Higher sFlt-1 Research Articles

SARS-CoV-2 seroprevalence and preeclampsia markers in Mozambican pregnant women with perinatal loss

BackgroundSARS-CoV-2 infection during pregnancy is known to be associated with poor pregnancy outcomes, including pre-eclampsia (PE), prematurity, perinatal and maternal mortality. Data on the burden of SARS-CoV-2 infection among pregnant women and their offspring in Sub-Saharan Africa is limited. We aimed to estimate SARS-CoV-2 seroprevalence and determine PE biomarkers in Mozambican pregnant women with perinatal loss.MethodsA cross-sectional study was conducted among women who had a fetal or an early neonatal death at the Maputo Central Hospital (MCH), Mozambique. Anti-SARS-CoV-2 IgG/IgM were determined in maternal and umbilical cord blood and PE biomarkers (sFlt-1 and PIGF) in maternal blood. SARS-CoV-2 RT-PCR was performed in placenta and fetal lung biopsies from participants found to be SARS-CoV-2 seropositive.ResultsA total of 100 COVID-19 unvaccinated women were included in the study from March 2021 to April 2022. Total SARS-CoV-2 antibodies were detected in 68 [68%; 95CI (58 – 76)] maternal and 55 [55%; 95CI (54 – 74)] cord blood samples. SARS-CoV-2 IgM was detected in 18 cord blood samples and a positive placental RT-PCR in three of these participants. The proportion of women with moderate to high sFlt-1/PIGF ratio was higher in SARS-CoV-2 seropositive women than in those seronegative (71.2% vs 28.8%, p = 0.339), although the difference was not statistically significant.ConclusionsSARS-CoV-2 seroprevalence among Mozambican women with perinatal loss was high during the second pandemic year, and there was evidence of vertical transmission in stillbirths. Findings also suggest that maternal SARS-CoV-2 infection may increase the risk of developing PE.

Utility of placental biomarkers and fetoplacental Dopplers in predicting likely placental pathology in early and late fetal growth restriction – A prospective study

IntroductionThe aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality. MethodsThis was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified. ResultsThere were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively). ConclusionMVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity.

Soluble Fms-like tyrosine kinase-1 as an endothelial dysfunction biomarker associated with pulmonary hypertension in adult patients with beta-thalassemia major.

The etiology of vascular problems in beta-thalassemia has been linked to endothelial damage. Antiangiogenic proteins such as soluble Fms-like tyrosine kinase-1 (sFLT-1) inhibit the signaling of vascular endothelial growth factor and placental growth factor, resulting in a decrease in the development of new blood vessels. Additionally, they promote the maturation of existing blood vessels and lead to endothelial dysfunction. This study aimed to assess the role of sFLT-1 in adult patients with beta-thalassemia major (TM) as a biomarker of endothelial dysfunction and its association with pulmonary hypertension (PHT). A total of 90 subjects were recruited and categorized into two groups: 45 patients with beta-TM, who were further divided based on the presence or absence of PHT, and 45 healthy individuals served as a control group. Serum sFLT-1 was determined using the enzyme-linked immunosorbent assay technique. The results revealed that Beta-TM patients had higher sFLT-1 levels than the control group. In addition, patients with PHT had significantly higher sFLT-1 levels compared to those without PHT. The levels of sFLT-1 were positively correlated with von Willebrand factor, serum ferritin, and high-sensitivity C-reactive protein. Regression analyses demonstrated a significant association between high sFLT-1 levels and the occurrence of PHT. Additionally, sFLT-1 (at a cutoff value of 8.84 pg/mL) demonstrated a sensitivity of 83.30% and a specificity of 80.0% in diagnosing thalassemic patients with PHT. In conclusion, beta-TM patients with elevated serum levels of sFLT-1 are at risk of developing endothelial dysfunction and subsequent development of PHT.

Predictive Value of the sFlt-1/PlGF Ratio and Interleukin-6 for the Presence of Placental Lesions in Spontaneous Preterm Labor with Intact Membranes with Delivery within 7 Days.

The aim of the study was to identify predictive values of the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively. This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within 7 days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys® sFlt-1, PlGF, and IL-6 immunoassays. Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p &lt; 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs. 8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p &lt; 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL. Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within 7 days.

