Bowtie Nanoantenna LSPR Biosensor for Early Prediction of Preeclampsia.

OBJECTIVE: The concentration of the placental circulating factor in early pregnancy is often extremely low, and the traditional prediction method cannot meet the clinical demand for early detection preeclampsia in high-risk gravida. It is of prime importance to seek an ultra-sensitive early prediction method. METHODS: In this study, finite-different time-domain (FDTD) and Discrete Dipole Approximation (DDA) simulation, and electron beam lithography (EBL) methods were used to develop a bowtie nanoantenna (BNA) with the best field enhancement and maximum coupling efficiency. Bio-modification of the placental circulating factor (sFlt-1, PLGF) to the noble nanoparticles based on the amino coupling method were explored. A BNA LSPR biosensor which can specifically identify the placental circulating factor in preeclampsia was constructed. RESULTS: The BNA LSPR biosensor can detect serum placental circulating factors without toxic labeling. Serum sFlt-1 extinction signal (Δλmax) in the preeclampsia group was higher than that in the normal pregnancy group (14.37 ± 2.56 nm vs. 4.21 ± 1.36 nm), p = 0.008, while the serum PLGF extinction signal in the preeclampsia group was lower than that in the normal pregnancy group (5.36 ± 3.15 nm vs. 11.47 ± 4.92 nm), p = 0.013. The LSPR biosensor detection results were linearly consistent with the ELISA kit. CONCLUSIONS: LSPR biosensor based on BNA can identify the serum placental circulating factor of preeclampsia with high sensitivity, without toxic labeling and with simple operation, and it is expected to be an early detection method for preeclampsia.

Maternal prediabetes as a risk factor of preeclampsia and placental dysfunction in pregnant female Sprague-Dawley rats.

BACKGROUND: Prediabetes (PD) is associated with intermediate hyperglycaemia, dyslipidaemia, reduced nitric oxide (NO) bioavailability and moderate hypertension. All these factors are risk factor for preeclampsia (PE). However, the effects of the PD on placental function have not been shown. Accordingly, this study sought to investigate a possible link between maternal PD and the risk of developing PE. METHODS: Pregnant female Sprague-Dawley rats (N = 18) were divided into normal, preeclamptic and prediabetic groups (n = 6 in each group) to study the effects of maternal PD on placenta function over the period of 19 days. Blood glucose and blood pressure were measured on gestational day (GND) 0, 9 and 18. Placental vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) mRNA expression were measured terminally. Data were analysed using ANOVA followed by the Tukey-Kramer post hoc test. Values of p < .05 were used to indicate statistical significance. RESULTS: Maternal PD and PE significantly increased blood glucose, decrease NO concentration and increase in MAP by comparison to the normal pregnant control group. Maternal PD significantly decreased VEGF, PlGF mRNA expression with a slight increase in sFlt-1 mRNA expression comparison to the normal pregnant control group. CONCLUSIONS: Maternal PD is associated with placental dysfunction due to impaired glucose handling, endothelial dysfunction and an imbalance in angiogenic and antiangiogenic factors. Therefore, maternal PD is a risk factor of PE.

People with prediabetes (PD) are at risk of developing type 2 diabetes. Studies have shown that PD can cause blood vessel problems in both men and women. However, there have not been any studies on prediabetic pregnant women, so we do not know much about the pregnancy problems they might face. Looking into new factors related to blood vessel growth and health in PD could help us understand how to diagnose and manage PD during pregnancy. This could reduce the risk of problems similar to pre-eclampsia. Research in this area will help mothers and their doctors be more aware of the complications PD can cause during pregnancy. This could lead to fewer health problems and deaths for both mothers and babies linked to type 2 diabetes.

Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

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

OBJECTIVES: We 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 DESIGN: This 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. RESULTS: Thirty-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). CONCLUSIONS: Women 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.

Does the use of angiogenic biomarkers for the management of preeclampsia and fetal growth restriction improve outcomes?: Challenging the current status quo.

