Search Results (147)

Preeclampsia (PE) occurs in approximately 2–8% of all pregnancies worldwide and represents one of the primary causes of maternal and fetal morbidity and mortality. Angiogenic growth factors such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), along with their tyrosine kinase receptor (Flt-1), play a central role in placental and fetal development. Impaired placentation results in the excessive release of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) which is pivotal in the pathogenesis of PE. By binding to and neutralizing angiogenic factors, sFlt-1 disrupts normal angiogenic signaling, creating an imbalance that is often detectable before clinical symptoms of PE appear. Recent studies have highlighted the prognostic potential of the sFlt-1/PlGf ratio as an early indicator of PE risk, since this ratio has demonstrated value in both confirming and excluding PE in the high-risk population. Its incorporation into routine medical care has the potential to reduce unnecessary hospital admissions, intensive management, and premature deliveries, ultimately lowering healthcare costs. The objective of this review is to highlight the clinical utility of the sFlt-1/PlGf ratio in the prediction, diagnosis, and management of preeclampsia and to emphasize the cost-effectiveness of implementing sFlt-1/PlGF ratio measurement in the care of women at risk of developing PE. Full article

Background/Objectives: Screening for late-onset and term preeclampsia (PE) is essential, as the early identification of women at high risk enables closer monitoring and reduces adverse outcomes. The existing algorithms combining maternal factors, biophysical and biochemical markers have not been validated outside the populations in which they were originally developed. This study aimed to evaluate the predictive performance of the Fetal Medicine Foundation (FMF) third-trimester algorithm in our population and develop a novel model to improve the predictions. Methods: An observational, analytical, prospective cohort follow-up study was conducted at the Health Department of Alicante, Dr. Balmis General University Hospital, including 1580 singleton pregnancies recruited between February 2022 and November 2023 during routine third-trimester ultrasounds. Maternal clinical characteristics, blood pressure, the uterine artery pulsatility index (UtA-PI), and the sFlt-1/PlGF ratio were recorded. The FMF third-trimester algorithm was retrospectively applied at the end of pregnancy using clinical, biophysical, and biochemical data from 30 + 0 to 37 + 6 weeks via the freely accessible online calculator. The data analysis was performed using SPSS v.28 and R v.4.3.1. Results: A total of 1580 women were included, with a prevalence of late-onset PE of 2.9%. The FMF model achieved an area under the curve (AUC) of 0.87 (95% CI: 0.81–0.92), while our own model showed a superior performance, with an AUC of 0.94 (95% CI: 0.92–0.97). Conclusions: The FMF third-trimester algorithm demonstrated a good predictive performance for late-onset PE. Our newly developed model achieves an even higher predictive accuracy and offers a simplified approach to excluding the UtA-PI, which facilitates its use in routine clinical practice. Full article

Placental dysfunction underlies the major obstetric syndromes, including preeclampsia, fetal growth restriction, placenta accreta spectrum, pregnancy loss, and monochorionic twin complications. Recent molecular studies have revealed that dysregulated oxygen sensing, impaired angiogenic signaling, altered immune tolerance, and defective trophoblast fusion represent shared pathogenic pathways that converge across these disorders. Integrating morphological evidence with mechanistic data highlights how villous maldevelopment, shallow trophoblast invasion, and aberrant vascular remodeling translate into clinical disease. Advances in biomarker research have already transformed clinical care: the sFlt-1/PlGF ratio is now established in the prediction and management of preeclampsia, while placental proteins such as PAPP-A and PP13, nucleic acid signatures including cfDNA, cfRNA and miRNAs, and extracellular vesicle cargo show promising potential for early, non-invasive detection of placental pathology. Multi-omics approaches, particularly single-cell and spatial transcriptomics combined with proteomic and metabolomic profiling, are paving the way for composite diagnostic panels that capture the polygenic and multicellular nature of placental disease. This review synthesizes current knowledge of molecular mechanisms, histological correlates, and translational biomarkers, and outlines how precision obstetrics may emerge from bridging mechanistic discoveries with clinical applications. Full article

