What is the role of sFlt-1 (soluble fms-like tyrosine kinase-1) and soluble endoglin as biomarkers in predicting and diagnosing preeclampsia?

Role of sFlt-1 and Soluble Endoglin as Biomarkers in Predicting and Diagnosing Preeclampsia

sFlt-1 and soluble endoglin are promising biomarkers for predicting preeclampsia, with elevated sFlt-1 and soluble endoglin levels being associated with increased risk of developing preeclampsia, though their current test accuracies are insufficient for routine clinical use. 1

Pathophysiological Basis

• Preeclampsia involves angiogenic imbalance characterized by elevated soluble fms-like tyrosine kinase 1 (sFlt-1), reduced placental growth factor (PlGF), and elevated soluble endoglin (sEng) 1
• These biomarkers reflect the underlying pathophysiology of preeclampsia, which includes placental ischemia, abnormal immune system activation, and metabolic dysfunction 1
• sFlt-1 is an anti-angiogenic factor that binds and reduces free circulating levels of vascular endothelial growth factor (VEGF) and PlGF, contributing to endothelial dysfunction 2
• Soluble endoglin is a co-receptor for transforming growth factor-β that interferes with normal vascular homeostasis 2, 3

Diagnostic Performance

• Studies show that women who later develop preeclampsia have:

  • Higher concentrations of sFlt-1 (standardized mean difference 0.48,95% CI 0.21-0.75) 2
  • Higher concentrations of soluble endoglin (standardized mean difference 0.54,95% CI 0.24-0.84) 2
  • Lower concentrations of PlGF (standardized mean difference -0.56,95% CI -0.77 to -0.35) 2

• The diagnostic odds ratios for these biomarkers are:

  • sFlt-1: 6.6 (95% CI 3.1-13.7) 2
  • Soluble endoglin: 4.2 (95% CI 2.4-7.2) 2
  • PlGF: 9.0 (95% CI 5.6-14.5) 2

• These correspond to sensitivities of 26%, 18%, and 32% respectively, at a 5% false-positive rate 2

Clinical Applications

Prediction of Preeclampsia

• First-trimester serum levels of both sFlt-1 and soluble endoglin are higher in women who subsequently develop late-onset preeclampsia 4

  • For soluble endoglin: 5.57 ± 1.18 ng/mL vs 5.02 ± 1.01 ng/mL in controls (p = 0.009)
  • For sFlt-1: 1764 ± 757 pg/mL vs 1537 ± 812 pg/mL in controls (p = 0.036)
  • Sensitivities and specificities: 63% and 57% for soluble endoglin; 64% and 56% for sFlt-1

• Serial measurements of soluble endoglin show higher levels from 22 weeks gestation onward in women who later develop early-onset preeclampsia (<34 weeks) and from 28 weeks onward in those who develop late-onset preeclampsia (≥34 weeks) 5

• The rate of change in soluble endoglin levels over time is also higher in women who later develop preeclampsia 5

Combined Biomarker Approaches

• The sFlt-1/PlGF ratio appears to be the most accurate predictor with:

  • Area under the curve (AUC) of 0.92 3
  • Specificity, sensitivity, and diagnostic accuracy of 88.5% using a cutoff of 38.47 3

• Combining soluble endoglin with other markers like inhibin A increases sensitivity to 68% with a specificity of 61% 4

Current Recommendations and Limitations

• Despite promising research, the International Society for the Study of Hypertension in Pregnancy (ISSHP) does not recommend routine use of these biomarkers as rule-out tests for preeclampsia 1

• The National Institute for Health and Care Excellence (NICE) has recommended the use of the sFlt-1/PlGF ratio or the Triage PlGF test with standard clinical assessment to help rule out preeclampsia requiring delivery within 7-14 days in women with suspected preeclampsia between 20 and 34+6 weeks' gestation 1

• Current test accuracies of all four markers (sFlt-1, soluble endoglin, PlGF, and VEGF) are considered too poor for accurate prediction of preeclampsia in routine clinical practice 2

• Further research is needed through well-designed, multi-center trials to test the clinical utility of these biomarkers in improving pregnancy outcomes while balancing costs and potential unnecessary interventions resulting from false positive screening 1

Special Considerations

• Women with multiple gestations have significantly higher baseline soluble endoglin levels compared to those with high-risk singleton pregnancies, even in the absence of preeclampsia 5

• This highlights the importance of developing specific reference ranges for different pregnancy types when interpreting these biomarkers 5

• The heterogeneity of preeclampsia (early vs late onset, with vs without severe features) may require different biomarker thresholds or combinations for optimal prediction 1