Prognostic value of serum soluble FMS-like tyrosine kinase (sFlt-1) levels in pre-eclampsia and eclampsia; a prospective cohort study

Objective: To evaluate the levels of circulating sFlt-1 in pre-eclampsia (PE) and eclampsia patients and to assess its prognostic value in detection of PE complications. Methods: The present study was a prospective cohort study conducted in tertiary hospital between January and December 2016. Included patients were divided into two groups; (Group I) severe PE group and (Group II) eclampsia group. Age-, parity-, and gestational age-matched women had approached to participate in the study as a control group (Group III). Serum sFlt-1 levels were measured at inclusion and 2 days later with all basic investigations. Patients were followed up until delivery to record any complications. Correlation analysis was performed between the serum sFlt-1 levels and clinical, laboratory investigations. Receiver operating characteristic analysis was constructed for the evaluation of the area under curve (AUC) as well as the sensitivity and specificity regarding the cutoff point of sFlt-1 level that predict occurrence of complications. Results: The study included 84 women. Women with complicated severe PE showed higher sFlt-1 levels than in non-complicated cases (120.2 ± 19.6 versus 72.2 ± 19.6, p < 0.001). Similarly, the mean serum level of sFlt-1 in complicated eclampsia was higher than in non-complicated cases (298.3 ± 75.2 versus 128.1 ± 36.5, p < 0.001) (OR = 1.119, 95% CI: 10.057–1.184, p < 0.001). SFlt-1 levels were strongly correlated with systolic blood pressure (r = 0.641) and diastolic blood pressure (r = 0.540) (p < 0.001 and p < 0.001, respectively). At cutoff point 102.60 ng/ml of sFlt-1 levels, the sensitivity was 90% and specificity was 80% with AUC = 0.923, 95% CI: 0.871–0.975. Conclusions: Serum sFlt-1 can be used as a prognostic marker to predict the occurrence of complications of preeclampsia.     

A comparison of the diagnostic utility of the sFlt-1/PlGF ratio versus PlGF alone for the detection of preeclampsia/HELLP syndrome

Objective: The Elecsys^® immunoassay sFlt-1/PlGF ratio and the Triage^® PlGF assay were compared (in a prospective, multicenter, case-control study) for diagnosis of preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Methods: Women in European perinatal care centers with singleton pregnancies were enrolled: 178 cases had confirmed preeclampsia and 391 controls had normal outcome. Patients in the preeclampsia/HELLP syndrome group were matched pairwise by gestational week to healthy controls (1:2). Maternal blood samples were analyzed using (a) fully automated Elecsys PlGF and Elecsys sFlt-1 immunoassays with two cutoffs (early-onset [<34 weeks] ≤33, ≥85; late-onset [≥34 weeks] ≤33, ≥110), and (b) Triage PlGF immunoassay (single cutoff). Diagnostic performance and utility were assessed. Results: Respectively, 83 and 95 women had early-onset or late-onset preeclampsia/HELLP syndrome. The overall diagnostic performance of the Elecsys immunoassay sFlt-1/PlGF ratio (area under the curve [AUC] 0.941) was higher than for Triage PlGF (AUC 0.917). The Elecsys immunoassay sFlt-1/PlGF ratio sensitivity and specificity was: 94.0% (95% confidence interval [CI] 86.5–98.0) and 99.4% (95% CI: 96.8–99.9) for early-onset preeclampsia; and 89.5% (95% CI: 81.5–94.8) and 95.4% (95% CI: 91.7–97.8) for late-onset preeclampsia. The Triage assay sensitivity and specificity was: 96.4% (95% CI: 89.8–99.3) and 88.5% (95% CI: 82.8–92.8) (early-onset); and 90.5% (95% CI: 83–96) and 64.5% (95% CI: 57.8–70.9) (late onset). Conclusions: The fully automated Elecsys immunoassay sFlt-1/PlGF ratio provides improved diagnostic utility over the Triage PlGF assay with improved specificity for the clinical management of pregnant women with suspected preeclampsia/HELLP syndrome.     

