Soluble Fms-like Tyrosine Kinase-1 Levels Research Articles

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

ObjectivesTo 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 DesignThis 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. ResultsUrine 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). ConclusionsUrinary 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.

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension.

Malignant hypertension (MHT) characterized by acute hypertension with retinopathy or multiorgan damage, is a severe form of hypertensive emergency and associated with target organ involvement and poor kidney outcome. However, the underlying mechanisms are unclear. Eighty-four patients with acute severe hypertension from the Nephrology Department and Emergency Department in a single center during January 2016 and December 2017 were prospectively enrolled and divided into MHT ( n = 48) and non-MHT ( n = 36) subgroups according to target organ evaluation. Forty healthy controls were recruited. Serum soluble Fms-like tyrosine kinase-1 (sFlt-1) levels and plasma ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity were examined at baseline and 12-month follow-up. Renal endpoints were defined as a significant decrease in the estimated glomerular filtration rate (eGFR) of more than 40% or the occurrence of end-stage renal disease. Serum sFlt-1 levels were persistently elevated in MHT. Baseline serum sFLT-1 levels were correlated with plasma ADAMTS13 activity and markers of target organ damage. Plasma ADAMTS13 activity was reduced in both MHT and non-MHT patients and recovered to the normal range at 12-month follow-up. During an average follow-up time of 53 ± 13 months, the restoration of reduced ADAMTS13 activity was correlated with the improvement of kidney function and independently reduced the risk of renal endpoints. Abnormal angiogenesis and endothelial damage are involved in the pathophysiology of hypertensive emergency. Evaluation of ADAMTS13 and sFlt-1 may help in the diagnosis and assessment of MHT. Recovery of ADAMTS13 predicts better renal outcome in patients with hypertensive emergencies.

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

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

Correlation of sFlt/PlGF ratio with severity of preeclampsia in an Indian population

Preeclampsia affects 2% to 8% of pregnant women and significantly increases the risk for maternal and perinatal morbidity, especially in low- and middle-income countries. There is increasing evidence to support the use of biochemical markers such as placental growth factor and soluble fms-like tyrosine kinase-1 in predicting the severity of preeclampsia and to rule out severe disease in clinical conditions masquerading as severe preeclampsia. This study aimed to assess the role of the sFlt-1/PlGF ratio in predicting adverse perinatal and maternal outcomes in women with preeclampsia in a South Asian population with a higher rate of the disease and its associated complications. This was a prospective cohort study of women diagnosed with preeclampsia or suspected to have preeclampsia who underwent biophysical and biochemical investigations to measure the severity, including determining maternal hemodynamic indices, mean arterial pressure, fetal biometric and Doppler parameters, and soluble fms-like tyrosine kinase-1 and placental growth factor levels. The performance of these markers, individually or in combination, in predicting adverse perinatal and maternal outcomes was then assessed using receiver operating characteristic curve analysis. An adverse maternal outcome was defined as 1 or more of severe hypertension; admission to the intensive care unit; eclampsia; placental abruption; hemolysis, elevated liver enzymes, low-platelet count syndrome; disseminated intravascular coagulation; platelets <100×109/L; creatinine >1.1 mg/dL; and alanine aminotransferase >100 U/L. An adverse perinatal outcome was defined as 1 or more of preterm birth ≤34+0 weeks' gestation, neonatal intensive care unit admission for >48 hours, respiratory distress syndrome, intraventricular hemorrhage, hypoxic ischemic encephalopathy, necrotizing enterocolitis, retinopathy of prematurity, and confirmed fetal infection. We recruited 91 women with preeclampsia with a mean gestational age of 30.63±2.86 weeks. Women who had adverse maternal events had higher median maternal concentrations of soluble fms-like tyrosine kinase (11,500.0 pg/mL vs 3051.0 pg/mL; P<.001), lower concentrations of placental growth factor (44.88 pg/mL vs 148.50 pg/mL; P<.001), and a higher sFlt-1/PlGF ratio (306.22 vs 30.63; P<.001) than women who did not. Pregnancies with an adverse perinatal outcome also had a higher soluble fms-like tyrosine kinase concentration (12,100.0 pg/mL vs 3051.0 pg/mL; P<.001), lower placental growth factor concentration (27.2 pg/mL vs 148.50 pg/mL; P<.001), and higher sFlt-1/PlGF ratio (378.45.4 vs 30.63; P<.001). The area under the receiver operating characteristic curve showed that soluble fms-like tyrosine kinase and placental growth factor were the best biomarkers when compared with other biochemical markers to predict adverse maternal (area under the curve, 0.81; 95% confidence interval, 0.72-0.90) and fetal (area under the curve, 0.88; 95% confidence interval, 0.80-0.96) outcomes in preeclampsia. The sFlt-1/PlGF ratio correlates better with adverse maternal and perinatal outcomes than any other biochemical marker in an Indian population. The incorporation of the sFlt-1/PlGF ratio in women with preeclampsia can help in predicting the severity of the condition and the timings of the delivery.

