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Introduction Transplacental fetal cell transfer results in the engraftment of fetal‐origin cells in the pregnant woman's body, a phenomenon termed fetal microchimerism. Increased fetal microchimerism measured decades postpartum is implicated in maternal inflammatory disease. Understanding which factors cause increased fetal microchimerism is therefore important. During pregnancy, circulating fetal microchimerism and placental dysfunction increase with increasing gestational age, particularly towards term. Placental dysfunction is reflected by changes in circulating placenta‐associated markers, specifically placental growth factor (PlGF), decreased by several 100 pg/mL, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), increased by several 1000 pg/mL, and the sFlt‐1/PlGF ratio, increased by several 10 (pg/mL)/(pg/mL). We investigated whether such alterations in placenta‐associated markers correlate with an increase in circulating fetal‐origin cells. Material and methods We included 118 normotensive, clinically uncomplicated pregnancies (gestational age 37+1 up to 42+2 weeks‘ gestation) pre‐delivery. PlGF and sFlt‐1 (pg/mL) were measured by Elecsys® Immunoassays. We extracted DNA from maternal and fetal samples and genotyped four human leukocyte antigen loci and 17 other autosomal loci. Paternally inherited, unique fetal alleles served as polymerase chain reaction (PCR) targets for detecting fetal‐origin cells in maternal buffy coat. Fetal‐origin cell prevalence was assessed by logistic regression, and quantity by negative binomial regression. Statistical exposures included gestational age (weeks), PlGF (100 pg/mL), sFlt‐1 (1000 pg/mL) and the sFlt‐1/PlGF ratio (10 (pg/mL)/(pg/mL)). Regression models were adjusted for clinical confounders and PCR‐related competing exposures. Results Gestational age was positively correlated with fetal‐origin cell quantity (DRR = 2.2, P = 0.003) and PlGF was negatively correlated with fetal‐origin cell prevalence (odds ratio [OR]100 = 0.6, P = 0.003) and quantity (DRR100 = 0.7, P = 0.001). The sFlt‐1 and the sFlt‐1/PlGF ratios were positively correlated with fetal‐origin cell prevalence (OR1000 = 1.3, P = 0.014 and OR10 = 1.2, P = 0.038, respectively), but not quantity (DRR1000 = 1.1, P = 0.600; DRR10 = 1.1, P = 0.112, respectively). Conclusions Our results suggest that placental dysfunction as evidenced by placenta‐associated marker changes, may increase fetal cell transfer. The magnitudes of change tested were based on ranges in PlGF, sFlt‐1 and the sFlt‐1/PlGF ratio previously demonstrated in pregnancies near and post‐term, lending clinical significance to our findings. Our results were statistically significant after adjusting for confounders including gestational age, supporting our novel hypothesis that underlying placental dysfunction potentially is a driver of increased fetal microchimerism. Alterations in the placental markers PlGF, sFlt‐1 and sFlt‐1/PlGF correlate with increased prevalence and quantity of nucleated fetal‐origin cells in maternal circulation in normotensive term pregnancies. Our novel findings raise questions about the potential for placental dysfunction to upregulate transplacental fetal cell transfer during pregnancy.

Introduction To assess the rate of change in soluble fms‐like tyrosine kinase‐1/placental growth factor (sFlt‐1/PlGF) ratio and PlGF levels per week compared to a single sFlt‐1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. Material and methods A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt‐1/PlGF ratio were measured at 4‐weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt‐1/PlGF ratio, change in PlGF levels per week or sFlt‐1/PlGF ratio per week. Cox‐proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. Results The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt‐1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85–0.76). The rate of increase per week of the sFlt‐1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39–10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25–1.67, p = 0.37, Harrell's C: 0.68). Conclusions Both a high sFlt‐1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt‐1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt‐1/PlGF ratio or low PlGF level. A single absolute high sFlt‐1/PlGF ratio or low PlGF level is sufficient to reliably predict PTB in women with FGR. The change in the sFlt‐1/PlGF ratio is not superior to either a single elevated sFlt‐1/PlGF ratio or low PlGF level.

The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1—sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR.

The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process. The aim of the present review is to highlight the contribution of VEGFs/VEGFR-1 signaling in the progression of different tumor types and to provide an overview of the therapeutic approaches targeting VEGFR-1 currently under investigation.

Preeclampsia involves an angiogenic imbalance, but circulating vascular endothelial growth factor A (VEGF A) remains inconsistently described, particularly in relation to maternal adiposity. We studied 90 second-trimester pregnancies, 30 uncomplicated and 60 with preeclampsia, recording maternal body mass index (BMI) and gestational age at sampling. Serum soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), and VEGF A were measured by enzyme-linked immunosorbent assay (ELISA), and the sFlt1-to-PlGF ratio was calculated. Preeclampsia was associated with higher pre-pregnancy and pregnancy BMI, lower PlGF, and an approximately threefold higher sFlt1-to-PlGF ratio, while sFlt1 alone was only borderline higher. VEGF A was elevated in preeclampsia and rose across higher sFlt1-to-PlGF ratio categories, supporting the interpretation of VEGF A within the integrated sFlt1,PlGF axis rather than as an isolated signal.

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.

