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.

The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor predicts time to delivery and mode of birth in patients with suspected preeclampsia: a secondary analysis of the INSPIRE trial.

BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor is a useful biomarker for preeclampsia. Since it is a measure of placental dysfunction, it could also be a predictor of clinical deterioration and fetal tolerance to intrapartum stress. OBJECTIVE: We tested the hypothesis that soluble fms-like tyrosine kinase 1 to placental growth factor ratio predicts time to delivery. Secondary objectives were to examine associations between the soluble fms-like tyrosine kinase 1 to placental growth factor ratio and mode of birth, fetal distress, need for labor induction, and birthweight z score. STUDY DESIGN: Secondary analysis of the INSPIRE trial, a randomized interventional study on prediction of preeclampsia/eclampsia in which women with suspected preeclampsia were recruited and their blood soluble fms-like tyrosine kinase 1 to placental growth factor ratio was assessed. We stratified participants into 3 groups according to the ratio result: category 1 (soluble fms-like tyrosine kinase 1 to placental growth factor ≤38); category 2 (soluble fms-like tyrosine kinase 1 to placental growth factor >38 and <85); and category 3 (soluble fms-like tyrosine kinase 1 to placental growth factor ≥85). We modeled time from soluble fms-like tyrosine kinase 1 to placental growth factor determination to delivery using Kaplan-Meier curves and compared the 3 ratio categories adjusting for gestational age at soluble fms-like tyrosine kinase 1 to placental growth factor determination and trial arm with Cox regression. The association between ratio category and mode of delivery, induction of labor, and fetal distress was assessed using a multivariable logistic regression adjusting for gestational age at sampling and trial arm. The association between birthweight z score and soluble fms-like tyrosine kinase 1 to placental growth factor ratio was evaluated using multiple linear regression. Subgroup analysis was conducted in women with no preeclampsia and spontaneous onset of labor; women with preeclampsia; and participants in the nonreveal arm. RESULTS: Higher ratio categories were associated with a shorter latency from soluble fms-like tyrosine kinase 1 to placental growth factor determination to delivery (37 vs 13 vs 10 days for ratios categories 1-3 respectively), hazards ratio for category 3 ratio of 5.64 (95% confidence interval 4.06-7.84, P<.001). A soluble fms-like tyrosine kinase 1 to placental growth factor ratio ≥85 had specificity of 92.7% (95% confidence interval 89.0%-95.1%) and sensitivity of 54.72% (95% confidence interval, 41.3-69.5) for prediction of preeclampsia indicated delivery within 2 weeks. A ratio category 3 was also associated with decreased odds of spontaneous vaginal delivery (Odds ratio [OR] 0.47, 95% confidence interval 0.25-0.89); an almost 6-fold increased risk of emergency cesarean section (OR 5.89, 95% confidence interval 3.05-11.21); and a 2-fold increased risk for intrapartum fetal distress requiring operative delivery or cesarean section (OR 3.04, 95% confidence interval 1.53-6.05) when compared to patients with ratios ≤38. Higher ratio categories were also associated with higher odds of induction of labor when compared to ratios category 1 (category 2, OR 2.20, 95% confidence interval 1.02-4.76; category 3, OR 6.0, 95% confidence interval 2.01-17.93); and lower median birthweight z score. Within subgroups of women a) without preeclampsia and with spontaneous onset of labor and b) women with preeclampsia, the log ratio was significantly higher in patients requiring intervention for fetal distress or failure to progress compared to those who delivered vaginaly without intervention. In the subset of women with no preeclampsia and spontaneous onset of labor, those who required intervention for fetal distress or failure to progress had a significantly higher log ratio than those who delivered vaginaly without needing intervention. CONCLUSION: The soluble fms-like tyrosine kinase 1 to placental growth factor ratio might be helpful in risk stratification of patients who present with suspected preeclampsia regarding clinical deterioration, intrapartum fetal distress, and mode of birth (including the need for intervention in labor).

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.

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.