SFlt-1/PlGF ratio predicts serious outcomes in confirmed early-onset preeclampsia

ObjectivesWe aimed to determine whether a high ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) would be associated with serious negative consequences and shorter pregnancy duration in cases of early-onset preeclampsia (PE). Study designThis retrospective cohort study included women (n = 65) diagnosed with PE at <34.0 weeks of gestation and recruited from a single primary and tertiary medical centre in Japan. The sFlt-1/PlGF ratio in the study participants was measured. To determine the optimal threshold for the sFlt-1/PlGF ratio, a receiver operating characteristic curve was employed, with the aim of predicting serious adverse outcomes within 1 week after serum angiogenic marker measurements. We performed Kaplan–Meier analysis and the log-rank test to assess delivery probability based on the sFlt-1/PlGF ratio. ResultsThirty-seven women (56.9 %) delivered within 1 week of serum angiogenic marker measurements due to the aggravation of early-onset preeclampsia. Women who developed serious adverse outcomes within 1 week had a significantly higher sFlt-1/PlGF ratio than that of women who did not develop serious complications (408.5 vs. 166.6, P < 0.001). A cut-off value of 224.6 for the sFlt-1/PlGF ratio predicted serious adverse outcomes, with a sensitivity of 81.1 % and a specificity of 71.4 % (area under the curve: 0.77). Moreover, 78.9 % of women with an sFlt-1/PlGF ratio ≥ 224.6 compared to 25.9 % of those with an sFlt-1/PlGF ratio < 224.6 delivered within 1 week of presentation (P < 0.001). ConclusionsWomen with confirmed early-onset preeclampsia and high sFlt-1/PlGF ratio are more likely to develop serious adverse outcomes within 1 week after serum angiogenic marker measurements.

The prognostic value of extremely high sFlt-1/PLGF in the progression of early onset severe preeclampsia

The prognostic value of extremely high sFlt-1/PLGF in the progression of early onset severe preeclampsia

Comparison of competing-risks model with angiogenic factors in midgestation screening for preterm growth-related neonatal morbidity.

First, to evaluate the predictive performance for preterm growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF at midgestation and, second, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for small-for-gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight and uterine artery pulsatility index. This was a prospective observational study in women attending for a routine hospital visit at 19-24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFlt-1. The primary outcome was delivery < 32 and < 37 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile and the competing-risks model for SGA were estimated and then compared using McNemar's test. In the study population of 40 241 women, prediction of preterm growth-related neonatal morbidity provided by the competing-risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF ratio. For example, at a screen-positive rate of 10.0%, as defined by the sFlt-1/PlGF ratio > 90th percentile, the competing-risks model predicted 70.1% (95%CI, 61.0-79.2%) of SGA < 10th percentile and 76.9% (95%CI, 67.6-86.3%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered < 32 weeks' gestation. The respective values for SGA with major neonatal morbidity were 73.8% (95%CI, 64.4-83.2%) and 77.9% (95%CI, 68.0-87.8%). These were significantly higher than the respective values of 35.1% (95%CI, 25.6-44.6%), 35.9% (95%CI, 25.3-46.5%), 38.1% (95%CI, 27.7-48.5%) and 39.7% (95%CI, 28.1-51.3%) achieved by the application of the sFlt-1/PlGF ratio > 90th percentile (all P < 0.0001). At midgestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of preterm birth in women with fetal growth restriction - Is the weekly change in sFlt-1/PlGF ratio or PlGF levels useful?

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. 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. 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). 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.

Ophthalmic artery Doppler at 36 weeks' gestation in prediction of pre-eclampsia: validation and update of previous model.