Monitoring and timing of delivery in preterm preeclampsia and fetal growth restriction is one of the biggest challenges in Obstetrics. Finding the optimal time of delivery of these fetuses usually involves a trade-off between the severity of the disease and prematurity. So far, most clinical guidelines recommend the use of a combination between clinical, laboratory and ultrasound markers to guide the time of delivery. Angiogenic biomarkers, especially placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), have gained significant attention in recent years for their potential role in the prediction and diagnosis of placenta-related disorders including preeclampsia and fetal growth restriction. Another potential clinical application of the angiogenic biomarkers is for the differential diagnosis of patients with chronic kidney disease, as this condition shares similar clinical features with preeclampsia. Consequently, angiogenic biomarkers have been advocated as tools for monitoring and deciding the optimal time of the delivery of fetuses affected by placental dysfunction. In this clinical opinion, we critically review the available literature on PlGF and sFlt-1 for the surveillance and time of the delivery in fetuses affected by preterm preeclampsia and fetal growth restriction. Moreover, we explore the use of angiogenic biomarkers for the differentiation between chronic kidney disease and superimposed preeclampsia.

A dynamic prediction model for preeclampsia using the sFlt-1/PLGF ratio combined with multiple factors.

OBJECTIVE: Preeclampsia (PE) is a pregnancy-related multi-organ disease and a significant cause of incidence rate and mortality of pregnant women and newborns worldwide. Delivery remains the only available treatment for PE. This study aims to establish a dynamic prediction model for PE. METHODS: A total of 737 patients who visited our hospital from January 2021 to June 2022 were identified according to the inclusion and exclusion criteria, forming the primary dataset. Additionally, 176 singleton pregnant women who visited our hospital from July 2022 to November 2022 comprised the verification set. We investigated different gestational weeks of sFlt-1/PLGF (soluble FMS-like tyrosine kinase-1, placental growth factor) ratio combined with maternal characteristics and routine prenatal laboratory results in order to predict PE in each trimester. Multivariate logistic regression was used to establish the prediction model for PE at different gestational weeks. The discrimination, calibration, and clinical validity were utilized to evaluate predictive models as well as models in external validation queues. RESULTS: At 20-24 weeks, the obtained prediction model for PE yielded an area under the curve of 0.568 (95% confidence interval, 0.479-0.657). At 25-29 weeks, the obtained prediction model for PE yielded an area under the curve of 0.773 (95% confidence interval, 0.703-0.842)and 0.731 (95% confidence interval, 0.653-0.809) at 30-34 weeks. After adding maternal factors, uterine artery pulsation index(Ut-IP), and other laboratory indicators to the sFlt-1/PLGF ratio, the predicted performance of PE improved. It found that the AUC improved to 0.826(95% confidence interval, 0.748 ∼ 0.904) at 20-24 weeks, 0.879 (95% confidence interval, 0.823 ∼ 0.935) at 25-29 weeks, and 0.862(95% confidence interval, 0.799 ∼ 0.925) at 30-34 weeks.The calibration plot of the prediction model indicates good predictive accuracy between the predicted probability of PE and the observed probability. Furthermore, decision-curve analysis showed an excellent clinical application value of the models. CONCLUSION: Using the sFlt-1/PLGF ratio combined with multiple factors at 25-29 weeks can effectively predict PE, but the significance of re-examination in late pregnancy is not significant.

Does a sFlt-1/PlGF ratio result > 655 before 34 weeks' gestation necessitate preterm delivery within 2 days? A retrospective observational study.