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.

Longitudinal assessment of angiogenic markers in prediction of adverse outcome in women with confirmed pre-eclampsia.

OBJECTIVES: Angiogenic marker assessment, such as the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF), is known to be a useful tool in the prediction of pre-eclampsia (PE). However, evidence from surveillance strategies in pregnancies with a PE diagnosis is lacking. Therefore, we aimed to assess the predictive performance of longitudinal maternal serum angiogenic marker assessment for both maternal and perinatal adverse outcomes when compared to standard laboratory parameters in pregnancies with confirmed PE. METHODS: This was a retrospective analysis of prospectively collected data from January 2013 to December 2020 at the Medical University of Vienna. The inclusion criteria were singleton pregnancy with confirmed PE and post-diagnosis maternal serum angiogenic marker assessment at a minimum of two timepoints. The primary outcome was the predictive performance of longitudinal sFlt-1 and PlGF assessment for adverse maternal and perinatal outcomes compared to conventional laboratory monitoring at the same time in pregnancies with confirmed PE. Composite adverse maternal outcome included intensive care unit admission, pulmonary edema, eclampsia and/or death. Composite adverse perinatal outcome included stillbirth, neonatal death, placental abruption, neonatal intensive care unit admission, intraventricular hemorrhage, necrotizing enterocolitis, respiratory distress syndrome and/or mechanical ventilator support. RESULTS: In total, 885 post-diagnosis sFlt-1/PlGF ratio measurements were obtained from 323 pregnant women with confirmed PE. For composite adverse maternal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (area under the receiver-operating-characteristics curve (AUC), 0.72 (95% CI, 0.62-0.81)), creatinine (AUC, 0.71 (95% CI, 0.62-0.81)) and lactate dehydrogenase (LDH) levels (AUC, 0.73 (95% CI, 0.65-0.81)). Maternal platelet levels (AUC, 0.65 (95% CI, 0.55-0.74)), serum alanine aminotransferase (ALT) (AUC, 0.59 (95% CI, 0.49-0.69)) and aspartate aminotransferase (AST) (AUC, 0.61 (95% CI, 0.51-0.71) levels had poor standalone predictive accuracy. The best prediction model consisted of a combination of maternal serum LDH, creatinine levels and sFlt-1/PlGF ratio, which had an AUC of 0.77 (95% CI, 0.68-0.85), significantly higher than sFlt-1/PlGF ratio alone (P = 0.037). For composite adverse perinatal outcome, the highest standalone predictive accuracy was obtained using maternal serum sFlt-1/PlGF ratio (AUC, 0.82 (95% CI, 0.75-0.89)) and creatinine (AUC, 0.74 (95% CI, 0.67-0.80)) levels, sFlt-1/PlGF ratio being superior to creatinine alone (P < 0.001). Maternal serum LDH levels (AUC, 0.65 (95% CI, 0.53-0.74)), platelet count (AUC, 0.57 (95% CI, 0.44-0.67)), ALT (AUC, 0.58 (95% CI, 0.48-0.67)) and AST (AUC, 0.58 (95% CI, 0.48-0.67)) levels had poor standalone predictive accuracy. No combination of biomarkers was superior to maternal serum sFlt-1/PlGF ratio alone for prediction of composite adverse perinatal outcome (P > 0.05 for all). CONCLUSIONS: In pregnancies with confirmed PE, longitudinal maternal serum angiogenic marker assessment is a good predictor of adverse maternal and perinatal outcomes and superior to some conventional laboratory parameters. Further studies should focus on optimal surveillance following diagnosis of PE. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prognostic value of angiogenic markers in pregnancies with fetal growth restriction.