可溶性血管内皮生长因子受体-1在子痫前期胎盘及在外周血的研究

目的研究可溶性血管内皮生长因子受体-1(sFlt-1) mRNA在正常妊娠和子痫前期胎盘中的表达差异及相应的母体外周血中sFlt-1水平的变化。方法选取15例子痫前期孕妇(子痫前期组)和14例孕周与之相匹配的血压正常妊娠孕妇(对照组),用ELISA方法测定其外周血中sFlt-1的水平;并应用实时荧光定量PCR测定两组胎盘组织中sFlt-1 mRNA水平。结果外周血中sFlt-1的水平子痫前期组明显高于对照组,分别为(16.9±8.32)μg/L、(5.48±2.09)μg/L,两者差异有显著性(P<0.05)。sFlt-1 mRNA在两组胎盘中均有表达,在子痫前期组的表达明显高于对照组的表达分别为(4.11±4.09)、(1.69±1.61),两者差异有显著性(P<0.05)。子痫前期组血清sFlt-1水平与24h尿蛋白定量呈明显正相关(r=0.741,P<0.05)。结论sFlt-1 mRNA在子痫前期组孕妇的外周血中及胎盘组织表达升高,可能与子痫前期的病因及病理生理有关。     

Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women

Abstract

Objective: Chronic hypertension, pregestational diabetes mellitus, history of prior preeclampsia and obese nulliparity are maternal conditions associated with increased preeclampsia risk. Whether altered maternal angiogenic factor levels allow for prediction of pending disease is unclear. Our objective was to evaluate angiogenic factors for early preeclampsia prediction in high-risk women.

Methods: Serial serum specimens were collected from 157 women at high preeclampsia risk and 50 low-risk controls between 23 and 36 weeks gestation in 3 windows (23–27.6, 28–31.6, and 32–35.6 weeks) in a two-center observational cohort. Soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) were measured by ELISA.

Results: Multivariate parsimonious logistic regression analyses using backward elimination for prediction of early-preeclampsia (diagnosed?<?34 weeks) found the best-fitting model included the predictors (1) sFlt1 measured in the second window (28–31.6 weeks) with AUC 0.85, sensitivity 67% and specificity 96% and (2) sFlt1 measured in the first window (23–27.6 weeks) and sEng change between first and second window with AUC 0.91, sensitivity 86% and specificity 96%.

Conclusions: Two-stage sampling screening protocol utilizing sFlt1 and sEng is promising for prediction of preeclampsia diagnosed before 34 weeks. Larger studies are needed to confirm these findings.     

An analysis on the roles of angiogenesis-related factors including serum vitamin D,soluble endoglin (sEng), soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF) in the diagnosis and severity of late-onset preeclampsia

Aim: The aim of this study was to evaluate the roles of proangiogenic factors including serum vitamin D and vascular endothelial growth factor (VEGF) and anti-angiogenic factors including soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt1) in the diagnosis and severity of late-onset preeclampsia.

Materials and methods: The study was conducted at Yuzuncu Yil University Research and Education Hospital Department of Gynecology and Obstetrics. The study included a patient group of 40 women with late-onset preeclampsia who were pregnant at?≥32 weeks of gestation according to the last menstrual period (LMP) or ultrasonographic fetal biometric measurement and a control group of 40 healthy pregnant women who presented to our clinic for routine pregnancy examination and were at the same age and gestational period with those in the patient group. The two groups were compared in terms of maternal age, gravida, parity, week of gestation, systolic/diastolic blood pressure, total protein in spot urine sample, 24-h urine protein, white blood cell (WBC), hemoglobin (Hgb), platelet count, urea, creatinine, liver function tests (AST, ALT, LDH), vitamin D₃, 25(OH) vitamin D₃, 1,25(OH) vitamin D₃, sEng, sFlt1, and VEGF levels, mode of delivery, the infant APGAR score at 1 and 5?min after delivery, and infant weight at delivery.