Preeclampsia affects 2–8% of pregnancies globally and remains a leading cause of maternal and perinatal morbidity, with limited preventive options beyond low-dose aspirin. Low-molecular-weight heparin (LMWH) has emerged as a promising therapeutic candidate due to its pleiotropic effects extending beyond anticoagulation, including anti-inflammatory, pro-angiogenic, and placental-protective properties. This comprehensive narrative review examines LMWH’s effects on preeclampsia-associated biomarkers and evaluates clinical evidence for its preventive efficacy. LMWH exerts multifaceted effects on disease pathophysiology, including restoration of angiogenic balance through sFlt-1 reduction and PlGF preservation, attenuation of inflammatory responses via decreased TNF-α and IL-6 production, normalization of coagulation parameters, and enhancement of trophoblast invasion and placental vascularization. Clinical trials reveal heterogeneous results, with meta-analyses suggesting significant benefit primarily in high-risk subgroups. Women with previous severe placenta-mediated complications demonstrate relative risk reductions of 40–60% for recurrent preeclampsia with LMWH prophylaxis, particularly when initiated before 16 weeks’ gestation. Combination therapy with low-dose aspirin appears to enhance protective effects. However, larger trials in unselected populations have failed to demonstrate significant benefit, highlighting the importance of appropriate patient selection. Current international guidelines reflect this evidence heterogeneity, with most recommending against routine LMWH use while acknowledging potential benefit in selected high-risk populations, particularly those with antiphospholipid syndrome or previous severe early-onset disease. Future research should focus on biomarker-guided patient selection, optimal dosing regimens, and integration with multimodal preventive strategies to maximize therapeutic benefit while minimizing unnecessary interventions. Full article

Background and Objectives: Third-trimester screening is widely used to identify small for gestational age (SGA) and fetal growth restriction (FGR), but optimal models and timing remain under investigation. This study aimed to assess the performance of combined maternal factors and biomarkers, including ultrasound estimated fetal weight (EFW), Doppler indices, mean arterial pressure (MAP), and angiogenic biomarkers, for predicting SGA neonates after a routine 35–36 weeks’ scan in an unselected population. Materials and Methods: We conducted a retrospective cohort study in three Spanish centers offering universal third-trimester ultrasound. Logistic regression analyses were carried out to predict birthweight < 10th and <5th percentile using maternal characteristics and medical history, EFW, MAP, Doppler indices, and the angiogenic biomarkers placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Using a 10-fold cross-validation, we estimated the area under the receiver operating characteristic curve (AUC), detection rates (DRs), false-positive rates (FPRs), and their corresponding screen-positive rates (SPRs). External validation was performed using an independent cohort. Results: Among 3992 pregnancies, the DR of ultrasound alone for birthweight <10th percentile was 47.9% (95% CI: 44.0 to 51.9), with an FPR of 7.3%. Adding maternal factors increased DR to 57.0% (95% CI: 53.0 to 60.9) at 10% FPR and to 83.0% (95% CI: 79.9 to 85.9) at 30% FPR. Similarly, the DR of ultrasound alone for birthweight < 5th percentile was 48.4% (95% CI: 43.1 to 53.6), with an FPR of 4.5%. Adding maternal factors increased DR to 65.7 (95% CI: 60.5 to 70.5) at 10% FPR and to 88.2 (95% CI: 84.4 to 91.3) at 30% FPR. The inclusion of MAP, Doppler, and biomarkers provided marginal additional gains, particularly for <5th percentile prediction. To achieve a DR > 80%, an SPR of approximately 40% was required. Performance improved when focusing on neonates born before 38 weeks, with a DR of 77.5 (95% CI: 68.6 to 84.9) at 10% FPR for SGA < 10th percentile. However, less than 40% of screen-positive women remained undelivered by 40 weeks, limiting the number requiring further surveillance. Conclusions: A third-trimester screening at 35–36 weeks using maternal characteristics and EFW identifies most SGA neonates, particularly those delivering before 38 weeks. Even including other biomarkers, an SPR of about 40% should be necessary to achieve a high DR. However, less than 40% of the women would remain undelivered before a subsequent follow-up is required. Full article

