First-trimester prediction of preeclampsia (PE) remains a major clinical challenge, particularly outside specialized fetal medicine centers. This study aimed to identify and validate serum protein biomarkers for early PE prediction using an integrated proteomic approach. A prospective cohort of 64 first-trimester singleton pregnancies (32 future PE cases, 32 matched controls) was analyzed. Untargeted proteomics was performed using DIA-PASEF-MS, followed by targeted cross-platform verification with MRM-MS. Machine learning classifiers (support vector machines, SVM, and random forest) were trained on differentially abundant proteins (FDR < 0.01, VIP > 1.5). DIA-MS identified 33 protein markers associated with complement activation, IGF transport regulation, and platelet degranulation. An SVM model with a linear kernel achieved 95% accuracy (AUC = 0.95, sensitivity = 95%, specificity = 97%). Four markers (AFM, AHSG, C8A, IGHG1) were confirmed across platforms, confirming the discovery findings. Cross-platform correlation was high: 71% of overlapping proteins showed r > 0.5 (p < 0.001), with the highest concordance observed for potential PE marker AHSG (r = 0.8, p < 0.001). PRSS1, IGHV1-4, and SERPINC1 showed a strong correlation with proteinuria (|r| > 0.5, p < 0.05), linking the proteomic signature to clinical severity. Integrated DIA-MS and MRM-MS proteomics yields a reproducible, high-performance serum signature for first-trimester PE prediction. The identified markers reflect core pathophysiological pathways and offer potential to augment current FMF-based screening algorithms.

Preeclampsia is a severe gestational complication whose molecular pathogenesis remains poorly understood despite extensive research. It is now recognized that both maternal and fetal cells contribute to disease progression. Notably, single-cell RNA sequencing of cord blood cells from preeclamptic pregnancies has not been previously investigated, and this became the focus of our study. In this work, we performed flow cytometry, single-cell RNA sequencing and bioinformatics analysis of cord blood mononuclear cells from preeclampsia and control groups. Bulk RNA-sequencing data of preeclamptic cord blood from open source was also analysed. We observed a significant decrease in the expression of the CD3, CD8 and CD4 markers in cord blood mononuclear cells in the preeclampsia group. Single-cell RNA sequencing revealed activation of iron- and heme-associated signalling pathways in various cell types (nonclassical monocytes, naive СD4+ and CD8+ T cells, T-helpers 2, NK cells and naive СD4+ regulatory T cells) in cord blood during preeclampsia. Analysis of open-source bulk RNA-sequencing data confirmed our findings of activation of heme-related signalling pathways in preeclamptic cord blood samples. These results may suggest the activation of compensatory mechanisms, potentially mediated by the proangiogenic heme degradation products carbon monoxide and biliverdin. Additionally, free heme may act as a proinflammatory damage-associated molecular pattern in preeclampsia. Further studies are needed to elucidate the direct relationship between these mechanisms and placental heme metabolism.

Introduction: The role of the TGF beta signaling pathway, an important cascade responsible for the anti-inflammatory polarization of macrophages, in the development of both early-and late-onset preeclampsia (eoPE and loPE), remains poorly understood. In this study, we examined the components of the TGF beta signaling cascade and macrophage markers within placental tissue in normal pregnancy and in PE.Methods: Patients with eoPE, loPE, and normal pregnancy were enrolled in the study (n = 10 in each group). Following techniques were used for the investigation: immunohistochemistry analysis, western blotting, qRT-PCR, isolation of monocytes by magnetic sorting, transfection, microRNA sequencing, and bioinformatic analysis.Results: We observed a significant decrease in the anti-inflammatory macrophage marker CD206 in the loPE group, alongside with a significant down-regulation of CD206 protein production in both eoPE and loPE groups. The level of CD68-positive cells and relative levels of CD163 and MARCO production were comparable across the groups. However, we identified a significant decrease in the TGF beta receptor 2 production and its gene expression in the PE group. Further analysis revealed a link between TGFBR2 and MRC1 (CD206) genes through a single miRNA, hsa-miR-27a-3p. Transfecting CD14-derived macrophages with the hsa-miR-27a-3p mimic significantly changed TGFBR2 production, indicating the potential role of this miRNA in regulating the TGF beta signaling pathway. We also revealed the up-regulation of hsa-miR-27a-5p and hsa-miR-27a-3p in the trophoblast BeWo b30 cell line under the severe hypoxia condition and the fact that TGFBR2 3 ' UTR could serve as a potential target for these miRNAs.Discussion: Our findings uncover a novel potential therapeutic target for managing patients with PE, significantly contributing to a deeper comprehension of the underlying mechanisms involved in the development of this pathology.