Results: The groups were similar in terms of age, gravida, parity, week of gestation, serum vitamin D₃, 25(OH) vitamin D₃, 1,25(OH)₂ vitamin D₃ and VEGF levels, and infant weight at delivery (p?>?0.05). Systolic/diastolic blood pressure, total protein in spot urine sample, 24-h urine protein, WBC, Hgb, serum urea, creatine, AST, ALT, and LDH were significantly higher in the preeclamptic group compared to the healthy group (p?p?3, 25(OH) vitamin D₃, and 1,25(OH)₂ vitamin D₃ levels. The sEng level was higher in the women with severe preeclampsia compared to the women with mild preeclampsia (p?3, 25(OH) vitamin D₃, and 1,25(OH)₂ vitamin D₃ levels between the subgroups of preeclampsia (p?>?0.05).

Conclusion: Both sEng and sFlt1 levels are remarkably high in patients with late-onset preeclampsia; however, only sEng may be a useful tool in the determination of the severity of preeclampsia.     

Serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1) level,and neonatal outcome in early onset,late onset preeclampsia,and normal pregnancy

ABSTRACT

Objective: To compare the level of serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1), and neonatal outcome in early onset preeclampsia (EO-PE), late onset preeclampsia (LO-PE), and normal pregnancy (NP).

Methods: In this prospective observational case control study, HO-1 and sFlt-1 levels were measured in blood samples within 24 h of hospital admission. Preeclampsia cases were divided into two groups based on gestational age at delivery: EO-PE (<34 weeks) and LO-PE (≥34 weeks). A total of 45 patients were involved in this study.

Result: Maternal serum level of sFlt-1 was higher in EO-PE than LO-PE and NP groups (mean ± SD; 14.50 ± 17.12 ng/ml vs 5.20 ± 6.69 ng/ml vs 2.72 ± 1.2 ng/ml [p = 0.020]. Maternal serum level of HO-1 was not different between EO-PE, LO-PE, and NP groups (p = 0.681). Birthweights were significantly lower in the EO-PE group compared with the LO-PE and NP groups (1580 ± 536 g vs 2635 ± 578 g vs 3010 ± 371 g [p = 0.000]). The rate of small for gestational age infant (26.7% vs 6.7% vs 0%; p = 0.046) and perinatal death (20% vs 0 vs 0; p = 0.037) was also significantly higher in EO-PE compared to LO-PE and NP. The maternal sFlt-1 level was negatively correlated with birthweight (p = 0.006; CC = ?0.445).

Conclusion: This study did not find a correlation between maternal HO-1 levels and sFlt-1 levels. Maternal serum sFLt-1 levels in preeclampsia were higher in EO-PE and were associated with a worse perinatal outcome.     

Increased placental sFlt-1 but unchanged PlGF expression in late-onset preeclampsia

Objective: To investigate whether differences between late-onset preeclampsia (PE) and intrauterine growth restriction (IUGR) can be explained by differential placental expression patters of sFlt-1, Flt-1, and placental growth factor (PlGF).

Methods: Placental tissues and maternal blood samples from seven patients with PE, five IUGR, and seven age-matched controls were studied for mRNA and protein levels as well as protein localization and expression intensity.

Results: Placental PlGF mRNA and protein expression were not altered by placental dysfunction while placental villous trophoblast expression intensity of PlGF was increased.

Conclusion: High sFlt-1 concentrations may account for diminished maternal serum PlGF levels.     

Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia

OBJECTIVE: We measured maternal serum soluble fms-like tyrosine kinase 1 concentrations across pregnancy and immediately postpartum in women who developed preeclampsia and normal pregnant women. STUDY DESIGN: This was a nested case control study of 113 normal pregnant women and 55 women with preeclampsia. RESULTS: Serum soluble fms-like tyrosine kinase 1 concentrations increased similarly in early pregnancy in both groups. Mean serum soluble fms-like tyrosine kinase 1 concentrations were increased in women who developed preeclampsia, compared with normal pregnant women, and this increase was most pronounced in severe preeclampsia. However, many women with preeclampsia had soluble fms-like tyrosine kinase 1 concentrations similar to normal pregnant women. Lastly, soluble fms-like tyrosine kinase 1 decreased rapidly after delivery, but this decrease was significantly slower in women with severe preeclampsia. CONCLUSION: Increased soluble fms-like tyrosine kinase 1 is not an early-pregnancy event among women who later develop preeclampsia. Increased soluble fms-like tyrosine kinase 1 is more likely to be present in women with severe preeclampsia, but it is not present in all women with preeclampsia. Soluble fms-like tyrosine kinase 1 concentrations decrease more slowly after delivery in women with preeclampsia, consistent with a decreased rate of excretion or continued production.     