Preeclampsia (PE) is not merely a pregnancy complication but a clinical manifestation of underlying vascular dysfunction with long-term health implications. It is diagnosed after 20 weeks of gestation as new-onset hypertension with proteinuria or organ involvement. The condition arises from impaired placental development, particularly defective spiral artery remodeling, which leads to placental ischemia and the release of antiangiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). These circulating factors contribute to systemic endothelial dysfunction, resulting in hypertension, inflammation, and multiorgan stress. Histopathological findings, including acute atherosis and abnormal vascular remodeling, further reflect the cardiovascular damage underlying PE. This review synthesizes emerging evidence on the vascular and histological mechanisms of PE, highlighting novel biomarkers such as microRNAs and neprilysin, and the potential of advanced diagnostic tools, including machine learning. Importantly, PE is now recognized not only as an obstetric disorder but also as an early marker of future cardiovascular disease. This paradigm shift emphasizes the need for personalized prevention strategies, close surveillance of high-risk women, and long-term cardiovascular follow-up. Pregnancy thus represents a critical window for early detection and intervention in women’s cardiovascular health. Full article

Gestational diabetes mellitus (GDM) is a frequently encountered medical complication during pregnancy that is increasing at a rapid pace globally, posing significant public health concerns. Similarly, there is a rising trend in the number of women who have utilized assisted reproductive technology (ART). Numerous studies have been carried out to investigate the relationship between GDM and ART. This comprehensive systematic review seeks to identify potential biomarkers for the early diagnosis of GDM in pregnancies conceived through ART. We conducted a PubMed search covering the past five years to identify studies that explore biomarkers associated with the development of GDM in pregnancies conceived through ART. The outcome measures included human chorionic gonadotropin (HCG), the body mass index (BMI), the Follicle Stimulating Hormone to Luteinizing Hormone (FSH/LH) ratio, increased hemoglobin A1c levels, fasting insulin concentrations, homeostatic model assessment of insulin resistance (HOMA-IR), triglyceride levels, total cholesterol levels, low-density lipoprotein cholesterol concentrations, low-density lipoprotein/high-density lipoprotein (LDL/HDL), total cholesterol to high-density lipoprotein (TC/HDL), the estradiol/follicle ratio, soluble fms-like tyrosine kinase-1 (sFlt-1), Placental Growth Factor (PLGF), endometrial thickness, and psychological stress. Seventeen studies were included. The identification and development of serum or ultrasound biomarkers for the early detection of GDM in pregnancies conceived through ART pose considerable challenges. These challenges arise from the multifactorial nature of GDM, the methodological variations in ART, and the limited availability of relevant studies. The most promising biomarker identified was the estradiol/follicle ratio. Women with a higher estradiol/follicle ratio exhibited significantly lower rates of GDM. There is a pressing necessity for biomarkers to enable the early detection of GDM in pregnancies conceived through ART. E2 levels, β-hCG, and the E2/F ratio, along with the TC/HDL and LDL/HDL ratios, show potential as reliable biomarkers for identifying GDM. Full article

Preeclampsia (PE) is a hypertensive disorder impacting 5–7% of pregnancies globally. With no causative treatment available, diagnosed patients have limited therapeutic options, putting them at risk for pregnancy complications. The induction of oxidative stress by ROS—one of the major contributors in PE pathogenesis—causes downstream signaling and production of anti-angiogenic factors, such as sFLT1 and sEng. The anti-angiogenic factors may cause endothelial and trophoblast dysfunction, contributing to the development of hypertension, proteinuria, and in severe cases, eclampsia. To target placental oxidative stress, we developed and evaluated an organofluorine hydrazone antioxidant, HY-12, in vitro. Human trophoblast (HTR8/SVneo) cells were incubated with hydrogen peroxide to induce oxidative stress and act as a model of PE. The goal of the study was to assess the efficacy of HY-12 and its ability to reduce cell injury, mitochondrial stress, and anti-angiogenic response. In our human trophoblast-based assays, pre-treatment with HY-12 reduced mitochondrial-derived ROS production in cells exposed to hydrogen peroxide, proving its ability to alleviate the oxidative stress associated with the pathogenesis of PE. HY-12 reduced HIF1A expression and sFLT1 protein expression in H₂O₂-exposed HTR8 cells. Furthermore, HY-12 improved the activity of the mitochondrial electron chain enzyme cytochrome C oxidase (COX) in the hydrogen-peroxide-treated HTR8/SVneo cells, which is a promising attribute of the compound. In reducing placental trophoblast oxidative stress, HY-12 shows promise as a potential treatment of preeclampsia. In vivo studies are warranted to further determine the efficacy of this compound. Full article