Introduction. Chronic kidney disease (CKD) in pregnancy poses certain risks of both gestational complications and adverse perinatal outcomes, which increase with the decline of renal function.Aim to access pregnancy outcomes in patients who underwent nephrotransplantation.Materials and methods. Retrospective study of pregnant women who gave birth at Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in the period from 2005 to 2021: 102 pregnancies in 97 patients were analyzed: five recipients had two successful pregnancies.Results. The average age of pregnant women was 31 ± 4.03 years. In equal proportions, patients underwent related or cadaveric kidney transplantation – 52% (n = 53) and 48% (n = 49) of cases, respectively. The average delivery time was 35.5 ± 2.7 weeks. The average weight of newborns was 2545 ± 655 grams. Premature birth (PB) occurred in 47.1%, the average period of birth was 33.4 ± 2.87 weeks, of which early birth (<32 weeks) was 22.5%. The average period of pregnancy after transplantation was 5 ± 3.31 (1–18) years, this period was not associated with obstetric complications or deterioration of graft function. A significant increase in the following parameters was noted during pregnancy: serum creatinine level (p = 0.006), proteinuria (p = 0.003). The glomerular filtration rate also decreased significantly by the end of pregnancy (p = 0.011). Preeclampsia was the leading cause of decreased graft function during pregnancy (32.4%).Conclusions. In general, pregnancy outcomes after nephrotransplantation are favorable, but there is an increased risk of preeclampsia, preterm birth, including operative delivery, urinary tract infection and anemia.

A comparative study was carried out to analyze the number of syncytial knots and the intensity of expression of vascular endothelial growth factor (VEGF) in the villi of the monochorionic diamniotic placenta in pregnancies complicated by the syndrome of selective fetal growth restriction (sFGR). We performed a morphological analysis of 32 monochorionic diamniotic placentas after term delivery which were divided into two groups. The main group included the placentas of 15 puerperas whose pregnancies were complicated by sFGR. The control group included twin placentas of 17 puerperas without signs of sFGR. The number of syncytial knots was determined by histological studies, and the levels of VEGF expression in syncytiotrophoblast and capillary endotheliocytes of the placental villi were determined by immunohistochemical studies. The study showed an increase in the number of syncytial knots in the villi of the placental part of the fetus with sFGR which indicated the development of preplacental hypoxia. A significant increase in the level of VEGF expression in the syncytiotrophoblast and vascular endothelium of the villi should be considered as a manifestation of a compensatory adaptational response to hypoxia, though it is insufficient to prevent the development of sFGR.

Fetal arrhythmia develops in 0.1–5% of pregnancies and may cause fetal heart failure and fetal hydrops, thus increasing fetal, neonatal, and infant mortality. The timely initiation of transplacental antiarrhythmic therapy (ART) promotes the conversion of fetal tachycardia to sinus rhythm and the regression of the concomitant non-immune fetal hydrops. The optimal treatment regimen search for the fetus with tachyarrhythmia is still of high value. Polymorphisms of these genes determines the individual features of the drug pharmacokinetics. The aim of this study was to study the pharmacokinetics of transplacental anti-arrhythmic drugs in the fetal therapy of arrhythmias using HPLC-MS/MS, as well as to assess the effect of the multidrug-resistance gene ABCB1 3435C > T polymorphism on the efficacy and maternal/fetal complications of digoxin treatment. The predisposition to a decrease in the bioavailability of the digoxin in patients with a homozygous variant of the CC polymorphism showed a probable association with the development of ART side effects. A pronounced decrease in heart rate in women with the 3435TT allele of the ABCB1 gene was found. The homozygous TT variant in the fetus showed a probable association with an earlier response to ART and rhythm disruptions on the digoxin dosage reduction. high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) methods for digoxin and sotalol therapeutic drug monitoring in blood plasma, amniotic fluid, and urine were developed. The digoxin and sotalol concentrations were determined in the plasma blood, urine, and amniotic fluid of 30 pregnant women at four time points (from the beginning of the transplacental antiarrhythmic therapy to delivery) and the plasma cord blood of 30 newborns. A high degree of correlation between the level of digoxin and sotalol in maternal and cord blood was found. The ratio of digoxin and sotalol in cord blood to maternal blood was 0.35 (0.27 and 0.46) and 1.0 (0.97 and 1.07), accordingly. The digoxin concentration in the blood of the fetus at the moment of the first rhythm recovery episode, 0.58 (0.46, 0.8) ng/mL, was below the therapeutic interval. This confirms the almost complete transplacental transfer of sotalol and the significant limitation in the case of digoxin. Previously, ABCB1/P-glycoprotein had been shown to limit fetal exposure to drugs. Further studies (including multicenter ones) to clarify the genetic features of the transplacental pharmacokinetics of antiarrhythmic drugs are needed.

