Sildenafil Citrate Added to Low Molecular Weight Heparin and Low Dose Aspirin to Improve Uteroplacental Perfusion in High-risk Pregnancy

Pregnancy is considered an acquired hypercoagulable state due to increased concentration of coagulation factors, decreased levels of anticoagulants and decreased fibrinolytic capacity. Adverse pregnancy outcomes affect up to 15% of gestations and are the major cause of maternal and fetal morbidity and mortality. A poor perinatal outcome is expected in pregnancies with high vascular resistance in uterine circulation, but the pregnancies in which the resistance values are normalized in the later trimesters have a significantly better outcome.

For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. Moreover, in vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent.

In a normal pregnancy, the trophoblast produces nitric oxide (NO) which plays an important role in vasodilatation in the fetoplacental circulation to improve oxygen and nutritional supply to the fetus (9,10). Nitric oxide relaxes arterial and venous smooth muscle potently and might inhibit platelet aggregation and adhesion. Moreover, increased circulating phosphodiesterase (PDE) activity is suspected in women with preeclampsia. In pregnancies with fetal growth restriction and without preeclampsia, a reversible increased myometrial arterial tone by phosphodiesterase inhibition has been reported in vitro.

Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)-5 leading to cyclic guanosine monophosphate (cGMP) accumulation and enhances the relaxation elicited by exogenous and neural-released nitric oxide in corpus cavernous. Sildenafil citrate increases uterine blood flow and potentiates estrogen-induced vasodilatation. Intravaginal administration of Sildenafil in the success of in vitro fertilization describes no deleterious effects on mother and fetus. The Natural Killer Cells activity and endometrial thickness were significantly changed after vaginal Sildenafil therapy so it might be an interesting therapeutic option before conception in women with recurrent reproductive failure.

Reduced flow / increased resistance in uterine and umbilical arteries, indicative of reduced uteroplacental flow in pregnancies with fetal growth restriction, has been documented by non-invasive Doppler ultrasound velocimetry.