Predelivery placenta-associated biomarkers and computerized intrapartum fetal heart rate patterns

BackgroundIncreasing syncytiotrophoblast stress in term and postdate placentas is reflected by increasing antiangiogenic dysregulation in the maternal circulation, with low “proangiogenic” placental growth factor concentrations and increased “antiangiogenic” soluble fms-like tyrosine kinase-1 concentrations. Imbalances in these placenta-associated proteins are associated with intrapartum fetal compromise and adverse pregnancy and delivery outcome. Cardiotocography is widely used to assess fetal well-being during labor, but it is insufficient on its own for predicting adverse neonatal outcome. Development of improved surveillance tools to detect intrapartum fetal stress are needed to prevent neonatal adverse outcome. ObjectiveThis study aimed to assess whether predelivery circulating maternal angiogenic protein concentrations are associated with intrapartum computerized fetal heart rate patterns, as calculated by the Oxford System for computerized intrapartum monitoring (OxSys) 1.7 prototype. We hypothesized that in pregnancies with low “proangiogenic” placental growth factor levels, increased “antiangiogenic” soluble fms-like tyrosine kinase-1 levels, and increased soluble fms-like tyrosine kinase-1–placental growth factor ratio, the OxSys 1.7 prototype will generate more automated alerts, indicating fetal compromise. Our secondary objective was to investigate the relationship between maternal circulating placenta-associated biomarkers and rates of automated alerts in pregnancies with and without adverse neonatal outcome. Study DesignThis was an observational prospective cohort study conducted at a single tertiary center from September 2016 to March 2020. Of 1107 singleton pregnancies (gestational week ≥37+0), 956 had available prelabor and predelivery placental growth factor and soluble fms-like tyrosine kinase-1 concentrations and intrapartum cardiotocography recordings. All neonatal and delivery outcomes were externally reviewed and categorized into 2 groups—the “complicated” group (n=32) and the “uncomplicated” group (n=924)—according to predefined adverse neonatal outcome. Eight different cardiotocography features were calculated by OxSys 1.7: baseline at start of cardiotocography, baseline at end of cardiotocography, short-term variation at start, short-term variation at end, nonreactive initial trace, and throughout the entire cardiotocography, maximum decelerative capacity, total number of prolonged decelerations, and OxSys 1.7 alert. OxSys 1.7 triggered an alert if the initial trace was nonreactive or if decelerative capacity and/or the number of prolonged decelerations exceeded a predefined threshold. Included women and attending clinicians were blinded to both biomarker and OxSys 1.7 results. ResultsMean maternal placental growth factor concentration was lower in the group with OxSys 1.7 alert compared with the group without the alert (151 vs 169 pg/mL; P=.04). There was a weak negative correlation between predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation start (rs=−0.068; 95% confidence interval, −0.131 to −0.004; P=.036), predelivery high soluble fms-like tyrosine kinase-1 and low short-term variation end (rs=−0.068; 95% confidence interval, −0.131 to −0.005; P=.036), and high soluble fms-like tyrosine kinase-1–placental growth factor ratio and low short-term variation end (rs=−0.071; 95% confidence interval, −0.134 to −0.008; P=.027). The rate of decelerative capacity alerts increased more rapidly as placental growth factor decreased in the “complicated” compared with the “uncomplicated” group (0% to 17% vs 4% to 8%). ConclusionMore automated alerts indicative of fetal distress were generated by OxSys 1.7 in pregnancies with low maternal predelivery placental growth factor level, in line with likely increasing placental stress toward the end of the pregnancy. An antiangiogenic predelivery profile (lower placental growth factor) increased the rates of alerts more rapidly in pregnancies with adverse neonatal outcome compared with those without. We suggest that future studies developing and testing prediction tools for intrapartum fetal compromise include predelivery maternal placental growth factor measurements.