OBJECTIVE: Pregnancies with fetal growth restriction are at increased risk of preeclampsia. Angiogenic markers including soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by fetal growth restriction (FGR). The utility of these markers as a predictor of preeclampsia in women with growth-restricted fetuses is still uncertain. This study aims to evaluate the prognostic value of angiogenic markers for predicting the development of preeclampsia in pregnancies with FGR and suspected preeclampsia. METHODS: This study included 93 women with FGR, defined according to Delphi consensus criteria, who were assessed for angiogenic markers sFlt-1 and PlGF for suspicion of preeclampsia at the Department of Obstetrics and feto-maternal Medicine at the Medical University of Vienna between 2013 and 2020. Women with established diagnosis of preeclampsia at sampling were excluded. Cox regression analysis and logistic regression were performed to demonstrate the association of angiogenic markers with the outcome. RESULTS: Within this cohort, 14 women (15.1%) developed preeclampsia within one week from sampling, 21 (22.6%) within two weeks, 38 (40.9%) at any time. The sFLT-1/PLGF ratio consistently showed a stronger association with development of preeclampsia compared to sFlt-1 or PlGF alone in pregnancies with fetal growth restriction (PE within a week, AUC 0.85 vs 0.82 and 0.72, respectively). Models including sFlt-1/PlGF were more strongly associated with preeclampsia hazard compared to sFlt-1 and PlGF alone models (C-index: 0.79±0.046 vs 0.76±0.048 and 0.75±0.047, respectively). Risk classification capabilities of sFlt-1/PlGF decreased after the two-week time point. The established cut-off value for ruling out preeclampsia (sFlt-1/PlGF ratio <38) was effective with a negative predictive value of 93.3% and sensitivity of 95.2%. CONCLUSION: Combined use of sFlt-1/PlGF can be preferred to PlGF alone in pregnancies with fetal growth restriction. Moreover, established cut-offs for ruling-out development of preeclampsia seem to be effective in these patients. This article is protected by copyright. All rights reserved.

Markers of placental function correlate with prevalence and quantity of nucleated fetal cells in maternal circulation in normotensive term pregnancies.

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

The sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction: A historical cohort study.

INTRODUCTION: The velocity of fetal deterioration in fetal growth restriction is extremely variable, which makes monitoring and counseling very challenging. The soluble fms-like tyrosine kinase to placental growth factor (sFlt1/PlGF) ratio provides a readout of the vasoactive environment that correlates with preeclampsia and fetal growth restriction and that could be useful to predict fetal deterioration. Previous studies showed a correlation between higher sFlt1/PlGF ratios and lower gestational ages at birth, although it is unclear whether this is due to the increased incidence of preeclampsia. Our goal was to evaluate whether the sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction. MATERIAL AND METHODS: This was a historical cohort study in a tertiary maternity hospital. Data from singleton pregnancies with early fetal growth restriction (diagnosed before 32 gestational weeks) confirmed after birth monitored between January 2016 and December 2020 were retrieved from clinical files. Cases of chromosomal/fetal abnormalities, infection and medical terminations of pregnancy were excluded. The sFlt1/PlGF ratio was acquired at diagnosis of early fetal growth restriction in our unit. The correlation of log10 sFlt1/PlGF with latency to delivery/fetal demise was assessed with linear, logistic (positive sFlt1/PlGF if >85) and Cox regression excluding deliveries for maternal conditions and controlling for preeclampsia, gestational age at time of ratio test, maternal age and smoking during pregnancy. Receiver-operating characteristic (ROC) analysis tested the performance of sFlt1/PlGF ratio in predicting delivery for fetal reasons in the following week. RESULTS: 125 patients were included. Mean sFlt1/PlGF ratio was 91.2 (SD 148.7) and 28% of patients had a positive ratio. A higher log10 sFlt1/PlGF ratio predicted shorter latency for delivery/fetal demise in linear regression after controlling for confounders, ß = -3.001, (-3.713 to -2.288). Logistic regression with ratio positivity confirmed these findings (latency for delivery 5.7 ± 3.32 weeks for ratios ≤85 vs 1.9 ± 1.52 weeks for ratios >85); ß = -0.698 (-1.064 to -0.332). Adjusted Cox regression showed that a positive ratio confers a significantly positive hazard ratio (HR) for earlier delivery/fetal demise, HR 9.869 (5.061-19.243). ROC analysis showed an area under the curve of 0.847 (SE ± 0.06). CONCLUSIONS: sFlt1/PlGF ratio is correlated with faster fetal deterioration in early fetal growth restriction, independently of preeclampsia.