INTRODUCTION: Preeclampsia is associated with adverse perinatal outcomes, including fetal growth restriction (FGR) and preterm delivery. The maternal serum ratio of soluble fms-like tyrosine kinase receptor-1 (sFlt-1) to placental growth factor (PlGF) can be used to evaluate placental dysfunction in cases of preeclampsia and FGR. A need for delivery within 2 days has been recommended for sFlt-1/PlGF ratios > 655 (normal ratio < 38) measured before 34 weeks' gestation. However, few studies have assessed this recommendation in a real-world setting and there remains a need for further evidence-based guidance on the use of the ratio in delivery timing planning in this situation. AIM: To assess the need for delivery within 2 days associated with sFlt-1/PlGF ratios > 655 before 34 weeks' gestation. METHODS: A retrospective audit of all sFlt-1/PlGF ratio test results obtained at a single maternity hospital between September 2016 and November 2022. The primary outcome was time to delivery after recording a ratio > 655 in patients with a pregnancy between 20 + 0 and 33 + 6 weeks' gestation. Statistical analysis was performed using IBM SPSS Statistics v29.0.0.0. RESULTS: During the study period a total of 33 patients with suspected or confirmed preeclampsia and/or FGR recorded sFlt-1/PlGF ratios > 655 before 34 + 0 weeks' gestation. Amongst cases with ratios > 655, median time to delivery was 4 days (IQR 1.0-9.0), with 14 (42.4%) delivering in ≤ 2 days, 8 (24.2%) delivering between 2 and 7 days and 11 (33.3%) delivering after 7 days. A significant inverse correlation was observed between time to delivery and gestational age at the time of ratio testing (rs = -0.484, p = 0.004). DISCUSSION: This study provides updated recommendations on the use of the sFlt-1/PlGF ratio in predicting the risk of imminent delivery amongst those with high ratios > 655 measured before 34 weeks' gestation. Our results suggest that the risk of imminent delivery can be stratified based on ratio level and gestational age, which in combination with the results of other clinical assessments, can be used to plan delivery timing and allow for considerations of fetal lung maturing corticosteroid and neuroprotective magnesium sulfate therapies prior to delivery.

The value of angiogenetic biomarkers in the detection of early onset fetal growth restriction.

OBJECTIVE: The identification of fetal growth restriction (FGR) due to uteroplacental insufficiency is important to improve perinatal outcomes. To distinguish FGR from small for gestational age (SGA), FGR consensus definition is currently based on biometry and/or additional biophysical parameters. This study aims to verify if this definition might be modified by including circulating angiogenic factors. STUDY DESIGN: This historical cohort study included singleton pregnancies with SGA fetuses after 20 weeks. All patients underwent detailed ultrasound and measurements of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) at first assessment. ISUOG criteria for FGR were applied. Total PlGF was calculated using free PlGF, sFlt-1 and a receptor pharmacology model, and multiple of the median (MoM) values for sFlt-1, free PlGF, total PlGF and sFlt-1/PlGF ratio were calculated to adjust for gestational age. RESULTS: 72 pregnancies with SGA were first evaluated at median (IQR) of 28+5 (26+2 -31+3) weeks' gestation, and 51 fetuses (70.8 %) satisfied the FGR consensus definition. Pregnancies with FGR showed significantly lower levels of free and total PlGF MoM (0.12, 95 % IQR: 0.07-0.36 vs 0.32, 95 % IQR: 0.20-0.53, p = 0.008) and 0.26, 95 % CI: 0.16-0.55 vs 0.43, 95 % IQR: 0.23-0.53, p = 0.028) respectively; and higher sFlt-1 MoM (4.62, 95 % IQR: 1.80-7.30 vs 1.74, 95 % IQR:1.11-3.61, p = 0.014) than pregnancies not classified as FGR. Free and total PlGF MoM correlated significantly with gestational age at delivery (r = 0.776, p < 0.001 and r = 0.707, p < 0.001, respectively). sFlt-1 MoM and sFlt-1/PlGF ratio MoM also correlated with gestational age at delivery (r = -0.681, p < 0.001 and r = -0.823, p < 0.001). Six cases identified as FGR at first ultrasound were not confirmed at birth showing significantly higher levels of free PlGF MoM (0.77, 95 % IQR: 0.27-3.07 vs 0.17, 95 % IQR: 0.08-0.43, p = 0.022). CONCLUSION: These findings show that total as well as free PlGF levels are lower in pregnancies affected with placental growth restriction. Angiogenic biomarkers might improve the differentiation between placental growth restriction and constitutional smallness. Further studies are needed to determine how to integrate them into the current definitions of FGR.

Maternal serum biomarkers of placental insufficiency at 24-28 weeks of pregnancy in relation to the risk of delivering small-for-gestational-age infant in Sylhet, Bangladesh: a prospective cohort study.

BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders. RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025). CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.

Plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio of 11.5 multiples of median predicts preeclampsia with severe features within 2 weeks of testing.

BACKGROUND: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform. OBJECTIVE: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features. STUDY DESIGN: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death). RESULTS: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values. CONCLUSION: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks.