Background: Antiphospholipid syndrome (APS) is one of the highest risk factors for obstetric complications. This article contains a case report of a patient with obstetric APS who experienced fetal loss during their first pregnancy and experienced a successful second pregnancy upon treatment with acetylsalicylic acid (ASA), low-molecular-weight heparin (LMWH), and hydroxychloroquine (HCQ). We compare placental pathology in these two pregnancies and discuss the impact of antiphospholipid antibodies and clinical management on pregnancy outcomes. We also propose methods to monitor obstetric antiphospholipid syndrome (OAPS) patients during pregnancy. Methods: A 26-year-old woman presented with a history of stillbirth at 25 weeks of pregnancy due to placental insufficiency. Before pregnancy, she experienced symptoms suggestive of autoimmune disease (thrombocytopenia, recurrent mouth aphthous ulcers, and Raynaud’s phenomenon) but had no diagnosis. Placental dysfunction correlated with the high ratio of sFlt-1/PIGF (soluble fms-like tyrosine kinase 1 and the placental growth factors index). Laboratory tests revealed the presence of antinuclear antibodies (ANAs) and triple positivity for antiphospholipid antibodies (aPLs). Results: Following the initiation of treatment for OAPS and regular monitoring consistent with current guidelines, the patient conceived and successfully delivered a healthy child. Conclusions: Adequate therapy and close monitoring during pregnancy, including clinical observation, placental biomarkers and regular ultrasonography, may help to reduce the risks and increase chances for optimal pregnancy outcomes. Additionally, pathological examination and clinical collaboration are essential components in future pregnancy counseling and should be a part of multidisciplinary management. Full article

To assess the association between known (PlGF, sFlt-1, betaHCG, PAPPA) and novel (cell-free DNA, cfDNA, and total endothelial and platelet microvesicles, MVs) maternal blood biomarkers measured at the first trimester with the later development of preeclampsia (PE) and PE-related severe adverse events (SAE), we conducted a retrospective case–control study including women with an established diagnosis of preeclampsia (cases) and healthy pregnant women (controls). Biomarkers were measured from first-trimester blood samples stored in a hospital biobank. A total of 89 women, 54 women with PE and 35 controls were included. PlGF showed good performance for diagnosing overall preeclampsia (AUC: 0.71; 95% CI 0.59–0.82), early-onset preeclampsia (AUC 0.80; 95% CI 0.68–0.9) and fetal-neonatal SAEs (AUC: 0.73; 95% CI 0.63–0.84). Multivariate models including clinical variables, PlGF and other biomarkers showed good to very good discrimination for the development of PE, early-onset PE and fetal-neonatal SAEs (AUCs of 0.87, 0.89 and 0.79, respectively). Platelet-derived MVs were the best isolated biomarker for late-onset PE and, combined with systolic blood pressure, showed good discrimination (AUC: 0.81; 95% CI 0.71–0.92). For maternal SAEs, a model incorporating cfDNA and sFlt-1 provided excellent discrimination (AUC 0.92; 95% CI 0.82–1.00). Our findings suggest that multivariate models incorporating both clinical variables and first-trimester biomarkers may improve risk stratification for PE, especially for late-onset PE and for identifying women at risk of severe maternal or fetal complications. Notably, the inclusion of novel biomarkers such as cfDNA and MVs added value in clinical scenarios where the predictive performance of existing tools remains suboptimal. Full article