Is Maternal Cardiovascular Performance Impaired in Altitude-Associated Fetal Growth Restriction?

Mundo, William, Lilian Toledo-Jaldin, Alexandrea Heath-Freudenthal, Jaime Huayacho, Litzi Lazo-Vega, Alison Larrea-Alvarado, Valquiria Miranda-Garrido, Rodrigo Mizutani, Lorna G. Moore, Any Moreno-Aramayo, Richard Gomez, Patricio Gutierrez, and Colleen G. Julian. Is maternal cardiovascular performance impaired in altitude-associated fetal growth restriction? High Alt Med Biol 00:000-000, 2022. Introduction: The incidence of fetal growth restriction (FGR) is elevated in high-altitude resident populations. This study aims to determine whether maternal central hemodynamics during the last trimester of pregnancy are altered in high-altitude FGR. Methods: In this cross-sectional study of maternal-infant pairs (FGR, n = 27; controls, n = 26) residing in La Paz, Bolivia, maternal heart rate, cardiac output (CO), stroke volume, and systemic vascular resistance (SVR) were assessed using continuous-wave Doppler ultrasound. Transabdominal Doppler ultrasound was used for uterine artery (UtA) resistance indices and fetal measures. Maternal venous soluble fms-like tyrosine kinase-1 (sFlt1) levels were measured. Results: FGR pregnancies had reduced CO, elevated SVR and UtA resistance, fetal brain sparing, and increased maternal sFlt1 versus controls. Maternal SVR was positively associated with UtA resistance and inversely associated with middle cerebral artery resistance and birth weight. Maternal sFlt1 was greater in FGR than controls and positively associated with UtA pulsatility index. Women with elevated sFlt1 levels also tended to have lower CO and higher SVR. Conclusion: Noninvasive assessment of maternal cardiovascular function may be an additional method for detecting high-risk pregnancies at high altitudes, thereby informing the need for increased surveillance and appropriate allocation of resources to minimize adverse outcomes.

Quercetin Supplement to Aspirin Attenuates Lipopolysaccharide-Induced Pre-eclampsia-Like Impairments in Rats Through the NLRP3 Inflammasome.

Aspirin is a common drug for the treatment of pre-eclampsia. We aimed to explore whether quercetin as a supplement to aspirin could enhance the therapeutic outcome in pre-eclampsia rat models. We further aimed to evaluate the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome as a potential pre-eclampsia-related molecular mechanism, which can be affected by quercetin treatment. Rat pre-eclampsia models were established using an intravenous lipopolysaccharide injection after gestation. Rats were treated with aspirin and quercetin at 6-18days after pregnancy. On day 20, blood, fetus, and placenta were harvested. Blood pressure and the level of proteinuria were measured every 4days. Fetal outcomes were analyzed by pup body weight. Serum soluble Fms-like tyrosine kinase-1, PIGF, interleukin-6, and interleukin-10 levels were measured using the enzyme-linked immunosorbent assay. Caspase-1, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and p-caspase-1 levels in the placenta were assessed using western blot or quantitative real-time polymerase chain reaction analyses. Pre-eclampsia rat models showed a pronounced increase in systolic blood pressure and proteinuria after 4days of pregnancy, while aspirin, quercetin, and aspirin/quercetin combinatory treatment significantly attenuated the blood pressure and proteinuria abnormalities. Notably, the aspirin/quercetin combinatory treatment showed the highest efficacy in attenuating pre-eclampsia-like symptoms. Placental caspase-1 and NLRP3 levels also showed the greatest attenuation in pre-eclampsia rats after aspirin/quercetin treatment. Our data suggested that quercetin supplementation to aspirin is more effective in attenuating symptoms of pre-eclampsia and improving pregnancy outcomes compared with quercetin or aspirin alone. Quercetin can ameliorate placental NLRP3 inflammasome activation, which might serve as an underlying mechanism for its therapeutic efficacies in pre-eclampsia.