To validate and extend a model incorporating maternal ophthalmic artery Doppler at 35-37 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE). This was a prospective validation study of screening for PE (defined according to the 2019 American College of Obstetricians and Gynecologists criteria) by maternal ophthalmic artery peak systolic velocity (PSV) ratio in 6746 singleton pregnancies undergoing routine care at 35 + 0 to 36 + 6 weeks' gestation (validation dataset). Additionally, the data from the validation dataset were combined with those of 2287 pregnancies that were previously used for development of the model (training dataset), and the combined data were used to update the original model parameters. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at any time and within 3 weeks from assessment by a combination of maternal demographic characteristics and medical history with PSV ratio alone and in combination with the established PE biomarkers of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). We evaluated the predictive performance of the model by examining, first, the ability to discriminate between the PE and non-PE groups using the area under the receiver-operating-characteristics curve and the detection rate (DR) at fixed screen-positive (SPR) and false-positive rates of 10% and, second, calibration by measuring the calibration slope and calibration-in-the-large. McNemar's test was used to compare the performance of screening by a biophysical test (maternal factors, MAP, UtA-PI and PSV ratio) vs a biochemical test (maternal factors, PlGF and sFlt-1), low PlGF concentration (< 10th percentile) or high sFlt-1/PlGF concentration ratio (> 90th percentile). In the validation dataset, the performance of screening by maternal factors and PSV ratio for delivery with PE within 3 weeks and at any time after assessment was consistent with that in the training dataset, and there was good agreement between the predicted and observed incidence of PE. In the combined data from the training and validation datasets, good prediction for PE was achieved in screening by a combination of maternal factors, MAP, UtA-PI, PlGF, sFlt-1 and PSV ratio, with a DR, at a 10% SPR, of 85.0% (95% CI, 76.5-91.4%) for delivery with PE within 3 weeks and 65.7% (95% CI, 59.2-71.7%) for delivery with PE at any time after assessment. The performance of a biophysical test was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio but not significantly different from the performance of a biochemical test combining maternal factors with PlGF and sFlt-1 for both PE within 3 weeks and PE at any time after assessment. Maternal ophthalmic artery PSV ratio at 35-37 weeks' gestation in combination with other biomarkers provides effective prediction of subsequent development of PE. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Screening for pre-eclampsia by maternal serum glycosylated fibronectin and angiogenic markers at 36 weeks' gestation.

First, to examine the predictive performance of maternal serum glycosylated fibronectin (GlyFn) at 35 + 0 to 36 + 6 weeks' gestation in screening for delivery with pre-eclampsia (PE) and delivery with gestational hypertension (GH) at ≥ 37 weeks' gestation, both within 3 weeks and at any time after the examination. Second, to compare the predictive performance for delivery with PE and delivery with GH of various combinations of biomarkers, including GlyFn, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Third, to compare the predictive performance for delivery with PE and delivery with GH by serum PlGF concentration, sFlt-1/PlGF concentration ratio and the competing-risks model with different combinations of biomarkers as above. Fourth, to compare the predictive performance of screening at 11 + 0 to 13 + 6 weeks vs 35 + 0 to 36 + 6 weeks for delivery with PE and delivery with GH at ≥ 37 weeks' gestation. This was a case-control study in which maternal serum GlyFn was measured in stored samples from a non-intervention screening study in singleton pregnancies at 35 + 0 to 36 + 6 weeks' gestation using a point-of-care device. We used samples from women who delivered at ≥ 37 weeks' gestation, including 100 who developed PE, 100 who developed GH and 600 controls who did not develop PE or GH. In all cases, MAP, UtA-PI, PlGF and sFlt-1 were measured during the routine visit at 35 + 0 to 36 + 6 weeks. We used samples from patients that had been examined previously at 11 + 0 to 13 + 6 weeks' gestation. Levels of GlyFn were transformed to multiples of the expected median (MoM) values after adjusting for maternal demographic characteristics and elements from the medical history. Similarly, the measured values of MAP, UtA-PI, PlGF and sFlt-1 were converted to MoM. The competing-risks model was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal risk factors, with various combinations of biomarker MoM values to derive the patient-specific risks of delivery with PE. The performance of screening of different strategies was estimated by examining the detection rate (DR) at a 10% fixed false-positive rate (FPR) and McNemar's test was used to compare the DRs between the different methods of screening. The DR, at 10% FPR, of screening by the triple test (maternal risk factors plus MAP, PlGF and sFlt-1) was 83.7% (95% CI, 70.3-92.7%) for delivery with PE within 3 weeks of screening and 80.0% (95% CI, 70.8-87.3%) for delivery with PE at any time after screening, and this performance was not improved by the addition of GlyFn. The performance of screening by a combination of maternal risk factors, MAP, PlGF and GlyFn was similar to that of the triple test, both for delivery with PE within 3 weeks and at any time after screening. The performance of screening by a combination of maternal risk factors, MAP, UtA-PI and GlyFn was similar to that of the triple test, and they were both superior to screening by low PlGF concentration (PE within 3 weeks: DR, 65.3% (95% CI, 50.4-78.3%); PE at any time: DR, 56.0% (95% CI, 45.7-65.9%)) or high sFlt-1/PlGF concentration ratio (PE within 3 weeks: DR, 73.5% (95% CI, 58.9-85.1%); PE at any time: DR, 63.0% (95% CI, 52.8-72.4%)). The predictive performance of screening at 35 + 0 to 36 + 6 weeks' gestation for delivery with PE and delivery with GH at ≥ 37 weeks' gestation was by far superior to screening at 11 + 0 to 13 + 6 weeks. GlyFn is a potentially useful biomarker in third-trimester screening for term PE and term GH, but the findings of this case-control study need to be validated by prospective screening studies. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Plasma VEGF-D and sFLT-1 are potential biomarkers of hemodynamics and congestion in heart failure and following heart transplantation

