Angiogenesis related biomarkers as a prognostic indicator in women with preterm preeclampsia.

Clinical Pearls:

• Studies and reviews have demonstrated that maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and sEng correlate with preeclampsia disease activity and are increased well before the onset of clinical signs and symptoms.
• Among the many markers evaluated, it was seen that a single angiogenesis related biomarker (PlGF, sFlt-1, or endoglin) alone can be used as an important diagnostic test for the primary endpoint in women with preterm preeclampsia.

The incidence of preeclampsia and related hypertensive disorders of pregnancy is 5-8% of all births in the United State while globally it is estimated that about 10,0000 women develop preeclampsia, and about 76,000 women succumb to preeclampsia, eclampsia and hypertensive disorders of pregnancy each year. [1]

According to WHO a woman in developing country is seven times more likely to develop preeclampsia than a woman in developed country. [2]

While preeclampsia presents itself clinically anytime between second trimester and postpartum, the pathological changes antedates it and begin at the end of first trimester and consist of abnormal remodeling of the spiral arteries.

While researchers all around the world have tried to develop various tests to accurately predict the women at risk of developing preeclampsia, but the current ability and availability of clinical test is still limited. Evidence suggests that preeclampsia develops because of endothelial injury, which sets forth a cascade of coagulation, vasoconstriction, and intravascular fluid redistribution.[3]Altered placentation and subsequent ischemia plays an important role in disease development. 

Among the sea of vast number of biomarkers, large number of studies and reviews have demonstrated that maternal serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and sEng correlate with preeclampsia disease activity and are increased well before the onset of clinical signs and symptoms. But clinical applications of these have not been materialized in actual clinical practice.[4]

Only few guidelines have included them in daily practice. The German guidelines have recently included the sFlt-1/PlGF ratio as aiding in the diagnosis of preeclampsia.

Earlier studies have demonstrated the use of sFlt-1/PlGF ratio to predict adverse pregnancy outcome. Rana et al showed that in cases evaluated under 34 weeks of gestation, delivery took place in the two weeks following its determination in 86% of patients with a sFlt-1/PlGF ratio ≥85, compared with only 16% of women with a sFlt-1/PlGF <85.[5]

Measuring the sFlt-1/PlGF ration as a prognostic indicator have been adopted in large hospitals in Spain and if results are good, they can be used for risk stratifications and management.

A recent study published in the forthcoming issue of Journal of Obstetrics and Gynecology evaluated 47 biomarkers individually as well as in combination with placental growth factor (PlGF) as a prognostic marker requiring delivery within 14 days in women with suspected preterm preeclampsia.

It was a prospective, multicenter observational study recruiting 423 women presenting with suspected preterm preeclampsia categorized into two groups (less than 35 weeks and 35 0/7 - 36 6/7 weeks based on gestational dating.

The primary endpoint in the study was preeclampsia requiring delivery within 14 days.  

In both the groups, the combination of markers was not statistically better than a single biomarker used alone. Among the many markers evaluated, it was seen that a single angiogenesis related biomarker (PlGF, sFlt-1, or endoglin) alone can be used as an important diagnostic test for the primary endpoint in women with preterm preeclampsia.

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[1] Villar J, Say L, Gulmezoglu AM, Meraldi M, Lindheimer MD, Betran AP, Piaggio G; Eclampsia and pre-eclampsia: a health problem for 2000 years. In Pre-eclampsia, Critchly H, MacLean A, Poston L, Walker J, eds. London, RCOG Press, 2003, pp 189-207.

[2] Maternal mortality in 2005: estimates developed by WHO, UNICEF, UNIFPA and the World Bank, Geneva, World Health Organization, 2007.

[3] Roberts, J. M., Taylor, R. N., Musci, T. J., Rodgers, G. M., Hubel, C. A., & McLaughlin, M. K. (1989). Preeclampsia: an endothelial cell disorder.American journal of obstetrics and gynecology, 161(5), 1200-1204.

[4] Levine, R. J., Maynard, S. E., Qian, C., Lim, K. H., England, L. J., Yu, K. F., ... & Sibai, B. M. (2004). Circulating angiogenic factors and the risk of preeclampsia. New England Journal of Medicine, 350(7), 672-683.

[5] Rana S., Powe C.E., Salahuddin S., Verlohren S., Perschel F.H., Levine R.J., Lim K.H., Wenger J.B., Thadhani R., Karumanchi S.A. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125:911–919. doi: 10.1161/CIRCULATIONAHA.111.054361.