孕中期血清PLGF、sFlt-1、sEng、sCD40L与子痫前期及胎儿不良结局的关系研究#br#

目的探讨孕中期血清胎盘生长因子(PLGF)、可溶性血管内皮生长因子受体1(sFlt-1)、可溶性内皮因子(s Eng)、可溶性CD40配体(sCD40L)与子痫前期及胎儿不良结局的关系。方法选取河北省唐山市妇幼保健院收治的子痫前期患者、健康孕妇各192例作为研究对象,采集两组孕妇孕20~24周的血液标本,测定血清PLGF、sFlt-1、sEng、sCD40L水平,对比检测结果。跟踪子痫前期孕妇的围产结局,对比不同围产结局孕妇的各项血清指标检测结果。结果与对照组相比,观察组孕妇的血清PLGF水平更低,sFlt-1、sEng、sCD40L水平更高(P<0.05)。轻度子痫前期、重度子痫前期与PLGF水平均呈负相关,与sFlt-1、sEng、sCD40L、Hcy水平均呈正相关(P<0.05)。相比轻度子痫前期,重度子痫前期与各血清学指标的相关性更强。胎儿妊娠结局良好162例(84.38%),结局不良30例(15.63%)。结局不良组的PLGF水平显著低于结局良好组,sFlt-1、sEng、sCD40L、Hcy水平显著高于结局良好组(P<0.05)。子痫前期患者胎儿不良结局与PLGF水平呈负相关,与sFlt-1、sEng、sCD40L、Hcy水平均呈正相关(P<0.05)。结论子痫前期的发生、进展及围产结局均与血清PLGF、s Flt-1、sEng、sCD40Ly水平密切相关,监测孕中期血清PLGF、sFlt-1、sEng、sCD40L水平变化可为临床评估子痫前期病情程度、预测胎儿不良结局提供参考依据。     

Variable expression of soluble fms-like tyrosine kinase 1 in patients at high risk for preeclampsia

Objective.?To explore angiogenic factor differences in preeclamptic patients according to the absence or presence of underlying vascular disease.

Methods.?We prospectively compared serum soluble fms-like tyrosine kinase 1 (sFlt1), soluble endoglin, and placental growth factor (PlGF) from 41 normal-risk and 32 high-risk (preexisting conditions) subjects at serial gestational ages.

Results.?Median sFlt1 was lower at delivery in preeclamptic patients with underlying chronic hypertension and/or chronic proteinuria (5115?pg/ml) compared with normal risk preeclamptic patients (16375?pg/ml). PlGF was consistently low in patients who developed preeclampsia.

Conclusions.?Effects of sFlt1 may be contextual, varying according to the health or disease state of vascular endothelium.     

可溶性血管内皮生长因子受体-1与胎盘生长因子在子痫前期

归纳子痫前期的病理生理过程以及可溶性血管内皮生长因子受体-l（sFlt-1）、胎盘生长因子（PLGF）与子痫前期的研究情况,PLGF是血管内皮生长因子（VEGF）家族成员之一,PLGF与Flt-1受体结合时,发挥促血管生成和促绒毛滋养细胞增殖、浸润的效应,而这些生物学功能均可被sFlt-1阻断,且sFlt-1对PLGF具有强效的拮抗作用,调节PLGF的功能。在子痫前期妊娠妇女血清中sFlt-1的水平升高,早于疾病的发生。子痫前期患者血浆中PLGF的水平降低。总结sFlt-1、PLGF预测诊断子痫前期发生及病情严重程度的研究进展,探讨sFlt-1、PLGF在子痫前期临床诊断中的意义。     

胎盘微环境改变与子痫前期

胎盘对于胎儿发育至关重要,胎儿血与母体血在胎盘单位内进行养分交换。子痫前期发病的关键环节即为滋养细胞浸润不足引起的对子宫螺旋动脉重塑障碍。可溶性血管内皮生长因子受体-1与胎盘生长因子的比值在子痫前期的发病、诊断及不良妊娠结局的发生率中可能有重要预测价值。