Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia
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.
References (14)
Pre-eclampsia
Lancet
(2016)The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP
Pregnancy Hypertens.
(2014)- et al.
Soluble endoglin production is upregulated by oxysterols but not quenched by pravastatin in primary placental and endothelial cells
Placenta
(2014) Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial
Obstet. Gynecol.
(2016)- et al.
Sildenafil citrate therapy for oligohydramnios: a randomized controlled trial
Obstet. Gynecol.
(2017) Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion, and endothelial dysfunction
Am. J. Obstet. Gynecol.
(2015)Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia
Hypertension
(2015)