Association of fetal sex with angiogenic factors in normotensive and hypertensive pregnancy states.

With the incorporation of angiogenic biomarkers into clinical practice, identification of potential modifiers of the angiogenic profile, including fetal sex, is essential. In this retrospective cohort analysis, patients with hypertensive disorders of pregnancy (HDP) and normotensive pregnancies were enrolled upon admission to Labor and Delivery. Blood samples for angiogenic factors were assessed using an automated platform. Clinical and demographic information was abstracted from each patient's medical records. Soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) levels and their ratio in relation to fetal sex in patients with normotensive pregnancies compared to those with HDP were evaluated. A total of 617 patients were analyzed (299 normotensive, 113 gestational hypertensive, 71 chronic hypertensive, and 134 preeclamptic patients). There was no difference between the number of patients who had a male fetus among preeclampsia and normotensive parturients (56.0% vs 50.2%, p=0.26). Normotensive patients carrying a male fetus had significantly higher sFlt1 (pg/ml) (3168 [IQR: 2160-4945] vs 2678 [IQR: 1752-4271]; p=0.01) and sFlt1/PlGF ratios (18 [IQR: 7-44] vs 12 [IQR: 5-30]; p=0.01) in comparison to pregnant patients carrying a female fetus. This difference between fetal sexes was not observed in the angiogenic profile of patients with HDP. Our study of primarily Black, obese patients demonstrates that normotensive patients carrying a male fetus have a significantly higher sFlt1 and sFlt1/PlGF ratio as compared to those carrying a female fetus at term gestation. Fetal sex should be considered as a covariate when studying angiogenic factors in normotensive pregnant patients.

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.

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. 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. 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%. 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.

Assessment of the value of measuring soluble fms-like tyrosine kinase-1 and placental growth factor levels following administration of tadalafil to treat fetal growth restriction

Purpose The aim of this study was to measure the blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) before and after tadalafil treatment in patients with fetal growth restriction. Materials and methods Maternal blood was collected from 13 women before and 2 weeks after tadalafil administration in the TADAFER II trial. The tadalafil treatment was conducted in addition to the conventional FGR treatment. As a control, maternal blood was also collected from 11 women before and 2 weeks after conventional treatment for fetal growth restriction. Blood sFlt-1 and PlGF were measured and the sFlt-1/PlGF ratio was calculated. Student’s t-test was used to statistically analyze differences in the sFlt-1 and PlGF levels, and in the sFlt-1/PlGF ratios. Results In both treatment groups, the levels of sFlt-1 and PlGF before and after treatment were not significantly different from each other. The sFlt-1/PlGF ratio was 2.0 ± 1.0 before and 17.6 ± 11.3 after treatment in the control group (p=.04). The sFlt-1/PlGF ratio was 2.2 ± 1.1 before and 22.2 ± 10.6 after tadalafil treatment in the tadalafil group (p=.06). The sFlt-1/PlGF ratios before and after tadalafil treatment were significantly increased in the control group. In both treatment groups, the sFlt-1/PlGF ratios before and after treatment were less than 38. Conclusions We conclude that the levels of sFlt-1 and PlGF were not significantly different as a result of tadalafil treatment. Further studies are needed to understand the mechanism of action of tadalafil in the treatment of fetal growth restriction.

Correlation between Apelin and Some Angiogenic Factors in the Pathogenesis of Preeclampsia: Apelin-13 as Novel Drug for Treating Preeclampsia and Its Physiological Effects on Placenta.