Analysis of Predictive Information From Biomarkers Added to Clinical Models of Preeclampsia: Consideration of PAPP-A2, Activin A, and sFlt-1:PlGF Ratio.

BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.

Repeat Placental Growth Factor-Based Testing in Women With Suspected Preterm Preeclampsia: A Stratified Analysis of the PARROT-2 Trial.

BACKGROUND: PlGF (placental growth factor)-based testing reduces severe maternal adverse outcomes. Repeat PlGF-based testing is not associated with improved perinatal or maternal outcomes. This planned secondary analysis aimed to determine whether there is a subgroup of women who benefit from repeat testing. METHODS: Pregnant individuals with suspected preterm preeclampsia were randomized to repeat revealed PlGF-based testing, compared with usual care where testing was concealed. Perinatal and maternal outcomes were stratified by trial group, by initial PlGF-based test result, and by PlGF-based test type (PlGF or sFlt-1 [soluble fms-like tyrosine kinase-1]/PlGF ratio). RESULTS: A total of 1252 pregnant individuals were included. Abnormal initial PlGF-based test identified a more severe phenotype of preeclampsia, at increased risk of adverse maternal and perinatal outcomes. Repeat testing was not significantly associated with clinical benefit in women with abnormal initial results. Of women with a normal initial result, 20% developed preeclampsia, with the majority at least 3 to 4 weeks after initial presentation. Repeat test results were more likely to change from normal to abnormal in symptomatic women (112/415; 27%) compared with asymptomatic women (163/890; 18%). A higher proportion of symptomatic women who changed from normal to abnormal were diagnosed with preeclampsia, compared with asymptomatic women. CONCLUSIONS: Our results do not demonstrate evidence of the clinical benefit of repeating PlGF-based testing if the initial result is abnormal. Judicious use of repeat PlGF-based testing to stratify risk may be considered at least 2 weeks after a normal initial test result, particularly in women who have symptoms or signs of preeclampsia. REGISTRATION: URL: https://www.isrctn.com/ISRCTN85912420; Unique identifier: ISRCTN85912420.

Urinary sFlt-1 and PlGF as preeclampsia predictors: sFlt-1/creatinine ratio improves the prediction value.

OBJECTIVES: To evaluate the correlation between maternal serum and urinary soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels and to assess their potential value in preeclampsia and fetal growth restriction. STUDY DESIGN: This case-control longitudinal prospective study was performed in 49 singleton pregnant women, divided into two clinical groups, low risk pregnancy (n = 23) and pregnancy complicated by preeclampsia (n = 26). Maternal serum and urinary sFlt-1 and PlGF levels were quantified by electrochemiluminescence. Every patient underwent an ultrasound for fetal biometry. Doppler assessment was done when estimated fetal weight was under the 10th centile. ROC curves were used to evaluate the predictive capability of serum and urinary angiogenic biomarkers and their ratios on preeclampsia. Linear regression was used to compare the values of serum and urinary sFlt-1 and PlGF and their ratios. RESULTS: Urine biomarkers were positively associated with their serum values, being the best associated urinary PlGF (R2 = 0.73), which also showed the highest predictive capability of preeclampsia of urine biomarkers (AUC 0.866). The predictive capability of urinary sFlt-1 was much lower (AUC 0.640), but increased when adjusting by serum creatinine, a more precise parameter (AUC 0.863). CONCLUSIONS: Urinary PlGF could be a lesser invasive alternative to circulating biomarkers to monitor pregnancies complicated with preeclampsia that need repeated controls of their pregnancy complication. Urinary sFlt-1 values need adjustment by serum creatinine to be reliable.

Reduced uterine perfusion pressure as a model for preeclampsia and fetal growth restriction in murine: a systematic review and meta-analysis.

