Biomarkers and the Prediction of Adverse Outcomes in Preeclampsia: A Systematic Review and Meta-Analysis
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( Obstet Gynecol . 2021;137:72–81) Progress has occurred recently to predict and diagnose preeclampsia in pregnant women. Angiogenic and antiangiogenic biomarkers such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were recently examined. In addition these factors have been implemented clinically as predictive measurements of preeclampsia. This study aims to review and analyze sFlt-1, PlGF, and the sFLt-1/PlGF ratio and their ability to predict time to delivery and adverse outcomes in patients with preeclampsia.Preeclampsia is a multisystem disorder of pregnancy that contributes to morbidity and mortality worldwide. Soluble FMS-like tyrosine kinase-1 (sFlt-1) is considered as an etiologic factor of endothelial damage in preeclampsia. Imbalance of sFlt-1 and PlGF could cause failure in trophoblastic invasion and physiological remodeling of spiral artery, and ultimately placental hypoxia. This study aimed to observe anti-angiogenic properties of black rice bran on preeclampsia through measurement of sFlt-1 and PIGF. Serum was collected from pregnant women at 28-34 weeks of gestational age with preeclampsia, and normal preeclampsia as control. Level sflt-1 and PGIF was quantified with enzyme linked immunosorbent assay (ELISA). Absorbance was read at 450 nm wavelength. Extract of black rice bran has anti-angiogenic properties by significantly decreasing sFlt-1 as well as increasing PIGF in preeclampsia-induced HUVEC. This makes black rice bran a promising agent which can be further used in preeclampsia treatment.
Spiral artery
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Objective:To detect serum levels of placenta growth factor (PLGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) during different periods in normal pregnancy and patients with preeclampsia and to evaluate their role in the pathogenesis of preeclampsia.Methods:Women enrolled prospectively in following groups:healthy pregnant control (n=200) and preeclampsia patients,who had mild preeclampsia (n=31) or severe preeclampsia (n=26).The serum PLGF and sFlt-1 levels were measured by enzyme linked immunoassay (ELISA).Results:Maternal serum PLGF levels during all periods were significantly lower in the preeclamptic women than in normal controls (P0.01).The levels of maternal plasma sFlt-1 were significantly higher in the preeclamptic women than in normal controls during the latter three periods of pregnancy (P0.01).The serum sFlt-1 /PLGF ratio was significantly higher in the preeclamptic women than in normal controls (P0.01).Conclusion:Alterations in the levels of sFlt-1 and free PLGF in maternal serum were associated with the occurrence and development of preeclampsia.
Pathogenesis
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Preeclampsia is a major cause of maternal, fetal, and neonatal mortality worldwide. Although the etiology of preeclampsia is still unclear, recent studies suggest that its major phenotypes, high blood pressure and proteinuria, are due in part to excess circulating soluble fms-like tyrosine kinase-1 concentrations. Soluble fms-like tyrosine kinase-1 is an endogenous antiangiogenic protein that is made by the placenta and acts by neutralizing the proangiogenic proteins vascular endothelial growth factor and placental growth factor. High serum soluble fms-like tyrosine kinase-1 and low serum free placental growth factor and free vascular endothelial growth factor have been observed in preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia but also antedate clinical symptoms by several weeks. Therefore, this raises the possibility of measuring circulating angiogenic proteins in the blood and the urine as a diagnostic and screening tool for preeclampsia. The availability of a test to predict preeclampsia would be a powerful tool in preventing preeclampsia-induced mortality, especially in developing nations, where high-risk specialists are limited. This review will summarize our current understanding of the role of circulating angiogenic proteins in the pathogenesis and clinical diagnosis/prediction of preeclampsia.
Pathogenesis
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Preeclampsia is one of the most common and most serious complications of pregnancy and the management of this condition still challenges obstetricians. Despite intensive research the etiology of preeclampsia still remains unclear. At the beginning of the 2000s preeclampsia-related research was directed towards factors that influence angiogenesis. Most studies have been carried out on the placental growth factor and soluble fms-like tyrosine kinase-1. Most publications confirm the increased concentrations of antiangiogenic factors and decreased concentrations of proangiogenic factors in maternal blood samples in preeclampsia even before the onset of clinical symptoms. According to our current knowledge antiangiogenic proteins are responsible for the endothelial dysfunction in the symptomatic stage of the disease. Placental growth factor and soluble fms-like tyrosine kinase-1 may have important roles in the prediction and treatment of the disease. The point of care detection of placental growth factor and soluble fms-like tyrosine kinase-1 may be used to predict preeclampsia. Rapid tests are available to determine the serum levels of the two proteins. Removal of soluble fms-like tyrosine kinase-1 from maternal circulation is a potential treatment option for early onset preeclampsia. Orv. Hetil., 2014, 155(47), 1860–1866.