Preeclampsia (PE) is one of the commonest causes for maternal and fetal morbidity and mortality. Imbalances of angiogenic factors, oxidative stress, and inflammatory response have a role in the pathogenesis of PE. Data regarding the circulating apelin level and its role in PE remains controversial. This study was formulated to assess the serum apelin level in PE, investigate its correlation with some inflammatory, oxidative stress, and angiogenic proteins in a nitric oxide synthase inhibitor; the N (gamma)-nitro-L-arginine methyl ester (L-NAME)-induced rat model of PE and determine whether apelin administration could protect against development of PE. 40 healthy adult female albino rats and 10 adult male albino rats were used in this study. The pregnant female rats were randomly divided into three groups: group 1 (normal pregnant group), group 2 (PE-induced group), injected subcutaneously with 75 mg L-NAME/kg bodyweight/day starting from day 9 to 20 of gestation, and group 3 (PE-induced group supplemented with apelin (PE + apelin)); PE induced as before and simultaneously subcutaneously injected with apelin-13 (6 × 10−8 mol/kg bodyweight/twice daily) beginning from day 6 to 20 of gestation. In all groups, blood pressure and urine protein were determined at gestation days (GD) 0, 10, and 18. Moreover, serum apelin, placental growth factor (PLGF), vascular endothelial growth factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), interferon-gamma (IFN-γ), and interleukin-10 (IL-10) levels and serum superoxide dismutase enzyme (SOD) and catalase (CAT) activities of all groups were estimated at the end of experiment. Placental histopathological examination was also performed. PE-induced rats showed significantly decreased serum apelin levels. Moreover, they showed significantly increased blood pressures, urine proteins, sFlt-1, sEng, and IFN-γ (mean arterial blood pressure, urine proteins, sFlt-1, sEng, and IFN-γ showed significant negative correlations with serum apelin level), but it showed significantly decreased VEGF, PLGF, IL-10, SOD, and CAT (VEGF, PLGF, IL-10, and SOD showed significant positive correlations with serum apelin level). In contrast, exogenous apelin administration significantly ameliorated these parameters together with improvement in the placental histoarchitecture in the apelin-supplemented PE group. This study demonstrated the protective effects of apelin administration on the pathogenesis of PE.

Evaluation of sFlt-1 and PlGF for predicting preeclampsia in pregnant women with diabetes mellitus

AIM: The aim of this study was to evaluate soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) levels in the blood of women with various types of diabetes mellitus, depending on the correction method applied, and to determine the prognostic significance of the sFlt-1 / PlGF ratio for predicting the development of preeclampsia in this patient population.&#x0D; MATERIALS AND METHODS: We examined 140 pregnant women who were included in six main study groups: type 1 diabetes mellitus (with or without pregravid preparation), type 2 diabetes mellitus (diet therapy or insulin therapy), and gestational diabetes mellitus (diet therapy or insulin therapy). The comparison groups consisted of pregnant women with preeclampsia and patients without complications of pregnancy. Using electrochemiluminescence analysis, PlGF and sFlt-1 levels in the blood serum were determined twice, at 11+013+6 and 30+033+6 weeks of gestation. Statistical data processing was performed using the IBM SPSS Statistics version 23 and GraphPad Prism version 8.0 software packages.&#x0D; RESULTS: In the blood serum of pregnant women with diabetes mellitus in the first and third trimesters of pregnancy, we found an increase in sFlt-1 level and a decrease in PlGF level, as well as an increase in the sFlt-1 / PlGF ratio. These changes were most pronounced in individuals with type 1 diabetes mellitus without pregravid preparation and with type 2 diabetes mellitus on insulin therapy. In patients with pregestational types of diabetes mellitus, the sFlt-1 / PlGF ratio was a predictor of preeclampsia already in the early stages of pregnancy. Analysis of the ROC curve showed that the threshold sFlt-1 / PlGF ratio for predicting preeclampsia in pregnant women with diabetes mellitus in the first trimester was 32.5 (sensitivity 92.9%, specificity 50.0%) and in the third trimester 71.8 (sensitivity 85.7%, specificity 82.3%) with AUC 0.78 (95% CI 0.680.88) and 0.89 (95% CI 0.830.95), respectively. In the first trimester, the positive and negative predictive values of the sFlt-1 / PlGF ratio as a predictor of preeclampsia in pregnant women with diabetes mellitus were 63.3% and 97.6%, respectively; in the third trimester, 38.9% and 93.6%, respectively.&#x0D; CONCLUSIONS: Blood level alterations of PlGF and sFlt-1 are characteristic of patients with diabetes mellitus in the first and third trimesters of pregnancy. An increase in the sFlt-1 / PlGF ratio is associated with a higher incidence of unfavorable perinatal outcomes in women with impaired carbohydrate metabolism. Determination of the sFlt-1 / PlGF ratio is a valid method for predicting the development or absence of preeclampsia in women with diabetes mellitus.