On December 18, 2022, an interdisciplinary Expert Council was held in St. Pe­ter­sburg, dedicated to the debatable issues of anticoagulation in the prevention of venous thromboembolism in pregnant women with cardiovascular and systemic diseases, at which a number of proposals and guidelines were adopted, and the results of the Highlow study were considered. Leading experts from the Russian Society of Cardiology, the Russian Society of Obstetricians and Gynecologists, the National Association of Specialists in Thrombosis, Clinical Hemostaseology and Hemorheology took part in the Expert Council.

Antihypertensive therapy is an essential part of management of patients with preeclampsia (PE). Methyldopa (Dopegyt®) and nifedipine (Cordaflex®) are basic medications of therapy since they stabilize blood pressure without affecting the fetus. Their effect on the endothelium of placental vessels has not yet been studied. In this study, we analyzed the effect of antihypertensive therapy on the expression of fucosylated glycans in fetal capillaries of placental terminal villi in patients with early-onset PE (EOPE) and late-onset PE (LOPE), and determined correlation between their expression and mother’s hemodynamic parameters, fetoplacental system, factors reflecting inflammatory response, and destructive processes in the endothelial glycocalyx (eGC). A total of 76 women were enrolled in the study: the comparison group consisted of 15 women with healthy pregnancy, and the main group comprised 61 women with early-onset and late-onset PE, who received one-component or two-component antihypertensive therapy. Hemodynamic status was assessed by daily blood pressure monitoring, dopplerometry of maternal placental and fetoplacental blood flows, and the levels of IL-18, IL-6, TNFα, galectin-3, endocan-1, syndecan-1, and hyaluronan in the blood of the mother. Expression of fucosylated glycans was assessed by staining placental sections with AAL, UEA-I, LTL lectins, and anti-LeY MAbs. It was found that (i) expression patterns of fucosylated glycans in eGC capillaries of placental terminal villi in EOPE and LOPE are characterized by predominant expression of structures with a type 2 core and have a similar pattern of quantitative changes, which seems to be due to the impact of one-component and two-component antihypertensive therapy on their expression; (ii) correlation patterns indicate interrelated changes in the molecular composition of eGC fucoglycans and indicators reflecting changes in maternal hemodynamics, fetoplacental hemodynamics, and humoral factors associated with eGC damage. The presented study is the first to demonstrate the features of placental eGC in women with PE treated with antihypertensive therapy. This study also considers placental fucoglycans as a functional part of the eGC, which affects hemodynamics in the mother–placenta–fetus system.

Systemic inflammation alongside endothelial dysfunction is considered to play a crucial role in PE pathogenesis. Endothelial dysfunction can be assessed by endothelial glycocalyx (eGC) damage. eGC is a superficial layer of cells associated with endothelial membrane that provides all endothelial cells functions. Its damage can be evaluated by the levels of its circulating components in blood. Patients with PE generally receive methyldopa (Dopegyt) solely or in combination with nifedipine (Cordaflex), and there is no understanding of their effect on proinflammatory state of blood vessels. Our study aimed to assess levels of IL-6, IL-18, TNFα, galektin-3 and homocysteine as well as levels of syndecan-1, eCG structural component, representing system inflammatory response and endothelial dysfunction development in blood of women with early- and late-onset PE receiving different antihypertensive treatment strategies. Eighty-two patients were enrolled into this interventional longitudinal pilot study. The comparison group included 15 patients before 34 gestational weeks and 15 patients after 34 weeks. Study subgroup 1 included 12 patients with early- onset PE receiving Dopegyt solely and 16 patients with early-onset PE receiving Dopegyt together with Cordaflex. Study subgroup 2 included 12 patients with late-onset PE receiving Dopegyt solely and 12 patients with late-onset PE receiving combined therapy. As for early-onset PE, only IL-6 demonstrated statistically significant differences in patients receiving both treatment strategies compared to control. Proinflammatory state was more profound in late-onset PE. IL-6 levels were significantly increased in late-onset PE treated with Dopegyt. IL-6 and TNFa levels were significantly higher in late-onset PE patients treated with Dopegyt + Cordaflex compared to control. Syndecan-1 levels were statistically significantly higher in patients with early-onset PE treated with Dopegyt solely. There were no statistically significant differences between the groups despite elevated mean values of syndecan-1 in late-onset PE. Galectin-3 and homocysteine levels did not differ significantly between the groups, representing lack of pronounced inflammatory response and endothelial dysfunction.