BackgroundInflammation and tyrosine-kinases are known mediators in the pathobiology of cardiovascular disease. Plasma biomarkers reflecting these systems may provide a non-invasive complement reflecting haemodynamics, aiding in clinical decision-making. We therefore aimed to investigate the plasma levels of vascular and inflammatory proteins, and their associations with invasive haemodynamics in advanced heart failure (HF) before, and at multiple follow-ups after heart transplantation (HT). MethodsUsing multiplex sandwich immunoassays, absolute plasma concentrations of nine vascular and inflammatory proteins were assessed in 26 patients with advanced HF, before-HT, and at four-weeks, six-months, and one-year after-HT. Right heart catheterization (RHC) haemodynamics were assessed at the time of blood sampling. Repeated measures correlations were performed to evaluate the overall intra-individual development of plasma protein levels in relation to haemodynamics’ development over time. ResultsOut of nine proteins included initially, in advanced HF, elevated plasma levels of vascular endothelial growth factor D (VEGF-D) and soluble fms-like tyrosine kinase-1 (sFlt-1) decreased most markedly, at four-weeks (p<0.0001), and decreased further at six-months (p<0.05) and at the one-year follow-ups after-HT (p<0.05). Over time, plasma VEGF-D correlated strongest with haemodynamic parameters including pulmonary arterial wedge pressure (PAWP) (rmr= 0.75, 95% bootstrapped confidence interval (CI) 0.61-0.84, p<0.0001), followed by mean right atrial pressure (MRAP) (rmr= 0.74, 95% CI 0.61-0.82, p<0.0001), and mean pulmonary arterial pressure (mPAP) (rmr= 0.74, 95% CI 0.58-0.82, p<0.0001). Plasma sFlt-1 correlated also with multiple haemodynamic parameters including PAWP (rmr= 0.66, 95% CI 0.58-0.79, p<0.0001), MRAP (rmr= 0.64, 95% CI 0.58-0.81, p<0.0001), and mPAP (rmr= 0.61, 95% CI 0.51-0.76, p<0.0001). ConclusionsIn advanced HF, elevated plasma VEGF-D and sFlt-1 levels decrease early, already within four weeks after HT, and further throughout the first year postoperatively. Our findings support that high plasma VEGF-D and sFlt-1 concentrations before HT are related to congestion, and overall haemodynamic improvement. Plasma VEGF-D and sFlt-1 may consequently be potential non-invasive biomarkers for monitoring hemodynamic deterioration and congestion in HF, and surveillance after HT.

Role of First Trimester Screening Biochemical Markers to Predict Hypertensive Pregnancy Disorders and SGA Neonates-A Narrative Review.

Early recognition of high-risk pregnancies through biochemical markers may promote antenatal surveillance, resulting in improved pregnancy outcomes. The goal of this study is to evaluate the possibilities of using biochemical markers during the first trimester of pregnancy in the prediction of hypertensive pregnancy disorders (HPD) and the delivery of small-for-gestational-age (SGA) neonates. A comprehensive search was conducted on key databases, including PubMed, Scopus, and Web of Science, for articles relating to the use of biochemical markers in the prediction of HPD and SGA. The findings show that changes in the levels of biomarkers in the early pregnancy phases could be an important indicator of adverse pregnancy outcomes. The literature shows that low PAPP-A (pregnancy-associated plasma protein A) and PlGF (placental growth factor) levels, low alkaline phosphatase (AP), higher sFlt-1 (soluble fms-like Tyrosine Kinase-1) levels, higher AFP (alfa fetoprotein) levels, and elevated levels of inflammatory markers such as β-HGC (free beta human chorionic gonadotropin), interferon-gamma (INF-γ), and tumor necrosis factor-α (TNF-α) may be associated with risks including the onset of HPD, fetal growth restriction (FGR), and delivery of SGA neonates. Comparatively, PAPP-A and PlGF appear to be the most important biochemical markers for the prediction of SGA and HPD.