Soluble Flt1 levels are associated with cardiac dysfunction in Black women with and without severe preeclampsia

ABSTRACT Background: We evaluate soluble fms-like tyrosine kinase-1 (sFlt-1) levels and cardiac function during pregnancy and postpartum among Black women with and without preeclampsia. Study design: Prospective longitudinal cohort study from 2015 to 2017 of Black women with preterm severe preeclampsia and normotensive pregnant controls.We obtained echocardiograms and sFlt-1 levels during pregnancy and postpartum. Results: 93 Black women were included (43 cases, 50 controls). Higher sFlt1 levels were correlated with worse longitudinal strain, diastolic dysfunction, decreased ventricular-arterial coupling, and increased chamber and arterial elastance at the time of preeclampsia diagnosis and postpartum. Conclusions: Higher sFlt1 levels are associated with cardiovascular dysfunction during pregnancy and postpartum.

Individual risk assessment for prenatal counseling in early-onset growth-restricted and small-for-gestational-age fetuses.

Early-onset fetal growth restriction and small-for-gestational age of fetuses lead to an increased risk of adverse pregnancy outcomes. Doppler abnormalities can predict the occurrence of complications in the short term, but normal fetal Doppler values at the time of diagnosis do not exclude their occurrence in the long term. The objective of this study was to investigate the capacity of a predictive model to assess individual risks for prenatal counseling at the time of diagnosis. This was a prospective observational study of singleton pregnancies with estimated fetal weight below the 10th centile between 20+0 and 31+6 weeks of gestational age. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) levels, estimated fetal weight centile, uterine artery pulsatility index, fetal Doppler and maternal risk factors for placental disease were assessed at the time of enrollment. The occurrence of adverse perinatal outcomes or the need for elective delivery at <30, <34 or <37weeks was considered an adverse pregnancy outcomes. Univariable logistic regression analysis was used to examine the association between each predictive variable and the adverse outcomes. A multivariable logistic regression-based model was constructed with the combination of all variables. An additional model without sFlt-1/PlGF was also created. Both models, and the sFlt-1/PlGF alone, were used to develop the different formulas to assess individual risks. Receiver operating characteristic curves were constructed to assess and compare their performance of screening. Forty-nine small-for-gestational-age fetuses and 124 with fetal growth restriction were enrolled at a median gestational age of 23.6weeks. Elective delivery was needed in 77 (44.5%) women at <37weeks, 53 (30.6%) women at <34weeks and 30 (17.3%) at <30weeks. Adverse perinatal outcomes occurred in 81 (55.9%) pregnancies. When areas under the curve were compared among models, no statistically significant differences were observed between the model with sFlt-1/PlGF and sFlt-1/PlGF alone; however, the model without sFlt-1/PlGF yielded an overall poorer performance. Individual risk assessment can be made at the time of early-onset fetal growth restriction/small-for-gestational-age diagnosis, which permits accurate counseling of parents with an affected fetus. Two formulas could be used: one combining maternal characteristics and ultrasound findings and the other with a single sFlt-1/PlGF measurement.

17-Hydroxyprogesterone caproate improves hypertension and renal endothelin-1 in response to sFlt-1 induced hypertension in pregnant rats.

