartate aminotransferase (AST), glutamyl transpeptidase (γ-GT), total bilirubin (TB), prothrombin time (PT), red blood cell (RBC), hematocrit (HCT), red cell distribution width (RDW), platelets (PLT), mean platelet volume (MPV), and thrombocytocrit (PCT)). Compared with the NC group (36.79 ± 19.91 pg/mL), the expression level of IGFBP2 in the PE group (19.76 ± 19.40 pg/mL) before 20 weeks of pregnancy was significantly decreased (P < 0.01). Two high-risk factors were found to be significantly associated with PE independently of confounders: anemia 4.35 (2.20-8.45) (P < 0.01) and cesarean section history 8.25 (2.67-26.67) (P < 0.01). As a result of the univariate logistic regression analysis, the following three variables were included in the final logistic regression model.: Y = −18.841 − 0.085 × (IGFBP‐2) + 0.630 × (RDW) + 0.165 × (AST) + 0.863 × (MPV). In comparison to IGFBP-2 alone as an independent predictor of PE (AUC = 0.897, 95% CI 0.830–0.964), the model's discriminatory power was considerably higher (AUC = 0.953, 95% CI 0.911–0.995). Conclusion Plasma IGFBP-2 before 20 weeks of pregnancy combined with high-risk factors and routine blood indexes has a high early predictive value for PE.

Сучасний погляд на етіологію та патогенез прееклампсії як основної причини перинатальних втрат

Preeclampsia (PE) is one of the most important problems of modern obstetrics. There is an opinion that the nature of PE is different when it starts before or after 34 weeks of pregnancy. Early onset of PE correlates with high neonatal morbidity and mortality and maternal complications. Being a multifactorial disease, PE has a number of candidate genes that are involved in the complex regulation of various endothelial functions. The article provides an overview of modern medical literature on the etiology and pathogenesis of PE. For a more detailed understanding of the pathogenesis, each angiogenesis factor is considered separately, as well as variations in the genes encoding them and the influence of these factors on the development of PE. Purpose - to clarify the causes of PE development, the role of timely diagnosis of genetic polymorphisms and angiogenesis markers for constructing an algorithm for diagnosing and predicting the development of PE. It has been established that the main pathogenetic moment in the development of PE is the lack of reconstruction of the junction of the spiral arteries and the trophoblast, which reflects a defect in deep placentation. This contributes to increased production of vasoconstrictor mediators from the very beginning of pregnancy and their progressive increase with gestational age. This does not allow the formation of adequate uteroplacental bleeding, which leads to relative hypoxia in the trophoblastic tissue, thereby causing oxidative stress of the entire placenta. This phenomenon further compromises placental villous angiogenesis and leads to an imbalance in the production of angiogenic and antiangiogenic growth factors. It has been proven that the presence of polymorphism in the angiogenesis genes worsens the pathomorphological conditions caused by PE. This is due to a genetically programmed decrease in the production of angiogenic factors, which further exacerbates the aforementioned imbalance. That is why a comprehensive genetic examination of a woman at the stage of preconception preparation will make it possible to predict the risks of developing PE. This prognosis will provide the possibility of earlier administration of drugs that can improve the effects of primary placentation and reduce rates of gestational complications and perinatal losses. No conflict of interests was declared by the authors.

Abnormal Expression of the LAG-3/FGL-1 Signaling Pathway in Patients with Early-Onset Preeclampsia.

BackgroundPreeclampsia (PE) is a serious pregnancy disorder associated with immune tolerance imbalance. The etiology of preeclampsia has not been fully elucidated. The aim of this study was to clarify the possible role of the lymphocyte activation gene 3 (LAG-3)/fibrinogen-like protein 1 (FGL-1) signaling pathway in the immune imbalance of early-onset PE.Material/MethodsWe enrolled 34 women with early-onset PE and 34 age-matched normal pregnancies (NPs). Flow cytometry was performed to determine the expression of LAG-3 on peripheral T cell subsets (CD3+, CD4+, and CD8+ T cells). We measured LAG-3 expression on decidual T cells to determine whether there was a difference in the expression of LAG-3 between decidual and peripheral T cells. Maternal plasma levels of FGL-1 were measured by ELISA.ResultsThere was no significant difference in LAG-3 expression on peripheral CD3+ T cells between NP and early-onset PE. Compared to NP, the significant decrease expression of LAG-3 by peripheral CD4+ and CD8+T cells was found in early-onset PE. The LAG-3 expression was higher on decidual T cells than peripheral counterparts in all pregnancies. The plasma level of FGL-1 was significantly elevated in early-onset PE compared with NP.ConclusionsAbnormal expression of LAG-3/FGL-1 signaling pathway may be associated with immune activation of effector T cells and impaired immune tolerance in early-onset PE.

Integrative exposomic, transcriptomic, epigenomic analyses of human placental samples links understudied chemicals to preeclampsia.