Abstract 023: Prior Sflt1 Induced Preeclampsia Exacerbates Post-partum Hypertension-mediated Aortic Stiffness And Hypercholesterolemia-induced Atherosclerotic Inflammation

Preeclampsia (PE) is new high blood pressure (BP) and organ damage occurring late in pregnancy in association with increased soluble VEGF receptor (sFlt1). PE survivors have increased risk of future hypertension and myocardial infarction/stroke. We hypothesized that exposure to high sFlt1 during pregnancy exacerbates hypertension and atherosclerosis post-partum. PE was induced by transient adenoviral expression of sFlt1 compared to control virus in pregnant mice. PE mice had elevated sFlt1, BP and kidney damage during pregnancy which resolve post partum. Two months post-partum, prior PE mice had significantly increased BP response to high salt diet. After high BP stimuli, we studied large and small artery function. Prior PE mice had diminished nitric oxide-mediated vasodilation and stiffer aortas with more fibrosis as measured by pulse wave velocity (Con:3.7 vs sFlt:5.9 mm/ms, p&lt;0.0001) and trichrome staining (Con:13.7% vs sFlt:33.9%, p=0.0009). Atherosclerosis studies exposed LDLR knockout mice to PE followed by high fat diet feeding for 8 weeks. Body weight, fasting glucose and cholesterol were not altered by prior PE. Aortic roots were histologically analyzed for plaque size and composition. Aortic root plaque size (Con:73.3 vs sFlt:78.0 AU, p=0.60) and necrotic core were not different between groups. Aortic arch plaque inflammation was quantified via flow cytometry showing significantly increased plaque CD45+ leukocytes (sFlt:1.6 fold, p=0.036) and T cells (sFlt:1.8 fold, p=0.031) from mice with prior PE. Atheroprone mice with prior PE had significantly increased aortic expression of CCL22 (sFlt:1.5 fold, p=0.047), providing a potential mechanism for increased T cell infiltration into atherosclerotic plaques. Experimental PE produces a state of enhanced sensitivity to hypertensive stimuli and increased vascular inflammation in atherosclerotic plaques supporting the concept that PE directly exacerbates hypertension, vascular stiffness, and atherosclerotic inflammation independent of pre-existing risk factors.

Associations between Maternal sFlt-1/PlGF Ratio and Perinatal and Neonatal Outcomes in Newborns Born to Mothers with Preeclampsia

Purpose: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is considered a predictive marker of preeclampsia. However, the relationship between the sFlt-1/PlGF ratio and perinatal and neonatal outcomes remains unknown. This study aimed to determine the associations of the sFlt-1/PlGF ratio with perinatal and neonatal outcomes in newborns born to mothers with preeclampsia.Methods: This retrospective cohort study reviewed singleton neonates born to mothers with preeclampsia who underwent testing for the sFlt-1/PlGF ratio. We investigated the relationship between maternal sFlt-1/PlGF ratios and gestational age (GA), birth weight (Bwt), Bwt z-score, morbidities, and mortality of neonates born to mothers tested for the sFlt-1/PlGF ratio. Maternal sFlt-1/PlGF ratios examined within 30 days before delivery were used for analysis. Neonatal morbidities and mortality were investigated only in preterm infants born earlier than 32 weeks GA.Results: A total of 225 neonates were included, of which 163 (72.4%) were preterm infants. GA (&lt;i&gt;R&lt;/i&gt;=– 0.577, &lt;i&gt;p&lt;/i&gt;&lt;0.001), Bwt (&lt;i&gt;R&lt;/i&gt;=–0.713, &lt;i&gt;p&lt;/i&gt;&lt;0.001), and Bwt z-score (&lt;i&gt;R&lt;/i&gt;=–0.608, &lt;i&gt;p&lt;/i&gt;&lt;0.001) exhibited significant negative correlations with the sFlt-1/PlGF ratios. Among the 50 preterm infants born earlier than 32 weeks GA, neonatal morbidities were not significantly associated with the sFlt-1/PlGF ratio after adjusting for GA and Bwt.Conclusion: In mothers with preeclampsia, a higher sFlt-1/PlGF ratio was associated with the delivery of newborns with lower GA and lower Bwt. However, this ratio was not associated with increased morbidity or mortality in premature infants born earlier than 32 weeks GA.