Etiology
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Objective The purpose of the present study was to explore the predictive effects of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) for preeclampsia. Methods A total of 1580 singleton pregnant women aged 18‐45 years were included in this study. Serum samples were collected and stored frozen during their regular obstetric examinations. A total of 48 women who were eventually diagnosed with preeclampsia among them were defined as the preeclampsia group, other 134 women who were matched with age and sample collecting gestational weeks and finally diagnosed without preeclampsia were selected as control. The concentration of sFlt‐1 and PlGF in prestored serum samples was examined. The optimal cut‐off of sFlt‐1, PlGF, and sFlt‐1/PlGF ratio in predicting preeclampsia was determined by establishing the receiver operating characteristic curve (ROC). Results Serum PlGF levels in patients with preeclampsia were significantly lower than those in normal pregnancy ( P < 0.05), On the contrary, sflt‐1 levels and sflt‐1/PlGF ratios were significantly higher than those in the normal pregnant women ( P < 0.05). The ROC curve study showed that using the sFlt‐1/PlGF ratio to predict preeclampsia was better than using PlGF alone but no difference with sFlt‐1. When the cut‐off of the sFlt‐1/PlGF ratio was 26.6, the area under the ROC curve was 0.918, and high sensitivity (85.42%) and specificity (96.27%) for predicting preeclampsia were obtained. Conclusion The cut‐off of sflt‐1/PlGF ratio determined by ROC curve has a good predictive value for the occurrence of preeclampsia.
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( Obstet Gynecol . 2021;137:72–81) Progress has occurred recently to predict and diagnose preeclampsia in pregnant women. Angiogenic and antiangiogenic biomarkers such as placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were recently examined. In addition these factors have been implemented clinically as predictive measurements of preeclampsia. This study aims to review and analyze sFlt-1, PlGF, and the sFLt-1/PlGF ratio and their ability to predict time to delivery and adverse outcomes in patients with preeclampsia.
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Fetal growth
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Preeclampsia is a major complication of pregnancy and is associated with significant fetal and maternal morbidity and mortality. Timely prediction of preeclampsia facilitates referral of potential patients to an adequate tertiary center, which helps reduce adverse outcomes associated with the disease. Moreover, by accurately ruling out preeclampsia, patients can be discharged safely and relieved of anxiety. Numerous candidate biomarkers have been proposed for the diagnosis and prediction of preeclampsia. Among these, maternal circulating factors such as soluble FMS-like tyrosine kinase-1 (sFlt-1), an anti-angiogenic factor, and placental growth factor (PlGF), an angiogenic factor, are considered the most promising. Measuring these factors as a ratio allows assessment of the angiogenic imbalance that characterizes incipient or overt preeclampsia. The sFlt-1/PlGF ratio increases before the onset of preeclampsia and thus may help predict the disease. The test is used as a predictive tool in several countries but not yet routinely performed in Japanese hospitals.
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Objective To detect the levels of serum soluble fms-like tyrosine kinase-1(sFlt-1) and placenta growth factor(PLGF) during the second trimester in the serum of women in normal pregnancy and women who subsequently develop preeclampsia,and investigate the role of sFlt-1/PLGF ratio as an early marker for the development of preeclampsia.Methods The serum levels of PLGF and sFlt-1 in 200 healthy pregnant women and 57 women with preeclampsia were determined by enzyme-linked immunosorbent assay(ELISA).The ratio of sFlt-1/PLGF was calculated.Results The serum sFlt-1 levels were significantly higher in the women with preeclampsia [(1 385.0±178.8)ng/L] than in healthy controls [(1 087.3±122.7)ng/L](P0.01).The PLGF levels were significantly lower in the women with preeclampsia [(501.9±86.3)ng/L] than in healthy controls [(712.7±103.6)ng/L](P0.01).In the women with preeclampsia,sFlt-1 levels were negatively correlated with PLGF(r =-0.629,P0.01),and in healthy controls,there were positively correlations between the PLGF and sFlt-1 levels(r =0.682,P0.01).In the second trimester,the ratio of sFlt-1/PLGF was 1.9,and its sensitivity and specificity were 89.5% and 97.5%.Conclusions Preeclampsia showes a strong association with increased levels of sFlt-1 and decreased levels of PLGF in the second trimester.The sFlt-1/PLGF ratio may be an early marker for the development of preeclampsia.
Second trimester
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