Gestational diabetes mellitus (GDM) affects approximately 14% of pregnancies globally, with rising incidence depending on the diagnostic criteria used. In the UK, screening relies on risk factors at booking, followed by a diagnosis via an oral glucose tolerance test in the second trimester. This approach may lack sensitivity and has poor tolerability. Emerging evidence suggests that GDM pathophysiology begins in the first trimester, with biomarkers showing potential for early prediction. Identifying these could enable earlier risk stratification, improved diagnostic pathways, and better maternal–fetal outcomes. This scoping review maps the existing literature on first‐trimester biomarkers of GDM to evaluate their clinical utility and integration into predictive models. A literature search was conducted using Medline, Embase, and PubMed to identify studies on first‐trimester biomarkers of GDM. Inclusion criteria included (1) studies investigating biomarkers at <15 weeks' gestation; (2) studies that diagnosed GDM using an OGTT with recognized diagnostic guidelines or clearly stated glucose thresholds. A total of 133 studies were included, reporting a wide range of biomarkers (145 in total). PAPP‐A was generally lower in GDM, with mixed findings for β‐hCG and PlGF. Metabolic markers, including lipid profiles, fasting glucose, and HbA1c, were often elevated. Inflammatory markers, such as WCC, neutrophils, and CRP, were higher in those later diagnosed with GDM. First‐trimester biomarkers highlight GDM's complex pathophysiology. PAPP‐A shows predictive potential, while metabolic and inflammatory biomarkers suggest early systemic dysfunction. Emerging tools like 3D ultrasonography indicate placental structural changes. Larger studies are needed to validate these biomarkers and integrate them into predictive models to improve maternal–fetal outcomes. Of the 145 first‐trimester biomarkers identified for gestational diabetes mellitus, many show potential for early prediction. This highlights a window for intervention before the current clinical standards of diagnosis in the second trimester.

Vascular endothelial growth factor (VEGF) signalling mediates pleiotropic effects within the brain, encompassing angiogenesis, neuronal survival, and immune signalling. There is growing interest in the role of VEGF signalling in the pathophysiology of Alzheimer's disease (AD). The generation of single‐cell brain atlases and recent large multi‐omic studies, including analysis of CSF and bloods alongside post‐mortem brain tissue, have provided novel insights into the role of VEGF signalling in AD. Disruption of the VEGF‐A/VEGFR2 signalling pathway, due in part to elevated soluble VEGFR1 expression may contribute to pathogenic angiogenesis, BBB leakiness, and neuronal loss in AD. Induction of VEGF‐B/VEGFR1 signalling in microglia suggests that dysregulated VEGF‐mediated immune cell signalling is a further influence on AD pathogenesis. A reduction in expression of the ‘protective’ VEGFR3 and co‐receptors neuropilin 1 and 2 has also been recently linked to cognitive decline in AD. In large clinical studies, lower VEGF‐A levels in CSF and serum, raised soluble VEGFR1in CSF and elevated PlGF in CSF and serum, are predictive of more rapid cognitive decline and accelerated Alzheimer's disease neuropathological change (ADNC). This review discusses findings from recent multi‐omic studies of large clinical and neuropathological studies that prompt reconsideration of the nature of VEGF signalling in AD and shed light on some of the complexities and previous conflicts within the field.

Background: To evaluate the feasibility and clinical utility of developing a risk prediction model for placental abruption among patients with severe preeclampsia, incorporating maternal age, baseline systolic blood pressure (SBP), baseline diastolic blood pressure (DBP), retroplacental hematoma width, placental growth factor (PlGF), and the soluble fms-like tyrosine kinase-1/PlGF factor (sFlt-1/PlGF) ratio. Methods: This retrospective study enrolled 260 patients with severe preeclampsia who were admitted to the hospital from January 2022 to October 2024. The cases were randomly divided into a training set (n = 182) and a validation set (n = 78) in a 7:3 ratio. The primary outcome was placental abruption. Clinical data, imaging parameters, and biomarker levels were collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors. A nomogram was subsequently developed, and its predictive performance was evaluated and validated. Results: The incidence of placental abruption was 35.16% (64/182) in the training set and 33.33% (26/78) in the validation set. Multivariate logistic regression analysis identified age, baseline SBP, baseline DBP, retroplacental hematoma width, PlGF, and the sFlt-1/PlGF ratio as independent risk factors (all p < 0.05). The nomogram demonstrated good discriminative ability, with C-index values of 0.890 and 0.848 in the training and validation sets, respectively. The area under the curve (AUC) was 0.890 (95% confidence interval [CI]: 0.827–0.953) and 0.848 (95% CI: 0.733–0.963), respectively. Sensitivity was 0.766 in the training set and 0.588 in the validation set, whereas specificity was 0.890 and 0.944, respectively. Calibration curves showed excellent agreement between predicted and observed outcomes. The Hosmer-Lemeshow test yielded p-values of 0.583 and 0.290, respectively, suggesting good model fit. Conclusions: The nomogram model, incorporating age, baseline SBP, baseline DBP, retroplacental hematoma width, PlGF, and sFlt-1/PlGF ratio effectively predicted the risk of placental abruption in patients with severe preeclampsia. This model may support early clinical intervention. However, the use of single-center data and lack of external validation limit its generalizability, highlighting the need for further verification through multicenter studies.