HIGH SERUM RATIO OF SOLUBLE FMS-LIKE TYROSINE KINASE 1 (sFlt-1) TO PLACENTAL GROWTH FACTOR (PIGF) AND HIGH LEVEL OF LOW-DENSITY LIPOPROTEIN (LDL) AS RISK FACTORS OF PREECLAMPSIA

Preeclampsia is an obstetric disease that is a health problem worldwide, including in Indonesia. Several studies have shown that changes in the maternal spiral arteries are thought to lead to preeclampsia. Preeclampsia in this decade has been associated with changes in angiogenesis regulatory proteins originating from the placenta and circulating in the mother's blood circulation, namely soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). The author was interested in examining the ratio of sFlt-1/PIGF and low-density lipoprotein (LDL) to the incidence of preeclampsia in pregnant women. This study used a case control analytic observational design. The research sample was selected by consecutive sampling of 20 cases and 20 controls. Univariate analysis was used to describe patient characteristics descriptively, and bivariate analysis was used to determine the relationship between the 2 variables There is no significant difference in the characteristics of the research subjects. Low PIGF levels are a risk factor for preeclampsia (OR 4.33; p 0.0302) with a cut-off value of 24.5. High sFlt-1 levels are a risk factor for preeclampsia (OR 4.33; p 0.027) with a cut-off value of 869.5. A high sFlt-1/PIGF ratio is a risk factor for preeclampsia (OR 4.33 p 0.030) with a cut-off value of 38. High LDL levels are a risk factor for preeclampsia (OR 6.0; p 0.013) with a cut-off value of 150 ,2. Low placental growth factor (PIGF), high levels of soluble FMS-like tyrosine kinase 1 (sFlt-1), and high levels of LDL are risk factors of preeclampsia in pregnant women.

High Serum Ratio of Soluble Fms-Like Tyrosine Kinase 1 (sFlt-1) to Placental Growth Factor (PIGF) and High Level of Low-Density Lipoprotein (LDL) as Risk Factors of Preeclampsia

Preeclampsia is an obstetric disease that is a health problem worldwide, including in Indonesia. Several studies have shown that changes in the maternal spiral arteries are thought to lead to preeclampsia. Preeclampsia in this decade has been associated with changes in angiogenesis regulatory proteins originating from the placenta and circulating in the mother's blood circulation, namely soluble FMS-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF). The author was interested in examining the ratio of sFlt-1/PIGF and low-density lipoprotein (LDL) to the incidence of preeclampsia in pregnant women. This study used a case control analytic observational design. The research sample was selected by consecutive sampling of 20 cases and 20 controls. Univariate analysis was used to describe patient characteristics descriptively, and bivariate analysis was used to determine the relationship between the 2 variables There is no significant difference in the characteristics of the research subjects. Low PIGF levels are a risk factor for preeclampsia (OR 4.33; p 0.0302) with a cut-off value of 24.5. High sFlt-1 levels are a risk factor for preeclampsia (OR 4.33; p 0.027) with a cut-off value of 869.5. A high sFlt-1/PIGF ratio is a risk factor for preeclampsia (OR 4.33 p 0.030) with a cut-off value of 38. High LDL levels are a risk factor for preeclampsia (OR 6.0; p 0.013) with a cut-off value of 150 ,2. Low placental growth factor (PIGF), high levels of soluble FMS-like tyrosine kinase 1 (sFlt-1), and high levels of LDL are risk factors of preeclampsia in pregnant women.

High sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Pregnancy-Onset Thrombotic Thrombocytopenic Purpura.