Preeclampsia (PE) is a serious gestational complication affecting the life of a mother and child. The immunophenotype and gene expression profile of isolated blood monocyte subpopulations of pregnant women with PE have not been studied before. In this work, we assessed changes in CD14++ and CD16++ monocyte subpopulations in PE and physiological pregnancy (n = 33). Immunophenotyping, immunomagnetic sorting of monocytes and analysis of the transcriptional profile of their genes were carried out. The percentage of classical monocytes was significantly lower, while the intermediate fraction of monocytes was significantly higher in late-onset PE compared to control. Transcriptome analysis of late-onset PE classical CD14++ monocytes revealed significant activation of inflammation mediated by chemokine and cytokine signalling pathways; apoptosis; regulation of transcription from RNA polymerase II promoter in response to stress and others. The most suppressed signalling pathways were associated with T cell activation and selection. In CD16++ monocytes of late-onset PE cases, positive regulation of cell–cell adhesion, integrin signalling pathway, blood coagulation cascade were the most activated ones. The inflammation mediated by chemokine and cytokine signalling pathway and p53 pathway were the most down-regulated in CD16++ monocytes. The obtained results indicate profound changes occurring to two most polar monocyte subpopulations in PE and their different roles in the pathogenesis of this disease.

This paper provides an assessment of molecular and functional changes in blood vessels, and a description of vascular patterns during preeclampsia (PE). Patients with normal pregnancy, and pregnancy complicated by PE at earlier (20–34 weeks) and later terms (≥34 weeks) underwent a 24 h monitoring of blood pressure, central hemodynamics, arterial stiffness, and myocardial function. The blood levels of the structural components of endothelial glycocalyx (eGC): syndecan-1 (SDC 1), heparan sulfate proteoglycan 2 (HSPG2), and hyaluronic acid (HA) were determined. In early-onset PE, the vascular pattern comprised changes in all structural components of eGCs, including transmembrane proteoglycans levels, and severe disorders of central hemodynamics, arterial stiffness, and myocardial changes, probably leading to more severe course of PE and the formation of morphological grounds for cardiovascular disorders. The vascular pattern in late-onset PE, including changes in HA levels, central hemodynamics, and myocardial function, may be a signal of potential cardiovascular disorder. PE may change adaptive hemodynamic responses to a pathological reaction affecting both arterial elasticity and the left ventricular myocardium, with its subsequent hypertrophy and decompensation, leading to a delayed development of cardiovascular disorders after PE. Further clinical studies of these indicators will possibly identify predictors of PE and long-term consequences of the disease.

Introduction: Preeclampsia is a pregnancy-specific complication characterized by hypertension in combination with proteinuria and/or various manifestations of multiple organ failure. It is believed that etiology of preeclampsia lies in dysfunction of the placenta and disorder of the maternal-fetal interactions. In preeclampsia decidual membrane, the maternal part of the placenta which normally supports immunological tolerance of the maternal organism to the semi-allogeneic fetus, becomes a site of inflammation. Methods: The aim of our study was to characterize the phenotype of decidual macrophages and plasma profiles in patients with late- and early-onset preeclampsia as compared with controls (n = 43). Decidual cells were obtained by enzymatic digestion method and characterized by flow cytometry analysis, real-time PCR, bioinformatics analysis, immunohistochemistry, and Western blot. Plasma samples were analyzed by multiplex assay. Results: The number of inflammation-associated CD86+ and CX3CR1+ cells was significantly higher in the early-onset preeclampsia while the portion of CD163+ cells was significantly higher among studied groups. We observed significant increase of endothelin-1 gene expression and a significant decrease in eNOS and GNB3 expression and TGFP relative protein level in decidual cells of the early-onset preeclampsia samples. We also revealed elevation of pm- and anti-inflammatory cytokines in plasma of preeclampsia groups. Discussion: Our findings reflect profound early-onset preeclampsia-associated alterations in the decidua and emphasize the importance of the decidua as a link in the development of preeclampsia.

Preeclampsia is a gestation-associated hypertensive syndrome that threatens the life and health of the mother and the child. The condition is presumably caused by systemic failure with a strong involvement of innate immunity. In particular, it has been associated with flexible phenotypes of macrophages, which depend on the molecules circulating in the blood and tissue fluid, such as cytokines and hormones. This study aimed at a comparative evaluation of pro-inflammatory (TNFα) and anti-inflammatory (CD206, MMP9, HGF) markers, as well as the levels of estrogen receptor α, expressed by decidual macrophages in normal pregnancy and in patients with early- and late-onset preeclampsia. The tissue samples of decidua basalis were examined by immunohistochemistry and Western blotting. Isolation of decidual macrophages and their characterization were performed using cultural methods, flow cytometry and real-time PCR. Over 50% of the isolated decidual macrophages were positive for the pan-macrophage marker CD68. In the early-onset preeclampsia group, the levels of estrogen receptor α in decidua were significantly decreased. Furthermore, significantly decreased levels of HGF and CD206 were observed in both preeclampsia groups compared with the control group. The observed downregulation of estrogen receptor α, HGF and CD206 may contribute to the balance of pro- and anti-inflammatory macrophages and thereby to pathogenesis of preeclampsia.