Elsevier

Pregnancy Hypertension

Volume 13, July 2018, Pages 1-6
Pregnancy Hypertension

Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia

https://doi.org/10.1016/j.preghy.2018.04.011Get rights and content

Highlights

Abstract

Objectives

To examine the effect of sildenafil on level of antiangiogenic proteins of preeclampsia. Firstly to examine the effect of sildenafil on serum biomarkers in a patient with preterm preeclampsia. Secondly, to examine the effect of sildenafil on sFlt-1 and soluble endoglin secretion from primary trophoblasts and placental explants.

Study design

The clinical team administered 50 mg tds sildenafil to a 26-year-old primigravid woman with severe preeclampsia at the threshold of viability (24 3/7 weeks gestation) and we collected bloods to examine the effect of slidenafil on antiangiogenic factors sFlt-1 and soluble endoglin (sENG), pro-angiogenic factor PlGF and vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET1). We administered sildenafil to human primary trophoblasts and placental explants and explored its effect on sFlt-1 and sENG secretion.

Main outcome measures

We examined serum anti-angiogenic factors sFlt-1 and sENG, pro-angiogenic factor PlGF, the potent vasoconstrictor ET1 and VCAM-1 by ELISA. We explored the effect of sildenafil on sFlt-1 secretion from primary trophoblasts and sFlt-1 and sENG secretion from placental explants.

Results

We found a reduction in serum sFlt-1, stabilisation in sENG and PlGF in a patient with peri-viable preterm preeclampsia administered oral sildenafil 50 mg three times daily (tds). Furthermore there was an initial stabilisation in serum VCAM-1 and a decline in ET1 with sildenafil administration. This was concordant with stabilisation of clinical and biochemical features of preeclampsia. Interestingly, treating placental cells and tissues in vitro with sildenafil did not appear to change sFlt-1 or sENG secretion.

Conclusion

Sildenafil administration was associated with a reduction in serum sFlt-1 and sENG secretion and increase in PlGF secretion in a patient with preterm preeclampsia, potentially via increasing placental perfusion rather than acting directly on the placenta.

Introduction

Preterm preeclampsia is a leading cause of perinatal morbidity and mortality. It is associated with the placental production of antiangiogenic factors sFlt-1 and sENG. Their secretion is driven by hypoxia and ischaemia, possibly resulting from compromised maternal blood flow to the preeclamptic placenta. A medical treatment reducing placental sFlt-1 and sENG secretion and increasing placental growth factor (PlGF) secretion allowing gestation prolongation to improve perinatal outcomes would be a major advance [1].

Tripani et al. [2] demonstrated sildenafil citrate may prolong gestation in patients with preterm preeclampsia. Their randomised controlled trial evaluated the effect of 50 mg of sildenafil or placebo three times daily (tds) in 100 patients with preeclampsia at 24–33 weeks gestation. They demonstrated a 4-day prolongation of gestation as well as improved maternal and fetal Doppler indices. Furthermore, an open label trial of sildenafil administered to women with fetal growth restriction raised the possibility that sildenafil may prolong gestation, reduce rates of caesarean section and reduce neonatal intensive care admission [3]. Circulating serum sFlt-1, sENG and PlGF levels were not reported in these trials.

Given elevated circulating levels of sFlt-1 and sENG are associated with the severity and development of preeclampsia, we explored the effect of sildenafil on anti-angiogenic and pro-angiogenic factors and markers of endothelial dysfunction. Firstly we examined the effect of 50 mg tds of sildenafil citrate in a patient at the peri-viable gestation of 24 3/7 with preterm preeclampsia. We assessed antiangiogenic factor sFlt-1 and sENG and angiogenic factor placental growth factor (PlGF) (known to be reduced in preeclampsia). We also assessed clinical and biochemical effects of sildenafil with respect to preeclampsia. Next we studied whether sildenafil altered the release of sFlt-1 and sENG from human placenta (explant tissue and primary trophoblast) in vitro.

Section snippets

Patient with preterm preeclampsia

The clinical team treated a peri-viable patient at 23 5/7 weeks gestation with preterm preeclampsia, with 50 mg sildenafil tds on compassionate grounds. Preeclampsia was defined using the International Society for the Study of Hypertension in Pregnancy (ISSHP) guidelines: the presence of new onset hypertension >140/90 and any of the following: proteinuria >300 mg/day, renal insufficiency, impaired liver function, neurological complications or haematological complications or fetal growth

Results

A 26-year-old nulliparous woman developed severe preeclampsia at 24 3/7 weeks of gestation as defined by the American College of Obstetricians and Gynecologists guidelines [9]. She was previously well, normotensive with an initial blood pressure of 120/70, had a normal body mass index of 20 and had no significant medical or surgical past history. Her prenatal course had been complicated by the incidental finding of a subamniotic placental hematoma of 10 × 2.5 cm noted during her morphology

Discussion

Here we report for the first time that sildenafil administration is associated with a reduction in circulating sFlt-1 levels in a patient with preterm preeclampsia. Whilst antiangiogenic factors reduced in our patient, there was no change to sFlt-1 secretion from isolated placental cytotrophoblast or tissue explants. Our data raises the possibility that sildenafil may decrease sFlt-1 in preeclampsia, however the precise mechanisms are not known. Perhaps sildenafil may exert these actions by

Acknowledgements

We would like to thank the patient for their involvement and the treating clinical team including Dr Alexis Shubb, Professor Susan Walker and Dr Hannah Skrzypek.

Sources of funding

FCB was supported by a Mercy Perinatal Fellowship. TKL (#1062418) and ST (#1050765) NJH by The University of Melbourne C R Roper Fellowship. The funders had no role in study design, data collection, analysis, decision to publish or the preparation of the manuscript.

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