Uncomplicated hypertension (UH) during pregnancy represents a common condition, worsening maternal and fetal prognosis. However, no single biomarker has proven optimal for determining the risk of UH. We developed an early risk multivariate model for UH, integrating hemodynamics with biochemistry, focusing on the relationship between blood pressure (BP) indices, uric acid (UA), and angiogenesis-related factors (AF). We collected and analyzed data on 24 h ambulatory BP monitoring, demographic, epidemiological, clinical, and laboratory variables from 132 pregnancies. The main predictors were BP indices and serum UA and AF levels. Uncomplicated hypertension, defined as the presence of gestational hypertension or worsening of essential hypertension beyond the 20th week, was the main outcome. The combined second-degree polynomial transformation of UA and the AF (sFlt-1/PIGF) ratio, called the UA-AF Index, consistently showed a positive association with UH. The models incorporating nighttime BP indices combined with the UA-AF Index outperformed the others, with the best-performing model based on the nocturnal systolic BP (SBP). Specifically, in the best-fitting model (nighttime SBP + UA-AF Index as predictors), each 1 mmHg increase in nocturnal SBP was associated with a 10% higher risk of UH, while each one-unit increase in the UA-AF Index raised the likelihood of UH by more than twofold (accuracy: 0.830, AUC 0. 874, SE 0.032, p-value < 0.001, 95%CI 0.811–0.938). The combination of nighttime blood pressure indices, serum uric acid, and angiogenesis-related factors may provide added value in the assessment of uncomplicated hypertension during pregnancy. Full article

Purpose. Genetic engineering of mesenchymal stromal cells (MSCs) using viral vectors has emerged as a promising approach to enhance the efficacy of anti-angiogenic gene therapies. Umbilical cord-derived MSCs are an attractive cell source due to their easy accessibility and potential for genetic modification. Adeno-associated viruses (AAVs) have been utilized in clinical settings to deliver therapeutic genes due to its characteristic of transient integration into the genome. In this study, we investigated the efficacy of using recombinant AAV-engineered umbilical cord-derived MSCs overexpressing anti-angiogenic factor, hsFlt-1 (MSCs.hsFlt1). Methods. The plasmid containing the hsFlt-1 gene was cloned into the AAV2 target backbone and validated using Sanger sequencing. The transduction process was studied to determine the optimal conditions, including the effect of MOI, media serum percentage, and attachment of MSCs, to achieve higher transduction efficiency. The functionality of MSCs.hsFtl1 was analyzed using qPCR, ELISA, and tube formation assays. Results. MSCs.hsFtl1 transduced at an MOI of 1 × 10⁶ demonstrated high transduction efficiency and exhibited robust gene and protein expression of hsFlt-1. The results revealed significant inhibition of growth in human umbilical vein endothelial cells (HUVECs) using a remarkably low dose of MSCs.hsFlt1 at 12.3 ng/mL. This observed anti-angiogenic effect was comparable to the clinically used Bevacizumab. Conclusions. The anti-angiogenic potential of MSCs.hsFlt1 effectively demonstrated in this study suggests their promising utility for targeted anti-angiogenic gene therapy approaches. Full article

Background/Objectives: Lung cancer screening can reduce patient mortality. Multiple issues persist including timely management of patients with a radiologically defined indeterminate pulmonary nodule (IPN), which carries unknown pathological significance. This pilot study focused on combining demographic, clinical, radiographic, and common circulating biomarkers for their ability to aid in IPN risk of malignancy prediction. Methods: A case-control cohort consisting of 379 patients with IPNs (251 stage I lung tumors and 128 nonmalignant nodules) was used for this effort, divided into training (70%) and testing (30%) sets. Demographic variables (age, sex, race, ethnicity), radiographic information (nodule size and location), smoking pack-years, and plasma biomarker levels of CA-125, SCC, CEA, HE4, ProGRP, NSE, Cyfra 21-1, IL-6, PlGF, sFlt-1, hs-CRP, Ferritin, IgG, IgE, IgM, IgA, and Kappa and Lambda Free Light Chains were assessed for this purpose. Results: Multivariable analyses of biomarker, demographic, and radiographic variables yielded a model consisting of age, lesion size, pack-years, history of extrathoracic cancer, upper lobe location, spiculation, hs-CRP, NSE, Ferritin, and CA-125 (AUC = 0.872 in training, 0.842 in testing) with superior performance over the Mayo Score model, which consists of age, lesion size, history of smoking, history of extrathoracic cancer, upper lobe location, and spiculation (AUC = 0.816 in training, 0.787 in testing). Conclusions: In conclusion, a simple reduced algorithm consisting of biomarkers, clinical information, and demographic variables may have value for malignancy prediction of screen-detected IPNs. Upon further validation, this method stands to reduce the need for serial radiographic studies and the risks of diagnostic delay. Full article