HomeHypertensionAhead of PrintHigh sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Pregnancy-Onset Thrombotic Thrombocytopenic Purpura No AccessResearch ArticleRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessHigh sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor) Ratio in Pregnancy-Onset Thrombotic Thrombocytopenic Purpura Nicolas Béranger, Vassilis Tsatsaris, Paul Coppo, Agnès Veyradier and Bérangère S. Joly Nicolas BérangerNicolas Béranger https://orcid.org/0000-0002-0685-2349 Service d’Hématologie biologique, Hôpital Lariboisière, AP-HP.Nord (N.B., A.V., B.S.J.) EA-3518, Institut de Recherche Saint-Louis (N.B., A.V., B.S.J.) Search for more papers by this author , Vassilis TsatsarisVassilis Tsatsaris Correspondence to: Vassilis Tsatsaris, Maternité Port Royal, Hôpital Cochin, AP-HP.Centre.Université Paris Cité, 123, boulevard de Port Royal, 75014 Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0002-7650-6660 Maternité Port Royal, Hôpital Cochin, AP-HP.Centre, Université Paris Cité, France. (V.T.) Inserm UMR-S 1139, Physiopathologie et pharmacotoxicologie placentaire humaine, Université Paris Cité, France. (V.T.) Search for more papers by this author , Paul CoppoPaul Coppo Service d’Hématologie, Centre de référence des microangiopathies thrombotiques (CNR-MAT), Hôpital Saint-Antoine, AP-HP.Sorbonne Université, Paris, France (P.C.). Search for more papers by this author , Agnès VeyradierAgnès Veyradier Service d’Hématologie biologique, Hôpital Lariboisière, AP-HP.Nord (N.B., A.V., B.S.J.) EA-3518, Institut de Recherche Saint-Louis (N.B., A.V., B.S.J.) Search for more papers by this author and Bérangère S. JolyBérangère S. Joly Service d’Hématologie biologique, Hôpital Lariboisière, AP-HP.Nord (N.B., A.V., B.S.J.) EA-3518, Institut de Recherche Saint-Louis (N.B., A.V., B.S.J.) Search for more papers by this author Originally published12 May 2023https://doi.org/10.1161/HYPERTENSIONAHA.123.20987Hypertension. 2023;0FootnotesFor Sources of Funding and Disclosures, see page XXX.Correspondence to: Vassilis Tsatsaris, Maternité Port Royal, Hôpital Cochin, AP-HP.Centre.Université Paris Cité, 123, boulevard de Port Royal, 75014 Paris, France. Email vassilis.[email protected]fr Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.123.20987PMID: 37170814 Originally publishedMay 12, 2023 Keywordsischemiathrombotic microangiopathypregnancylife-threatening disorderspreeclampsiaPDF download Advertisement SubjectsBiomarkersPreeclampsiaPregnancyThrombosis

Predictive Value of Sflt-1/Plgf Ratio for Occurrence of Preeclampsia in Singleton Pregnancies: A Retrospective Study

Introduction: Preeclampsia is multisystem disorder of pregnancy, characterized by endothelial and placental dysfunction. It is classified as an early onset (which occurs &lt; 34 weeks) and late onset (which occurs ≥ 34 weeks). There is an increase of level of antiangiogenic factor of soluble form similar to tyrosine kinase 1 (sFlt-1) and decrease of level of proangiogenic placental growth factor (PlGF) at preeclampsia. High ratio sFlt-1/PlGF is connected to occurrence of preeclampsia. Materials and Methods: There was a retrospective study of the Clinic for Gynecology and Obstetrics of the University Clinical Center of Republic of Srpska (KGA UKC RS), which was implemented in period January 1st, 2020 – December 31st, 2021 and which included 224 patients hospitalized at the Department of Perinatology for suspected preeclampsia development, from 26+0 weeks of gestation until birth. One of the key criteria for the inclusion of patients in the study is the use of the sFlt-1/PlGF ratio as a marker for the onset of preeclampsia, and the determination of protein values in 24-hour urine (biuret). The antenatal state of the fetus was also monitored by ultrasound measurement of the flow resistance ratio (Ri) through the middle cerebral artery and the umbilical artery (C/U), as well as the values of the newborn’s Apgar score in the first and fifth minute of life (AS 1 and 5). The patients included in the study were divided into two groups according to gestational age: group 1 (&lt;33+6 NG) and group 2 (≥34NG). For the purposes of the research, data from patient protocol books for the specified period, as well as corresponding data from the Clinical Information System (KIS), were used. Results: Calculated values for cut off 38 for group 1 are: NPV= 76.9%, PPV=72.0%, sensitivity=85.7%, specificity=58.8%, and for group 2 are: NPV= 89 ,1%, PPV=40.8%, sensitivity=72.1%, specificity=68.5%. For cut off 85, the calculated values for group 1 are: NPV= 82.4%, PPV=85.7%, sensitivity=85.7%, specificity=82.4%, and for group 2 they are: NPV= 84.9 %, PPV=70.4%, sensitivity=44.2%, specificity=94.4%. For cutt off 110, the calculated values for group 1 are: NPV= 77.8%, PPV=85%, sensitivity=81%, specificity=82.4%, and for group 2 they are: NPV= 83.5 %, PPV=72.7%, sensitivity=37.2%, specificity=95.8%. The measured value of protein in 24h urine (biuret) in comparison with the measured values of the sFlt-1/PlGF ratio have statistical significance for predicting the onset of preeclampsia. Statistical data processing obtained by examining the measured values of the sFlt-1/PlGF ratio and the antenatal and natal condition of the fetus (C/U and AS 1 and 5) showed statistical significance, except for C/U for group 2, where p=0.32. Conclusion: Determination of the sFlt-1/PlGF ratio as well as biuret and monitoring of the antenatal and postnatal state of the fetus significantly contributes to the timely diagnostic of preeclampsia, which impacts reducing the incidence of undesirable outcomes for the mother and the fetus.