Literature Review: The sFlt1/PlGF Ratio and Pregestational Maternal Comorbidities: New Risk Factors to Predict Pre-Eclampsia.

One of the main causes of maternal and neonatal morbidity and mortality is pre-eclampsia. It is characterized by a high sFlt1/PlGF ratio, according to prior research. Pregestational diseases in mothers may increase the risk of developing pre-eclampsia. Only a few studies have looked at the connection between maternal comorbidities before conception and the sFlt1/PlGF ratio. The most recent information regarding the association between maternal pregestational diseases and the ratio of sFlt1/PlGF is described in this review. The paper also examines current research suggesting that changes in pregnancy hormones and metabolites are related to a high sFlt1/PlGF ratio. Certain maternal disorders have been found to dramatically raise sFlt-1 and sFlt1/PlGF levels, according to an analysis of the literature. There is still debate about the data on the association between the sFlt1/PlGF ratio and maternal disorders such as HIV, acute coronary syndromes, cardiovascular function in the mother between 19 and 23 weeks of pregnancy, thyroid hormones, diabetes, and cancer. Additional research is needed to confirm these findings.

sFLT1, PlGF, the sFLT1/PlGF Ratio and Their Association with Pre-Eclampsia in Twin Pregnancies-A Review of the Literature.

Twin pregnancies demonstrate a 2-3-fold higher chance of developing PE compared to singletons, and recent evidence has demonstrated that the sFLT1/PIGF ratio is strongly associated with PE, adverse pregnancy outcomes, as well as imminent deliveries due to PE complications. The primary objective of this systematic review was to summarise the available data on the levels of sFLT1, PlGF and their ratios in twin pregnancies and to investigate their association with the development of PE, adverse pregnancy outcomes and the timing of the delivery. A systematic search of Ovid Embase, Web of Science, Science Direct, PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. sFLT1 levels and the sFLT1/PIGF ratio appeared higher in twins compared to singleton pregnancies, especially in the third trimester, while PlGF levels appeared higher up until the third trimester, with their values showing no difference or being even lower than in singletons thereafter. The sFLT1/PIGF ratio has been reported to be an independent marker of adverse outcomes related to pre-eclampsia and is associated with the mean time until delivery in an inverse manner. Further research is required in order to establish the optimal sFLT1/PIGF cut-off values and to stratify the risk of adverse outcomes in twin pregnancies.

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.

sFlt-1/PlGF ratio as a predictive and prognostic marker for preeclampsia.

OBJECTIVE: Preeclampsia is clinically unpredictable and associated with adverse outcomes. Pregnant women with suspected preeclampsia require intensive monitoring or hospitalization for elevated sFlt-1 (soluble fms-like tyrosine kinase-1) to PlGF (placental growth factor) ratios before symptoms arise. We aimed to determine the sFlt-1/PlGF ratio's usefulness in predicting adverse pregnancy outcomes in preeclampsia. METHODS: From January 2017 to February 2019, we measured the sFlt-1/PlGF ratio in 73 singleton pregnant women suspected of preeclampsia and classified them into three groups: low-risk (sFlt-1/PlGF ratio < 38, n = 19), intermediate (38 ≤ ratio < 85, n = 9), and high-risk (ratio ≥ 85, n = 32). RESULTS: Although the low- and high-risk groups both experienced weight gain during pregnancy, their body mass index (BMI) differed after pregnancy (p = 0.004). The number of women who had been taking antihypertensive medications for chronic hypertension since early pregnancy was higher in the low-risk group (31.6% vs. 22.2%, 6.7%). The gestational weeks at birth were lower in the high-risk group compared to that of the low-risk group (32.0 weeks vs. 35.79 weeks, p < 0.001). In the high-risk group, the average neonatal weight was significantly lighter (p = 0.021), and the period of stay in the neonatal intensive care unit was longer than that in the low-risk group (p = 0.003). CONCLUSION: The sFlt-1/PlGF ratio is a useful indicator of preeclampsia severity and can be utilized as a prognostic marker.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Comparison of three commercially available placental growth factor-based tests in women with suspected preterm pre-eclampsia: the COMPARE study.