The reduced uterine perfusion pressure (RUPP) model is frequently used to study preeclampsia and fetal growth restriction. An improved understanding of influential factors might improve reproducibility and reduce animal use considering the variability in RUPP phenotype. We performed a systematic review and meta-analysis by searching Medline and Embase (until 28 March, 2023) for RUPP studies in murine. Primary outcomes included maternal blood pressure (BP) or proteinuria, fetal weight or crown-rump length, fetal reabsorptions, or antiangiogenic factors. We aimed to identify influential factors by meta-regression analysis. We included 155 studies. Our meta-analysis showed that the RUPP procedure results in significantly higher BP (MD = 24.1 mmHg; [22.6; 25.7]; n = 148), proteinuria (SMD = 2.3; [0.9; 3.8]; n = 28), fetal reabsorptions (MD = 50.4%; [45.5; 55.2]; n = 42), circulating soluble FMS-like tyrosine kinase-1 (sFlt-1) (SMD = 2.6; [1.7; 3.4]; n = 34), and lower fetal weight (MD = -0.4 g; [-0.47; -0.34]; n = 113. The heterogeneity (variability between studies) in primary outcomes appeared ≥90%. Our meta-regression identified influential factors in the method and time point of BP measurement, randomization in fetal weight, and type of control group in sFlt-1. The RUPP is a robust model considering the evident differences in maternal and fetal outcomes. The high heterogeneity reflects the observed variability in phenotype. Because of underreporting, we observed reporting bias and a high risk of bias. We recommend standardizing study design by optimal time point and method chosen for readout measures to limit the variability. This contributes to improved reproducibility and thereby eventually improves the translational value of the RUPP model.

Biomarkers for Early Prediction and Management of Preeclampsia: A Comprehensive Review.

Preeclampsia is a common complication of pregnancy. It is a multi-organ disorder that remains one of the main causes of maternal morbidity and mortality. Additionally, preeclampsia leads to many complications that can occur in the fetus or newborn. Preeclampsia occurs in about 1 in 20 pregnant women. This review focuses on the prediction of preeclampsia in women, using various biomarkers, in particular, a factor combining the use of soluble FMS-like tyrosinokinase-1 (sFlt-1) and placental growth factor (PlGF). A low value of the sFlt-1/PlGF ratio rules out the occurrence of preeclampsia within 4 weeks of the test result, and its high value predicts the occurrence of preeclampsia within even 1 week. The review also highlights other factors, such as pregnancy-associated plasma protein A, placental protein 13, disintegrin and metalloprotease 12, ß-human chorionic gonadotropin, inhibin-A, soluble endoglin, nitric oxide, and growth differentiation factor 15. Biomarker testing offers reliable and cost-effective screening methods for early detection, prognosis, and monitoring of preeclampsia. Early diagnosis in groups of women at high risk for preeclampsia allows for quick intervention, preventing the undesirable effects of preeclampsia. However, further research is needed to validate and optimize the use of biomarkers for more accurate prediction and diagnosis. This article aims to review the role of biomarkers, including the sFlt1/PlGF ratio, in the prognosis and management of preeclampsia.

Value of soluble fms-like tyrosine kinase 1 for predicting acute pancreatitis severity: a systematic review and meta-analysis.

OBJECTIVE: The objective of this study was to explore the relationship between serum soluble fms-like tyrosine kinase 1 and the severity of acute pancreatitis and its diagnostic utility. METHODS: This study was carried out by searching Chinese and English literature from the establishment of the database to July 9, 2023, systematically, and assessing the quality and heterogeneity of the articles included. RESULTS: Thirteen studies with a total of 986 patients were included. Patients with severe acute pancreatitis showed higher levels of soluble fms-like tyrosine kinase 1 compared with mild acute pancreatitis [weighted mean difference=76.64 pg/mL, 95% confidence interval (95%CI 50.39-102.89, p<0.001)]. Soluble fms-like tyrosine kinase 1 predicted pooled sensitivity, specificity, and area under the curve were 79%, 74%, and 0.85 for severe acute pancreatitis, with some heterogeneity (I2>50% or p<0.05). In the subgroup analysis, cutoff >150 pg/mL was found to be a heterogeneous factor. CONCLUSION: Soluble fms-like tyrosine kinase 1 is a reliable tool for identifying acute pancreatitis severity, but only as a screening tool.

The sFLT-1/PlGF Ratio for the Prediction of Preeclampsia-Related Adverse Fetal and Maternal Outcomes in Women with Preexisting Diabetes.