Аналіз перинатальних наслідків у жінок із високим і критичним рівнем співвідношення sFlt-1/PlGF

Purpose - to analyze the maternal and perinatal outcomes of pregnancy in women with high and critical water-soluble tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratios. Materials and methods. A prospective analysis of the course of pregnancy in 137 women with a threat of miscarriage aged 20 to 47 years was performed (the Group I - 60 patients with retrochorionic hematoma (RCH), the Group II - 77 patients with a threat of pregnancy termination without hematoma). Additionally, the level of sFlt-1/PlGF ratio was determined at gestational ages 19-23+6 weeks and 32-33+6 weeks using TRACE-technology (BRAHSMS Kryptor). Patients with a ratio value of more than 110 were included in the further study group. The antenatal risk of perinatal complications was assessed retrospectively in all patients according to the adapted Alberta perinatal health program scale. Results. The mean age of women in the Group I was 31.2±0.6 (95% CI: 30.0-32.4) years, and in the Group II - 32.2±0.6 (95% CI: 31.0-33.3) years (p=0.243 by t-test). The calculation of the risk of pre-eclampsia (PE) in women of the thematic groups using the Fetal medicine foundation (FMF) calculator «Preeclampsia risk assessment first and second trimester» revealed a high risk of its development in 28 (46.7%) women of the Group I against 23 (29.9%) women of the Group II (p=0.044 at 2). An analysis of the results of the sFlt-1/PlGF ratio at 19-23+6 weeks revealed a high or critical value in 7 (5.1%) cases. During the study of sFlt-1/PlGF at 32-33+6 weeks in both groups, cases of high or critical values of the ratio were observed in women who had no changes in the sFlt-1/PlGF ratio during the previous study at 19-23+6 weeks: in 3 cases - high value of the sFlt-1/PlGF ratio, in 1 case - critical. In all cases of high and critical levels of the ratio, the pregnancy ended prematurely due to the development of moderate or severe PE and fetal growth retardation. Conclusions. A high sFlt-1/PlGF ratio during the second half of pregnancy is associated with placental dysfunction (PD) and has a high predictive value. An important role is played by the gestational age at which these changes were first detected, as well as by a burdened medical history. The occurrence of RCH in early placentation increases the risk of developing PD and the obstetric complications associated with it. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness. Postpartum BP response to high salt intake was studied in women with prior preeclampsia. MR transcriptional activity was assessed in vitro in sFlt1-treated SMC by reporter assays and PCR. Preeclampsia was modeled by transient sFlt1 expression in pregnant mice. Two months post-partum, mice were exposed to high salt and then to AngII (angiotensin II) and BP and vasoconstriction were measured. Women exposed to preeclampsia had significantly enhanced salt sensitivity of BP verses those with a normotensive pregnancy. sFlt1 overexpression during pregnancy in mice induced elevated BP and glomerular endotheliosis, which resolved post-partum. The sFlt1 exposed post-partum mice had significantly increased BP response to 4% salt diet and to AngII infusion. In vitro, SMC-MR transcriptional activity in response to aldosterone or AngII was significantly increased after transient exposure to sFlt1 as was aldosterone-induced expression of AngII type 1 receptor. Post-partum, SMC-MR-KO mice were protected from the enhanced response to hypertensive stimuli after preeclampsia. Mechanistically, preeclampsia mice exposed to postpartum hypertensive stimuli develop enhanced aortic stiffness, microvascular myogenic tone, AngII constriction, and AngII type 1 receptor expression, all of which were prevented in SMC-MR-KO littermates. These data support that sFlt1-induced vascular injury during preeclampsia produces a persistent state of enhanced sensitivity of SMC-MR to activation. This contributes to postpartum hypertension in response to common stresses and supports testing of MR antagonism to mitigate the increased cardiovascular risk in women after PE.