Soluble fms-Like Tyrosine Kinase-1 (sFlt-1) and Serum Placental Growth Factor (PlGF) as Biomarkers for Ectopic Pregnancy and Missed Abortion

Daponte, Alexandros; Pournaras, Spyros; Polyzos, Nikolaos P.; Tsezou, Aspasia; Skentou, Hara; Anastasiadou, Foteini; Lialios, Georgios; Messinis, Ioannis E.

doi:10.1210/jc.2011-0037

Cited by 35 publications

(34 citation statements)

References 30 publications

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“…Compared to the benchmark sFlt-1/PIGF ratio in PE assessment, our biomarker panels perform comparably during early gestational age but clearly outperform at later gestational weeks. Although the sFlt-1 and PIGF imbalance used for PE diagnosis has been demonstrated, there is mounting evidence to support the notion that normal sFlt-1 and PIGF expression actually characterizes healthy pregnancies [50]. Therefore, sFlt-1 and PIGF may really be general markers for failed pregnancies, for example, ectopic pregnancies, missed abortions, rather than specific to PE.…”

Section: Discussionmentioning

confidence: 99%

Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

Liu

Yang

et al. 2013

BMC Med

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BackgroundPreeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-’omics’ based discovery approach.MethodsSeven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment.ResultsIn addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively.ConclusionsBoth early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

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Section: Discussionmentioning

confidence: 99%

Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

Liu

Yang

et al. 2013

BMC Med

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“…(10) Other groups have suggested multiple marker tests including combinations of markers of inflammation and corpus luteum function,(11) or of trophoblast and corpus luteum function(12). In addition, A Disintegrin And Metalloprotease-12 (ADAM12) (13, 14) and placental like growth factor (PlGF) (15,16), have been suggested as potential biomarker candidates. However, these markers have yet to be assessed when miscarriage is included as a potential outcome of early pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Predicting first trimester pregnancy outcome: derivation of a multiple marker test

Senapati

Sammel

Butts

et al. 2016

Fertility and Sterility

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Objective To predict first trimester pregnancy outcome using biomarkers in a multi-center cohort. Design Case-control study Setting Three academic centers Patients Women with pain and bleeding in early pregnancy Interventions Sera from women 5-12 weeks’ gestational age (GA) with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage (SAB) was analyzed via ELISA and immunoassay for Activin A (AA), Inhibin A (IA), Progesterone (P4), ADAM12, PAPP-A, pregnancy specific beta-glycoprotein-1 (SP1), Placental-like growth factor (PlGF), Vascular endothelial growth factor (VEGF), Glycodelin (Glyc), and human chorionic gonadotropin (hCG). Classification trees were developed to optimize sensitivity/specificity for pregnancy location and viability. Main Outcome Measure(s) Area under receiver operating characteristic curve, sensitivity, specificity, and accuracy of first trimester pregnancy outcome. Results In 230 pregnancies, the combination of trees to maximize sensitivity and specificity resulted in 73% specificity, (95% CI [0.65-0.80]) and 31% sensitivity (95% CI [0.21-0.43]) for viability. Similar methods had 21% sensitivity (95% CI [0.12-0.32]) and 33% specificity (95% CI [0.26-0.41]) for location. AA, Glyc, and ADAM12 definitively classified pregnancy location in 29% of the sample with 100% accuracy for EP. P4 and PAPP-A classified the viability in 61% of the sample with 94% accuracy. Conclusions Multiple marker panels can distinguish pregnancy location and viability in a subset of women at risk for early pregnancy complications. This strategy of combining markers to maximize sensitivity and specificity results in high accuracy in a subset of subjects. Activin A, ADAM12, and Glycodelin are the most promising markers for pregnancy location; Progesterone and PAPP-A for viability.

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“…Furthermore, in a cohort with threatened miscarriage (vaginal bleeding during pregnancy), those with depressed sFlt1, PlGF and sEng were all significantly more likely to undergo complete miscarriage [11]. However, in all of these studies clinical samples were only obtained once women had presented with symptoms of miscarriage (abdominal pain and bleeding).…”

Section: Introductionmentioning

confidence: 99%

Serum Concentrations of Soluble Flt-1 Are Decreased among Women with a Viable Fetus and No Symptoms of Miscarriage Destined for Pregnancy Loss

et al. 2012

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Miscarriage is the most common complication of pregnancy. Pre-clinical miscarriage has an estimated incidence of 30%, whilst clinical miscarriage has an incidence of 12-15%. Two thirds of pregnancies lost to miscarriage are believed to be attributable to defective placentation, thus a number of studies have sought to identify markers of defective placentation that could be used as clinical biomarkers of miscarriage. Decreased soluble FMS-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) in the maternal circulation during the first trimester have recently been proposed as potential markers of pregnancy loss. However, in these studies clinical samples were only obtained once women had presented with symptoms of miscarriage. In this study we prospectively screened serum samples collected from asymptomatic women with a viable fetus. We assessed maternal serum levels of sFlt1, PlGF and sEng across the first trimester of normal pregnancy and compared levels between women who continued to a live birth, to those who subsequently miscarried. Both sFlt1 and PlGF significantly (p≤0.05) increased across gestation in normal pregnancy with serum levels rising from 0.65±0.12 ng/ml at 6 weeks to 1.85±0.24 ng/ml at 12 weeks for sFlt1, and 57.2±19.2 pg/ml to 106±22.7 pg/ml for PlGF. sEng remained unchanged throughout the the first trimester. Importantly we detected a significant (35%, p≤0.05) decrease in sFlt1 levels between our control and miscarriage cohort, however there was significant overlap between cases and controls, suggesting serum sFlt1 is unlikely to be useful as a clinical biomarker in asymptomatic women. Nevertheless, our data suggests a dysregulation of angiogenic factors may be involved in the pathophysiology of miscarriage.

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Soluble fms-Like Tyrosine Kinase-1 (sFlt-1) and Serum Placental Growth Factor (PlGF) as Biomarkers for Ectopic Pregnancy and Missed Abortion

Abstract: Combined measurement of sFlt-1 and PlGF levels can differentiate normal from failed pregnancies, whereas sFlt-1 as well as sFlt-1/PlGF ratio can also discriminate EP from MA. PlGF and Flt-1 gene expression in trophoblasts from women with EP and MA appears impaired.

Cited by 35 publications

References 30 publications

Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

Predicting first trimester pregnancy outcome: derivation of a multiple marker test

Serum Concentrations of Soluble Flt-1 Are Decreased among Women with a Viable Fetus and No Symptoms of Miscarriage Destined for Pregnancy Loss

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