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.

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.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Angiogenic factors and the lectin pathway of complement in women with secondary recurrent pregnancy loss.

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

Angiogenic imbalance in pregnancies with preterm prelabor rupture of membranes between 34 and 37 weeks of gestation.

INTRODUCTION: This study aimed to identify whether microbial invasion of the amniotic cavity and/or intra-amniotic inflammation in women with late preterm prelabor rupture of membranes (PPROM) was associated with changes in concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and its ratio in maternal serum, and whether placental features consistent with maternal vascular malperfusion further affect their concentrations. MATERIAL AND METHODS: This historical study included 154 women with singleton pregnancies complicated by PPROM between gestational ages 34+0 and 36+6 weeks. Transabdominal amniocentesis was performed as part of standard clinical management to evaluate the intra-amniotic environment. Women were categorized into two subgroups based on the presence of microorganisms and/or their nucleic acids in amniotic fluid (determined by culturing and molecular biology method) and intra-amniotic inflammation (by amniotic fluid interleukin-6 concentration evaluation): (1) those with the presence of microorganisms and/or inflammation (at least one present) and (2) those with negative amniotic fluid for infection/inflammation (absence of both). Concentrations of sFlt-1 and PlGF were assessed using the Elecsys® sFlt-1 and Elecsys® PlGF immunoassays and converted into multiples of medians. RESULTS: Women with the presence of microorganisms and/or inflammation in amniotic fluid had lower serum concentrations of sFlt-1 and sFlt-1/PlGF ratios and higher concentrations of PlGF compared with those with negative amniotic fluid. (sFlt-1: presence: median 1.0 multiples of the median (MoM), vs negative: median: 1.5 MoM, P = 0.003; PlGF: presence: median 0.7 MoM, vs negative: median 0.4 MoM, P = 0.02; sFlt-1/PlGF: presence: median 8.9 vs negative 25.0, P = 0.001). Higher serum concentrations of sFlt-1 and sFlt-1/PlGF ratios as well as lower concentrations of PlGF were found in the subsets of women with maternal vascular malperfusion than in those without maternal vascular malperfusion. CONCLUSIONS: Among women experiencing late PPROM, angiogenic imbalance in maternal serum is primarily observed in those without both microbial invasion of the amniotic cavity and intra-amniotic inflammation. Additionally, there is an association between angiogenic imbalance and the presence of maternal vascular malperfusion.

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

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.

Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.

BACKGROUND: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. METHOD: The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. RESULTS: At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30). CONCLUSIONS: People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. CLINICAL TRIAL: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791.

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

OBJECTIVE: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). DESIGN: Prospective, observational cohort study. SETTING: Tertiary maternity hospital in Australia. POPULATION: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). METHODS: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. MAIN OUTCOME MEASURES: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. RESULTS: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). CONCLUSIONS: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Reference Interval of Soluble FMS­like Tyrosine Kinase­1 in Non-Pregnant and Pregnant Females: A Novel Biomarker for Pre-eclampsia.

OBJECTIVE: To determine the reference interval of soluble FMS-like tyrosine kinase-1 (sFIt-1) in healthy, non-pregnant and pregnant females. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Chemical Pathology, Chughtai Institute of Pathology, Lahore, from January to May 2023. METHODOLOGY: Blood samples were collected from 120 disease-free non-pregnant females of reproductive age group and 120 disease-free pregnant females with singleton fetuses from 15 to 28 weeks of gestational age. Healthy reference individuals were selected by correlating history with medical disorders like diabetes mellitus, hypertension, autoimmune diseases, inherited disorders, and by excluding any other drug history. All findings were recorded on health screening questionnaire. Levels of sFlt-1 were measured by a fully automated immunoassay analyser Cobas e601. Kolmogorov-Smirnov test was applied. The value of p <0.05 was considered significant. The 2.5th and 97.5th percentiles were computed at 90% CI by using the formula 0.025x (n+1) and 0.975x (n+1) which corresponded to rank number 1 and 7, respectively. The reference interval was calculated by the Rank-based method. RESULTS: Reference interval of sFlt-1 in non-pregnant and pregnant females were determined on the basis of 2.5th and 97.5th percentiles which were 57.7 to 118.5 pg/mL and 563.5 to 3288.0 pg/mL, respectively. CONCLUSION: The present study determined reference interval of sFlt-1 in healthy, non-pregnant and pregnant females in Lahore. KEY WORDS: Reference interval, Soluble FMS-like tyrosine kinase-1, Pre-eclampsia, Rank-based method.