OBJECTIVE: To compare the performance of three placental growth factor (PlGF)-based tests in predicting delivery within 14 days from testing in women with suspected preterm pre-eclampsia before 35 weeks' gestation. METHODS: This was a retrospective analysis of samples collected from three prospective pregnancy cohort studies. Participants were pregnant women with suspected preterm pre-eclampsia recruited in tertiary maternity units in the UK and Ireland. Samples were analyzed simultaneously according to the manufacturers' directions. The tests compared were the DELFIA Xpress PlGF 1-2-3 test, the Triage PlGF test and the Elecsys immunoassay soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio. Areas under receiver-operating characteristics curves (AUCs) were compared. The main outcome measure was detection of a difference of 0.05 in AUC between tests for delivery within 14 days of testing. RESULTS: Plasma samples from 396 women and serum samples from 244 women were assayed. In predicting delivery within 14 days secondary to suspected pre-eclampsia prior to 35 weeks' gestation, no significant differences were observed in AUCs (P = 0.795), sensitivities (P = 0.249), positive predictive values (P = 0.765) or negative predictive values (P = 0.920) between the three tests. The specificity of the Elecsys sFlt-1/PlGF ratio test was higher than that of the other two tests (P < 0.001). CONCLUSIONS: The tests perform similarly in their prediction of need for delivery within 14 days in women with suspected pre-eclampsia. The high negative predictive values support the role of PlGF-based tests as 'rule-out' tests for pre-eclampsia. © 2018 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Use of the sFlt-1/PlGF ratio to rule out preeclampsia requiring delivery in women with suspected disease. Is the evidence reproducible?

BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio has been proven to predict preeclampsia occurrence. METHODS: Blood samples from 195 pregnant women with suspected preeclampsia were obtained at obstetric triage admission or from the high-risk pregnancy outpatient office. Serum PlGF and sFlt-1 were measured by an electrochemiluminescence immunoassay (ECLIA) on the immunoanalyser Cobas e601 (Roche Diagnostics) and the corresponding ratio was calculated. Final outcomes were reviewed by an independent obstetrician. Only the first determination was considered. RESULTS: A sFlt-1/PlGF ratio of 38 or lower ruled out the need for pregnancy termination due to preeclampsia in the subsequent week with a negative predictive value (NPV) of 99.1% (sensitivity 97.1% and specificity 67.5%). None of the 76 pregnancies with first determination of an sFlt-1/PlGF ratio of 38 or lower between 24 and 34 weeks of gestation delivered due to early-onset preeclampsia. Positive likelihood ratio (PLR) of an sFlt-1/PlGF ratio above 38 for prediction of pregnancy termination due to preeclampsia within 4 weeks is analogous to published evidence. CONCLUSIONS: Between 24 and 34 weeks of gestation, no subsequent determination was needed to completely rule out early-onset preeclampsia when the first sFlt-1/PlGF ratio determination was 38 or lower in singleton pregnancies with signs or symptoms of this syndrome. These findings, if confirmed, will reduce costs and facilitate the implementation of the sFlt-1/PlGF ratio in women with clinical suspicion of preeclampsia in the third trimester.

Soluble fms-like tyrosine kinase-1 and placental growth factor kinetics during and after pregnancy in women with suspected or confirmed pre-eclampsia.