Heartworm disease is caused by Dirofilaria immitis, which mainly affects canids and felids. Adult D. immitis worms are located between the heart’s right ventricle and the pulmonary artery. These parasites produce an inflammatory and hypoxic process in the vascular endothelium. It has been demonstrated that D. immitis excretory/secretory antigens are able to stimulate the angiogenic process as a survival mechanism of D. immitis in the vascular endothelium, stimulating the proangiogenic pathway and related cellular processes. Our goal was to study the role of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and galectin (GAL) (proteins of D. immitis excretory/secretory antigens) plus vascular endothelial growth factor isoform A (VEGF-A) in the angiogenic process and their relationship with three cellular processes (cell proliferation, cell migration, and pseudocapillary formation) in an in vitro model of vascular endothelial cells. Cell viability and cytotoxicity were analyzed by live cell analysis and a commercial kit, respectively. VEGF-A, sVEGFR-2, VEGFR-1/sFlt, soluble endoglin, and membrane endoglin were analyzed by commercial ELISA kits. Cell proliferation, cell migration, and pseudocapillary formation were analyzed by MTT-based assay, the wound healing technique, and counting cell connections and cell clusters, respectively. rDiGAPDH+VEGF-A and rDiGAL+VEGF-A significantly increased the expression of sVEGFR-2, mEndoglin, and VEGF-A compared to cultures treated with only the proteins (rDiGAPDH and rDiGAL), VEGF-A, or unstimulated cultures. In addition, they also produced a significant increase in cell proliferation, cell migration, and pseudocapillary formation. Therefore, these proteins together with VEGF-A can activate the proangiogenic pathway and could be related to D. immitis survival in the circulatory system. Full article

Objective: This study aimed to evaluate the dose-dependent therapeutic effects of pomegranate juice on preeclampsia symptoms using an L-NAME-induced rat model. Methods: Pregnant rats (n = 5/group) were assigned to a negative control group or groups receiving L-NAME to induce preeclampsia, with pomegranate juice administered at low, medium, and high doses from gestation day 7 to 20. Maternal parameters, including body weight, systolic blood pressure, urinary protein, and sFlt-1 levels, were monitored. Kidney and placental histology were assessed on gestation day 20. Results: L-NAME successfully induced preeclampsia symptoms, including significant maternal weight gain, hypertension, proteinuria, and increased sFlt-1 levels. Pomegranate juice administration alleviated these symptoms in a dose-dependent manner. High doses significantly prevented weight gain from gestation day 14, reduced the systolic blood pressure from gestation day 16, and lowered proteinuria and the sFlt-1 levels by gestation day 18, achieving values comparable to those of normal pregnant controls. Medium doses showed a moderate improvement, particularly in later gestational stages, while low doses had minimal effects. Pomegranate juice also enhanced placental health by increasing the labyrinth depth and reducing endocapillary hypercellularity, contributing to higher fetal and placental birth weights. The dose–response analysis indicated that the kidneys exhibited a stronger response to pomegranate juice than the placenta, suggesting different sensitivity thresholds. Conclusions: Pomegranate juice alleviates preeclampsia symptoms in a dose-dependent manner, significantly improving maternal weight regulation, blood pressure, and proteinuria. The therapeutic effects of pomegranate juice are attributed to its high phenolic content, which reduces sFlt-1 and improves placental function. These findings support pomegranate juice as a potential natural intervention for preeclampsia management. Full article