Aspirin Discontinuation at 24 to 28 Weeks' Gestation in Pregnancies at High Risk of Preterm Preeclampsia: A Randomized Clinical Trial.

Importance: Aspirin reduces the incidence of preterm preeclampsia by 62% in pregnant individuals at high risk of preeclampsia. However, aspirin might be associated with an increased risk of peripartum bleeding, which could be mitigated by discontinuing aspirin before term (37 weeks of gestation) and by an accurate selection of individuals at higher risk of preeclampsia in the first trimester of pregnancy. Objective: To determine whether aspirin discontinuation in pregnant individuals with normal soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1:PlGF) ratio between 24 and 28 weeks of gestation was noninferior to aspirin continuation to prevent preterm preeclampsia. Design, Setting, and Participants: Multicenter, open-label, randomized, phase 3, noninferiority trial conducted in 9 maternity hospitals across Spain. Pregnant individuals (n = 968) at high risk of preeclampsia during the first-trimester screening and an sFlt-1:PlGF ratio of 38 or less at 24 to 28 weeks of gestation were recruited between August 20, 2019, and September 15, 2021; of those, 936 were analyzed (intervention: n = 473; control: n = 463). Follow-up was until delivery for all participants. Interventions: Enrolled patients were randomly assigned in a 1:1 ratio to aspirin discontinuation (intervention group) or aspirin continuation until 36 weeks of gestation (control group). Main Outcomes and Measures: Noninferiority was met if the higher 95% CI for the difference in preterm preeclampsia incidences between groups was less than 1.9%. Results: Among the 936 participants, the mean (SD) age was 32.4 (5.8) years; 3.4% were Black and 93% were White. The incidence of preterm preeclampsia was 1.48% (7/473) in the intervention group and 1.73% (8/463) in the control group (absolute difference, -0.25% [95% CI, -1.86% to 1.36%]), indicating noninferiority. Conclusions and Relevance: Aspirin discontinuation at 24 to 28 weeks of gestation was noninferior to aspirin continuation for preventing preterm preeclampsia in pregnant individuals at high risk of preeclampsia and a normal sFlt-1:PlGF ratio. Trial Registration: ClinicalTrials.gov Identifier: NCT03741179 and ClinicalTrialsRegister.eu Identifier: 2018-000811-26.

Vascular Endothelial Growth Factor and Its Soluble Receptor in Systemic Lupus Erythematosus Patients.

Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis. Its soluble receptor (sVEGFR) is a potent VEGF antagonist. Systemic lupus erythematosus (SLE) is an autoimmune disease with a diverse array of clinical manifestations that affect virtually any organ. We aimed to analyze the relationship of VEGF and sVEGFR with SLE disease-related features including disease activity, damage, and severity. Serum levels of VEGF165 isoform and sVEGFR (receptor 1) were assessed in 284 well-characterized patients with SLE. Linear regression analysis was performed to analyze the relationship of disease characteristics with both VEGF and sVEGFR. Patients with a disease damage index (SLICC score) equal to or greater than 1 had significantly elevated serum levels of VEGF and sVEGFR. Regarding disease-specific features, musculoskeletal manifestations were the disease feature most commonly associated with the upregulation of both VEGF and sVEGFR. SLE disease damage is associated with higher levels of VEGF and sVEGFR.

Associations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia.

Background The angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are postulated to be pathogenic disease drivers of preeclampsia. If true, then circulating levels should become more deranged with increasing disease severity. Methods and Results We investigated the association between circulating sFlt-1 and PlGF levels and severe adverse maternal outcomes among 348 women with preeclampsia. Compared with 125 women with preeclampsia without severe features, 25 women with preeclampsia and any of hemolysis, elevated liver enzymes, low platelet count syndrome, disseminated intravascular coagulation, or severe renal involvement had sFlt-1 levels that were 2.63-fold higher (95% CI, 1.81-3.82), sFlt-1/PlGF levels that were 10.07-fold higher (95% CI, 5.36-18.91) and PlGF levels that were 74% lower (adjusted fold change, 0.26 [95% CI, 0.18-0.39]). Compared with 125 women with preeclampsia without severe features, 37 with eclampsia had sFlt-1 levels that were 2-fold higher (2.02 [95% CI, 1.32-3.09]), sFlt-1/PIGF levels that were 4.71-fold higher (95% CI, 2.30-9.66) and PIGF levels that were 63% lower (0.43-fold change [95% CI, 0.27-0.68]). Compared with those without severe features, preeclampsia with severe hypertension (n=146) was also associated with altered angiogenic levels (sFlt-1, 1.71-fold change [95% CI, 1.39-2.11]; sFlt/PlGF, 2.91 [95% CI, 2.04-4.15]; PlGF, 0.59 [95%CI 0.47-0.74]). We also found that sFlt-1 and PlGF levels were altered by the number of maternal complications experienced. Conclusions Further angiogenic imbalance among women with preeclampsia is likely a pathogenic disease driver responsible for the life-threatening maternal complications.

sFlt-1/PlGF Ratio at 24 Weeks Gestation in Twin Pregnancies as a Predictor of Preeclampsia or Fetal Growth Restriction.