OBJECTIVES: To assess the evolution of the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio in women with suspected or confirmed pre-eclampsia (PE), and to investigate the changes in sFlt-1 and PlGF levels in pre-eclamptic women after delivery. METHODS: This was an exploratory study in which secondary analysis was performed on a prospective cohort study that enrolled women with a singleton pregnancy and suspected or confirmed PE from 18 weeks' gestation, carried out between December 2013 and April 2016 at the Department of Obstetrics of the Erasmus Medical Center in Rotterdam. sFlt-1 and PlGF were determined using Roche Diagnostics Elecsys assays in two groups of patients. In the first group, patients with suspected or confirmed PE had sFlt-1 and PlGF levels measured at least twice during their pregnancy. Changes in these biomarkers over the course of pregnancy were compared for patients in this group with a baseline sFlt-1/PlGF ratio of ≤ 38 and for those with a ratio > 38. In the second group, sFlt-1 and PlGF levels of women with PE or HELLP syndrome were measured before and after delivery. For this group, pre- and postpartum sFlt-1 and PlGF levels were compared and half-lives were calculated. RESULTS: Women with suspected or confirmed PE for whom sFlt-1 and PlGF levels were measured at least twice during pregnancy (n = 46) had a median gestational age at inclusion of 26 weeks (range, 18-40 weeks). In 27 of the 30 patients with sFlt-1/PlGF ratio ≤ 38 at baseline, thereby ruling out PE, the sFlt-1/PlGF ratio remained stable for up to 100 days. In the remaining three patients with a ratio ≤ 38 and in most of the 16 patients with a ratio > 38, the ratio increased further. For women diagnosed with PE or HELLP syndrome for whom sFlt-1 and PlGF levels were measured before and after delivery (n = 26), median gestational age at inclusion was 29 weeks (range, 16-37 weeks) and median time between antepartum measurement and delivery was 2 days (range, 1-17 days). In this group, after delivery, sFlt-1 dropped to < 1% of its pre-delivery value, with a half-life of 1.4 ± 0.3 days, while PlGF dropped to ∼30% of its pre-delivery value, with a half-life of 3.7 ± 4.3 days. CONCLUSIONS: Based on this small cohort, up to 10% of pregnant women admitted with suspected or confirmed PE presenting with a sFlt-1/PlGF ratio of ≤ 38 display a rise in sFlt-1/PlGF ratio in subsequent weeks, implying that repeat determination of the sFlt-1/PlGF ratio is required to exclude definitively a diagnosis of PE. Furthermore, the rapid and pronounced decline in sFlt-1 levels after delivery in patients with PE/HELLP syndrome suggests that sFlt-1, in contrast to PlGF, is almost entirely derived from the placenta. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Addition of N-terminal pro-B natriuretic peptide to soluble fms-like tyrosine kinase-1/placental growth factor ratio > 38 improves prediction of pre-eclampsia requiring delivery within 1 week: a longitudinal cohort study.

OBJECTIVE: Short-term prediction of pre-eclampsia (PE) using the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio is characterized by frequent false-positive results. As such, no treatment can be recommended to test-positive patients and multiple measurements are often required. The aim of this study was to evaluate the effectiveness of N-terminal pro-B natriuretic peptide (NT-proBNP), uric acid and the sFlt-1/PlGF ratio for prediction of delivery with PE within 1 week in singleton pregnancies with suspected PE and sFlt-1/PlGF ratio > 38. METHODS: This was a longitudinal prospective cohort study of singleton pregnancies presenting at 24 + 0 to 36 + 6 weeks of gestation with clinically suspected PE and sFlt-1/PlGF ratio > 38, enrolled between January 2015 and June 2017. Multiple samples per patient were allowed but were restricted to one sample per gestational week. From 495 enrolled patients, 270 blood samples from 134 patients were ultimately analyzed. By using generalized estimating equations (GEE), the best-fit model was selected for prediction of delivery with PE within 1 week. The predictive value of this model was then assessed using area under the paired-ROC curve (AUC) analysis. RESULTS: The best-fit model included the sFlt-1/PlGF ratio, NT-proBNP and the gestational week at the time of the measurement. This combined model was compared with the GEE model based on the sFlt-1/PlGF ratio and the gestational week at the time of the measurement (reduced model). The AUC for the combined model was 0.845 (95% CI, 0.787-0.896), which was significantly greater (P = 0.011) than that of the reduced model (0.786 (95% CI, 0.722-0.844)). CONCLUSION: The addition of NT-proBNP assessment improves the short-term prediction of delivery as a result of PE compared with sFlt-1/PlGF ratio alone, when the sFlt-1/PlGF ratio is > 38. This finding should be considered in future research on the assessment of short-term risk of delivery as a result of PE. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