To evaluate the predictive value of the sFlt-1/PlGF ratio for the prediction of preeclampsia in women with preexisting diabetes mellitus. This is a monocentric retrospective observational study conducted between January 2018 and December 2020. All singleton pregnancies with preexisting diabetes mellitus, who had a dosage of the sFlt-1/PlGF ratio between 30 and 34 + 6 weeks of gestation were included. The principal outcome was preeclampsia. The secondary outcomes were preterm preeclampsia, gestational hypertension, placental abruption, intrauterine fetal death, IUGR, small for gestational age and a composite outcome named "hypertensive disorder of pregnancy" including gestational hypertension, preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count). Of 63 patients, 22% presented preeclampsia. The area under the curve of sFlt-1/PlGF ratio was 0.90 (95% CI: 0.79-0.96) for the prediction of preeclampsia. The receiver operator characteristic analysis suggested that the optimal sFlt-1/PlGF cutoff to predict preeclampsia was 29, with a sensitivity of 86% (95% CI: 60.1-96.0) and a specificity of 92% (95% CI: 80.8-96.8). A cut-off of 38 provided a sensitivity of 71% (95% CI: 45.4-88.3), a specificity of 92% (95% CI: 80.8-96.8). Further analysis using multivariable methods revealed nephropathy was significantly associated with PE (p = 0.014). The use of the sFlt-1/PlGF ratio during the third trimester of pregnancy seems to be of interest as a prognostic tool to improve multidisciplinary management of patients with preexisting diabetes mellitus.

Stability of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1).

Placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) are biomarkers used for diagnosis and risk estimation of preeclampsia. Stability in room temperature (RT) may affect the usefulness of these analyses, as shipping at ambient temperature is the most practical and suitable way to ship samples. To date, scientific studies of such stability are lacking. We aimed to assess the stability of PlGF and sFlt-1 at RT in serum from pregnant women. In addition, a smaller study of stability at 4 °C was performed. Serum was collected from 69 pregnant women and stored at RT or at 4 °C for up to 192 h. Analytes were considered stable if the mean percent change ± 90 confidence interval of the mean was within the baseline concentration ± allowable bias. Allowable bias was calculated from data on biological variation. In addition, an instability equation was calculated to assess loss of stability, in line with recent European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recommendations. The mean percent change was <3.5% for PlGF, <1% for sFlt-1 and <4.5% for sFlt-1/PlGF ratio up to 192 h. PlGF was considered stable for 168 h, and sFlt-1 and sFlt-1/PlGF ratios were considered stable for 192 h at RT. At 4 °C, PlGF was considered stable for 120 h, sFlt-1 for 168 h and sFlt-1/PlGF ratio for 120 h. Both PlGF and sFlt-1 as well as sFlt-1/PlGF ratio show sufficient stability (minimum 168 h) for samples to be shipped at RT.

Prediction of preeclampsia using maternal circulating mRNAs in early pregnancy.

PURPOSE: Preeclampsia (PE) is one of the most common and serious complications of pregnancy, and novel methods for the early prediction of PE are needed for clinical application. METHODS: In this study, a circulating cell-free RNA (cfRNA) panel of target genes for PE prediction was designed and validated in a case-control cohort and a nested case-control cohort. The QPCR was applied to quantify the copy number of cfRNA, and the data were normalized as multiples of the median. Ratios of serum placental growth factor (PIGF) and soluble fms-like tyrosine kinase 1 (sFLT-1) were also measured, and transabdominal ultrasonography was conducted for subjects in the prospective cohort. Binary logistic regression models for PE prediction were constructed and tested. RESULTS: Our results revealed that the women with PE showed significant alterations in serum cfRNA profiles from early pregnancy onward and before the onset of PE symptoms. Compared with PIGF/sFLT-1 measurement and ultrasonographic imaging, cfRNA test can detect PE at a very early stage of pregnancy. The predictive model exhibited the best performance at gestation week 32, with a detection rate of 100%. At 12 weeks of gestation, the model still manifested an area under curve (AUC) of 0.9144, and sensitivity of 1.0000. If combined with clinical parameters and ultrasonographic indicators, the model can achieve the highest AUC for PE prediction at early gestation. CONCLUSION: Measurement of cfRNA can be used to effectively predict PE with high performance, providing an additional method for monitoring PE throughout the course of pregnancy.