INTRODUCTION: The objective was to elucidate if the sFlt-1/PlGF ratio at 24 weeks in twin pregnancies could be useful to select patients who subsequently develop diseases related to placental dysfunction, such as preeclampsia or fetal growth restriction (FGR). METHODS: This was a prospective study among all twin pregnancies followed up at a tertiary hospital. The sFlt-1/PlGF ratio was determined at 24 weeks. RESULTS: A total of 108 patients with a twin gestation were included. Pregnant women who developed preeclampsia and/or FGR displayed a significantly higher sFlt-1/PlGF ratio at 24 weeks, compared to those who did not develop these diseases (20.3 vs. 4.3, p = 0.002). The mean sFlt-1/PlGF ratio was not significantly different between patients who subsequently developed preeclampsia compared with those that developed FGR (29.8 vs. 18.45, p = 0.42). A sFlt-1/PlGF ratio ≥17 at 24 weeks is associated with a significant increase in the frequency of preeclampsia (odds ratio, 37.13 [95% confidence interval, 4.78-288.25]; p = 0.002), and FGR (odds ratio, 39.58 [95% confidence interval, 6.31-248.17]; p < 0.001). The addition of maternal characteristics and mean pulsatility index of the uterine arteries to the sFlt-1/PlGF ratio at 24 weeks enhances the identification of patients who develop preeclampsia or FGR. CONCLUSION: The sFlt-1/PlGF ratio at 24 weeks in twin pregnancies, combined with the mean pulsatility index of the uterine arteries and maternal characteristics, could select patients who develop preeclampsia or FGR. These patients might benefit from a close follow-up in order to avoid maternal-fetal adverse outcomes.

Distinguishing placenta accreta from placenta previa via maternal plasma levels of sFlt-1 and PLGF and the sFlt-1/PLGF ratio.

INTRODUCTION: Our study aimed to distinguish patients with placenta accreta (crete, increta, and percreta) from those with placenta previa using maternal plasma levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PLGF) and the sFlt-1/PLGF ratio. METHODS: We obtained maternal plasma from 185 women in late pregnancy and sorted them into three groups: 72 women with normal placental imaging results (control group), 50 women with placenta previa alone (PP group), and 63 women with placenta previa and placenta accreta (PAS group). The concentrations of sFlt-1 and PLGF in the maternal plasma were measured using ELISA kits and the sFlt-1/PLGF ratio was calculated. RESULT: The median (min-max) sFlt-1 levels and the sFlt-1/PLGF ratio in the PAS group (12.8 ng/ml, 3.8-34.2 ng/ml) (133, 14-361) were lower than in the PP group (28.7 ng/ml, 13.1-60.3 ng/ml) (621, 156-2013) (p < 0.0001 and P < 0.0001, respectively). The median (min-max) PLGF levels in the PAS group (108 pg/ml, 38-679 pg/ml) was higher than that in the PP group (43 pg/ml, 12-111 pg/ml) (p < 0.0001 and p < 0.0001, respectively). The area under the ROC of the sFlt-1 levels, PLGF levels, and sFlt-1/PLGF ratio were 0.91, 0.90, and 0.99, respectively; the cut-off values were 18.9 ng/ml, 75.9 pg/ml, and 229.5, respectively. The concentration of sFlt-1 and sFlt-1/PLGF ratio were associated with the volume of blood loss (-.288*, -.301*). DISCUSSION: The concentrations of sFlt-1 and PLGF and ratio of plasma sFlt-1/PLGF may distinguish patients with placenta accreta from those with placenta previa.

Soluble Fms-like tyrosine kinase-1 (sFlt-1) is associated with subclinical and clinical atherosclerotic cardiovascular disease: The Dallas Heart Study.