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and preproendothelin-1 (PPET-1) levels. Currently there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to elevated sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7μg·kg-1·day-1 for 6days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), pup and placenta weights, renal cortex PPET-1 mRNA levels and nitrate-nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 115±1 (n=13) vs. 99±2mmHg (n=12, p<0.05). 17-OHPC attenuated this hypertension reducing MAP to 102±3mmHg in sFlt-1 treated pregnant rats (n=8). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Importantly, renal cortex PPET-1 mRNA levels were elevated 3 fold in NP+sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 44±9µM in NP rats (n=9), 20±3µM in NP+sFlt-1 (n=7), which increased to 42±11µM NP+sFlt-1+17OHPC (n=6). Administration of 17-OHPC improves clinical characteristics of preeclampsia in response to elevated sFlt-1 during pregnancy.

Placental Growth Factor and Soluble, Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Case-Cohort (PEARL) Study.

Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. We conducted a case-cohort study including low-risk nulliparous women recruited at 11-13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35-37 weeks) and late-onset (>37 weeks) preeclampsia. The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25-38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P < 0.05). We observed a significant difference between cases and controls, with a median ratio 100 times higher in early preeclampsia (P < 0.001), 13 times higher in intermediate preeclampsia (P < 0.001), but no significant difference between groups in late-onset preeclampsia with matched controls. PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

Prediction of preterm pre-eclampsia at midpregnancy using a multivariable screening algorithm.

Competing risk models used for midpregnancy prediction of preterm pre-eclampsia have shown detection rates (DR) of 85%, at fixed false-positive rate (FPR) of 10%. The full algorithm used between 19+0 and 24+6 weeks includes maternal factors, mean arterial pressure (MAP), mean uterine artery pulsatility index (UtAPI), serum placental growth factor (PlGF) level in multiples of the median (MoM), and soluble Fms-like tyrosine kinase-1 (sFlt-1) level in MoM. To assess performance of the Fetal Medicine Foundation (FMF) algorithm at midpregnancy to screen for preterm (<37weeks) pre-eclampsia. The outcome measured was preterm pre-eclampsia. This is a prospective study including singleton pregnancies at 19-22weeks gestation. Maternal bloods were collected and analysed using three different immunoassay platforms. Maternal characteristics, medical history, MAP, mean UtAPI, serum PlGF MoM and serum sFlt-1 MoM were used for risk assessment. DR and FPR were calculated, and receiver operating characteristic curves produced. Five hundred and twelve patients were included. Incidence of preterm pre-eclampsia was 1.6%. Using predicted risk of pre-eclampsia of one in 60 or more and one in 100 or higher, as given by the FMF predictive algorithm, the combination with the best predictive performance for preterm pre-eclampsia included maternal factors, MAP, UtAPI and PlGF MoM, giving DRs of 100% and 100%, respectively, and FPRs of 9.3 for all platforms and 12.9-13.5, respectively. Addition of sFlt-1 to the algorithm did not appear to improve performance. sFlt-1 MoM and PlGF MoM values obtained on the different platforms performed very similarly. Second trimester combined screening for preterm pre-eclampsia by maternal history, MAP, mean UtAPI and PlGF MoM using the FMF algorithm performed very well in this patient population.

First trimester serum angiogenic and anti-angiogenic factors in women with chronic hypertension for the prediction of preeclampsia