First and Second Trimester Serum sFlt-1/PlGF Ratio and Subsequent Preeclampsia: A Systematic Review.

OBJECTIVE: Angiogenic biomarkers may be predictive of preeclampsia before clinical symptoms. The objective of this review was to determine the relationship between first and second trimester soluble fms-like tyrosine kinase-1/ placental growth factor (sFlt-1/PlGF) ratio and preeclampsia. METHODS: A search algorithm using appropriate medical subject headings was developed. PubMed, EMBASE, and Cochrane were searched for publications from inception to July 4, 2017. Observational studies, including prospective and retrospective cohorts, that measured serum sFlt-1/PlGF ratio at ≤24 weeks' gestation were included. Study characteristics, study design, timing of blood samples, and outcome data were systematically extracted. Study cohorts were grouped into women with low-risk and high-risk factors for preeclampsia. RESULTS: Fifteen studies were included for analysis, including 11 779 pregnancies. In studies of women with low-risk features, four subgroups from seven studies demonstrated higher sFlt-1/PlGF ratios in women who developed preeclampsia versus those who did not. In studies of women with high-risk features, six subgroups from nine studies demonstrated a higher sFlt-1/PlGF ratio in women who later developed preeclampsia. Elevated sFlt-1/PlGF ratios were especially seen in women who had early-onset or severe preeclampsia. CONCLUSION: The serum sFlt-1/PlGF ratio measured at ≤24 weeks' gestation may be elevated in select women who later develop preeclampsia, but inconsistently so.

Serum sFlt-1/PlGF ratio has better diagnostic ability in early- compared to late-onset pre-eclampsia.

Background To establish gestational specific cutoffs for the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio as a diagnostic tool for pre-eclampsia (PE) in an Asian population. Methods 82 subjects (48 PE patients and 34 controls) were recruited. sFlt-1 and PlGF were analysed on the Roche Cobas e411 analyzer and their ratio was calculated. Diagnostic performance was evaluated using receiver-operating characteristics (ROC) curves. Optimal cutoffs for sFlt-1/PlGF ratio were determined for different gestation phases. Results The most optimal cut-off for the study group is 32 with a sensitivity and specificity of 85.1% and 100% and Youden Index (J) of 0.85. Applying this cutoff for early-onset PE (EO-PE), sensitivity increased to 95.8% while specificity remains at 100% (J=0.96). However, for late onset PE (LO-PE), sensitivity decreases to 73.9% while specificity remains at 100% (J=0.74). Two cutoffs were further determined for EO-PE and LO-PE - the first focusing on high sensitivity; the second focusing on high specificity. For EO-PE, cutoff <17 yielded sensitivity of 100% and specificity of 94.4% (J=0.94) while cutoff ≥32 yielded sensitivity of 95.8% and specificity of 100% (J=0.95). For LO-PE, cutoff <22 has a sensitivity of 82.6% and a specificity of 91.7% (J=0.74) while cutoff ≥32 yielded sensitivity of 73.9% and specificity of 100% (J=0.74). Conclusion While our study found an overall cutoff at 32 regardless of gestation age, it has limited diagnostic accuracy for LO-PE in our study. Multiple cutoffs focusing on either high sensitivity or high specificity enhance the performance of the sFlt-1/PlGF ratio as a diagnostic tool for PE and contribute to the identification of women at risk of PE in our Asian region.