BACKGROUND AND AIMS: Soluble Fms-like tyrosine kinase-1 (sFlt-1) plays a role in angiogenesis, atherogenesis, and preeclampsia. The relationship of sFlt-1 with markers of subclinical atherosclerosis and future atherosclerotic cardiovascular disease (ASCVD) events in a generally healthy population is unknown. METHODS: Participants in the Dallas Heart Study with sFlt-1 measured were included (n = 3292). Abdominal aortic atherosclerosis was measured by MRI and coronary artery calcium (CAC) by CT. The cohort was also followed for subsequent ASCVD events (CV death, MI, stroke, unstable angina, revascularization). Multivariable linear and logistic regression analyses and Cox regression analyses were performed adjusting for demographics and traditional cardiac risk factors. RESULTS: sFlt-1 levels were higher in older individuals, males, and African Americans, and tracked with most traditional risk factors. sFlt-1 was significantly associated with higher prevalence of aortic plaque [OR 1.33 (95% CI 1.02-1.73)], greater abdominal aortic wall thickness (p<0.01) and aortic plaque area (p<0.02) but no difference in coronary artery calcification. There were 322 ASCVD events over 12 years of follow-up. Higher sFlt-1 levels associated with increased ASCVD events in unadjusted (16.1% vs. 8.9%, p<0.001, quartile 4 vs. quartile 1) and adjusted analyses (HR 1.58 [1.14-2.18], p<0.01, quartile 4 vs. quartile 1). Findings were unchanged when analyzing sFlt-1 as a continuous variable or when excluding those with a history of ASCVD. CONCLUSIONS: In a population-based cohort, sFlt-1 is associated with measures of subclinical aortic atherosclerosis and clinical ASCVD events. Future studies are warranted on the therapeutic potential of targeting sFlt-1 for atherosclerotic disease.

The feasibility of soluble Fms-Like Tyrosine kinase-1 (sFLT-1) and Placental Growth Factor (PlGF) ratio biomarker in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers in Kuala Lumpur, Malaysia.

BACKGROUND: Preeclampsia significantly contributes to maternal and perinatal morbidity and mortality. It is imperative to identify women at risk of developing preeclampsia in the effort to prevent adverse pregnancy outcomes through early intervention. Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) level changes are noticeable several weeks before the onset of preeclampsia and its related complications. This study evaluated the feasibility of the sFlt-1/PlGF biomarker ratio in predicting preeclampsia and adverse pregnancy outcomes using a single cut-off point of >38. METHODS: This is a prospective cohort study conducted at a single tertiary centre, in an urban setting in Kuala Lumpur, Malaysia, between December 2019 and April 2021. A total of 140 medium to high risk mothers with singleton pregnancies were recruited at ≥20 weeks' gestation. sFlt-1/PlGF ratio was measured and the participant monitored according to a research algorithm until delivery. The primary outcome measure was incidence of preeclampsia and the secondary outcome measure was incidence of other adverse pregnancy outcomes. RESULTS: The overall incidence of preeclampsia was 20.7% (29/140). The mean sFlt-1/PlGF ratio was significantly higher in preeclampsia (73.58 ± 93.49) compared to no preeclampsia (13.41 ± 21.63) (p = 0.002). The risk of preeclampsia (adjusted OR 28.996; 95% CI 7.920-106.164; p<0.001) and low Apgar score (adjusted OR 17.387; 95% CI 3.069-98.517; p = 0.028) were significantly higher among women with sFlt-1/PlGF ratio >38 compared with sFLT-1/PlGF ratio ≤38. The area under the receiver-operator characteristic curve (AUC) for a combined approach (maternal clinical characteristics and biomarker) was 86.9% (p<0.001, 95% CI 78.7-95.0) compared with AUC biomarker alone, which was 74.8% (p<0.001, 95% CI 63.3-86.3) in predicting preeclampsia. The test sensitivity(SEN) was 58.6%, specificity (SPEC) 91%,positive predictive value (PPV) 63% and negative predictive value (NPV) 89.3% for prediction of preeclampsia. For predicting a low Apgar score at 5 minutes, the SEN was 84.6%, SPEC 87.4%, PPV 40.7%, and NPV 98.2%; low birth weight with SEN 52.6%,SPEC 86.0%, PPV 37.0%, NPV 92.0%; premature delivery with SEN 48.5%, SPEC 89.5%, PPV 59.3%, NPV 84.7% and NICU admission with SEN 50.0%, SPEC 85.8%, PPV 37.0% and NPV 91.2%. CONCLUSIONS: It is feasible to use single cut-off point of >38 ratio of the biomarkers sFlt-1/PlGF in combination with other parameters (maternal clinical characteristics) in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers without restricting outcome measurement period to 1 and 4 weeks in a single urban tertiary centre in Kuala Lumpur, Malaysia.