Environmental health research has recently undergone a dramatic shift, with ongoing technological advancements allowing for broader coverage of exposure and molecular biology signatures. Approaches to integrate such measures are still needed to increase understanding between systems-level exposure and biology. We address this gap by evaluating placental tissues to identify novel chemical-biological interactions associated with preeclampsia. This study tests the hypothesis that understudied chemicals are present in the human placenta and associated with preeclampsia-relevant disruptions, including overall case status (preeclamptic vs. normotensive patients) and underlying transcriptomic/epigenomic signatures. A non-targeted analysis based on high-resolution mass spectrometry was used to analyze placental tissues from a cohort of 35 patients with preeclampsia (n = 18) and normotensive (n = 17) pregnancies. Molecular feature data were prioritized for confirmation based on association with preeclampsia case status and confidence of chemical identification. All molecular features were evaluated for relationships to mRNA, microRNA, and CpG methylation (i.e., multi-omic) signature alterations involved in preeclampsia. A total of 183 molecular features were identified with significantly differentiated abundance in placental extracts of preeclamptic patients; these features clustered into distinct chemical groupings using unsupervised methods. Of these features, 53 were identified (mapping to 40 distinct chemicals) using chemical standards, fragmentation spectra, and chemical metadata. In general, human metabolites had the largest feature intensities and strongest associations with preeclampsia-relevant multi-omic changes. Exogenous drugs were second most abundant and had fewer associations with multi-omic changes. Other exogenous chemicals (non-drugs) were least abundant and had the fewest associations with multi-omic changes. These global data trends suggest that human metabolites are heavily intertwined with biological processes involved in preeclampsia etiology, while exogenous chemicals may still impact select transcriptomic/epigenomic processes. This study serves as a demonstration of merging systems exposures with systems biology to better understand chemical-disease relationships.

Mesenchymal Stem Cells-Induced Trophoblast Invasion Is Reduced in Patients with a Previous History of Preeclampsia.

Endometrial stromal cells play an important role in reproductive success, especially in implantation and placentation. Although Mesenchymal stem cells (MSCs) have been studied to assess decidualization disorders in preeclampsia (PE), their role during trophoblast invasion remains unclear. This study aims to determine: (i) whether MSCs isolated from menstrual fluid (MenSCs) from nulliparous, multiparous, and women with a previous history of preeclampsia exhibited different patterns of proliferation and migration and (ii) whether reproductive history (i.e., prior pregnancy or prior history of PE) was able to produce changes in MenSCs, thus altering trophoblast invasion capacity. MenSCs were collected from nulliparous and multiparous women without a history of PE and from non-pregnant women with a history of PE. Proliferation and migration assays were performed on MenSCs with sulforhodamine B and transwell assays, respectively. Trophoblast invasion was analyzed by culturing HTR-8/SVneo trophospheres on a matrigel overlying MenSCs for 72 h at 5% O2, simulating a 3D implantation model. A previous history of pregnancy or PE did not impact the proliferative capacity or migratory behavior of MenSCs. Following exposure to physiological endometrial conditions, MenSCs demonstrated upregulated expression of IGFBP-1 and LIF mRNA, decidualization and window of implantation markers, respectively. The mRNA expression of VIM, NANOG, and SOX2 was upregulated upon trophosphere formation. Relative to co-culture with multiparous MenSCs, co-culture with PE-MenSCs was associated with reduced trophoblast invasion. The findings of this study suggest a potential role for communication between maternal MenSCs and invading trophoblast cells during the implantation process that could be implicated in the etiology of PE.

Gut Dysbiosis Promotes Preeclampsia by Regulating Macrophages and Trophoblasts.

Preeclampsia is one of the leading causes of maternal and perinatal morbidity and is characterized by hypertension, inflammation, and placental dysfunction. Gut microbiota plays key roles in inflammation and hypertension. However, its roles and mechanisms in preeclampsia have not been fully elucidated. 16S rRNA gene sequencing and targeted metabolomics were conducted on stool samples from 92 preeclamptic patients and 86 normal late-pregnant women. Then, fecal microbiota transplantation and in vitro and in vivo functional experiments were performed to explore the roles and mechanisms of gut microbiota in preeclampsia development. We revealed the gut microbiota dysbiosis in preeclamptic patients, including significant reductions in short-chain fatty acid-producing bacteria and short-chain fatty acids. The gut microbiota of preeclamptic patients significantly exacerbated pathologies and symptoms of preeclamptic rats, whereas the gut microbiota of healthy pregnant women had significant protective effects. Akkermansia muciniphila, propionate, or butyrate significantly alleviated the symptoms of preeclamptic rats. Mechanistically, they significantly promoted autophagy and M2 polarization of macrophages in placental bed, thereby suppressing inflammation. Propionate also significantly promoted trophoblast invasion, thereby improved spiral arterial remodeling. Additionally, we identified a marker set consisting of Akkermansia, Oscillibacter, and short-chain fatty acids that could accurately diagnose preeclampsia. Our study revealed that gut microbiota dysbiosis is an important etiology of preeclampsia. Gut microbiota and their active metabolites have great potential for the treatment and diagnosis of preeclampsia. Our findings enrich the gut-placenta axis theory and contribute to the development of microecological products for preeclampsia.