An imbalance between angiogenic and antiangiogenic factors is thought to be a central pathogenetic mechanism in preeclampsia. In pregnancies that subsequently experience preeclampsia, the maternal serum concentration of the angiogenic placental growth factor is decreased from as early as the first trimester of pregnancy, and the concentration of the antiangiogenic soluble fms-like tyrosine kinase-1 is increased in the last few weeks before the clinical presentation of the disease. Chronic hypertension, which complicates 1-2% of pregnancies, is the highest risk factor for the development of preeclampsia among all other factors in maternal demographic characteristics and medical history. Two previous studies in women with chronic hypertension reported that first-trimester serum placental growth factor and soluble fms-like tyrosine kinase-1 levels were not significantly different between those who experienced superimposed preeclampsia and those who did not, whereas a third study reported that concentrations of placental growth factor were decreased. The purpose of this study was to investigate whether, in women with chronic hypertension, serum concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 and soluble fms-like tyrosine kinase-1/placental growth factor ratio at 11+0-13+6 weeks gestation are different between those women who experienced superimposed preeclampsia and those who did not and to compare these values with those in normotensive control subjects. The study population comprised 650 women with chronic hypertension, which included 202 women who experienced superimposed preeclampsia and 448 women who did not experience preeclampsia, and 142 normotensive control subjects. Maternal serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1 were measured by an automated biochemical analyzer and converted into multiples of the expected median with the use of multivariate regression analysis in the control group. Comparisons of placental growth factor and soluble fms-like tyrosine kinase-1 levels and soluble fms-like tyrosine kinase-1/placental growth factor ratio in multiples of the expected median values between the 2 groups of chronic hypertension and the control subjects were made with the analysis of variance or the Kruskal-Wallis test. In the group of women with chronic hypertension who experienced preeclampsia compared with those women who did not experience preeclampsia, there were significantly lower median concentrations of serum placental growth factor multiples of the expected median (0.904 [interquartile range, 0.771-1.052] vs 0.948 [interquartile range, 0.814-1.093]; P=.014) and soluble fms-like tyrosine kinase-1 multiples of the expected median (0.895 [interquartile range, 0.760-1.033] vs 0.938 [interquartile range, 0.807-1.095]; P=.013); they were both lower than in the normotensive control subjects (1.009 [interquartile range, 0.901-1.111] and 0.991 [interquartile range, 0.861-1.159], respectively; P<.01 for both). There were no significant differences among the 3 groups in soluble fms-like tyrosine kinase-1/placental growth factor ratios. In women with chronic hypertension, serum placental growth factor and soluble fms-like tyrosine kinase-1 levels provided poor prediction of superimposed preeclampsia (area under the curve, 0.567 [95% confidence interval, 0.537-0.615] and 0.546 [95% confidence interval, 0.507-0.585], respectively). Women with chronic hypertension, and particularly those who subsequently experienced preeclampsia, have reduced first-trimester concentrations of both placental growth factor and soluble fms-like tyrosine kinase-1.

NAMPT levels are inversely related to nitric oxide formation and positively related to soluble fms-like tyrosine kinase-1 levels in preeclampsia.

NAMPT is a biomarker for endothelial dysfunction, but its relationship with nitrite (marker of NO formation) and soluble fms-like tyrosine kinase-1 (sFLT-1) has not been previously evaluated in preeclampsia. Therefore, we measured plasma NAMPT and sFLT-1 levels using enzyme immunoassays and plasma nitrite concentrations using an ozone-based chemiluminescence assay. NAMPT was positively correlated to nitrite (r = 0.217; P = 0.034) and inversely related to sFLT-1 (r = -0.340; P = 0.029) in healthy pregnant women, but inversely related to nitrite (r = -0.259; P = 0.035) and positively correlated to sFLT-1 (r = 0.326; P = 0.007) in preeclamptic patients, suggesting that NAMPT inhibits NO formation and interacts with the antiangiogenic factor sFLT-1 in preeclampsia.

444: 17-Hydroxyprogesterone caproate improves hypertension and endothelin-1 in response to sFlt-1induced hypertension in pregnant rats

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1) levels. We and others have previously demonstrated that infusion of sFlt-1 into pregnant rodents causes hypertension, indicating an important role for sFlt-1 in mediating the pathophysiology of the disease. Currently there is no effective treatment for PE except for delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth, but not for treatment of PE. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1 for 6 days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), renal cortex endothelin-1 expression and Nitrate-Nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 112+2 (n=11) vs. 98+2 mmHg (n=15, p<0.05). Administration of 17-OHPC attenuated this hypertension reducing MAP to 99+4 mmHg in sFlt-1 treated pregnant rats (n=8). Importantly, renal cortex PPET-1 expression was elevated 3 fold in NP+sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 26 μM in NP rats (n=6), 17 μM in NP+sFlt-1 (n=4), which increased to 27 μM NP+sFlt-1+17OHPC (n=5). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Administration of 17-OHPC improves hypertension in response to elevated sFlt-1 during pregnancy and should be considered further in the management of PE.