A systematic review of experimental and clinical studies of sildenafil citrate for intrauterine growth restriction and pre-term labour

Abstract

Sildenafil could be an alternative in the treatment of intrauterine growth retardation (IUGR) and premature delivery. In order to systematically review the reproductive-related effects of sildenafil, a search was made on PubMed and the Science Citation Index for studies evaluating the effects of sildenafil on uterine vessels or myometrium either in vitro or in experimental animal models as well as for any clinical trial or case reporting the outcome of pregnant women treated with sildenafil. The information was obtained from: three in vitro studies, five studies performed in experimental animal models, four studies on women with fertility and sterility disorders receiving 100 mg/day of sildenafil intravaginally, and two case reports of pregnant women who received sildenafil for the treatment of pulmonary hypertension. Incubation with sildenafil of different in vitro preparations resulted in vasodilator and uterine relaxant effects. No evidence of teratogenicity was observed in the studies performed in mice, rats and dogs. Sildenafil increased fetal weight in rats. In women, contradictory results on uterine blood flow and endometrial development were reported after the intravaginal administration of sildenafil. No adverse fetal outcomes were reported in the two pregnant women with pulmonary hypertension receiving sildenafil late in their pregnancy. In conclusion, there is still limited information about the efficacy of sildenafil for the treatment of IUGR and premature delivery. However, studies in experimental animal models and two human case reports have reported no deleterious effects on the mother or offspring.

The use of low dose sildenafil citrate in cases of intrauterine growth restriction

“…Sildenafil citrate is increasingly used for pulmonary hypertension in pregnancy, and is also emerging as a potential candidate for the treatment of intrauterine growth retardation and for premature labour [14]. Sildenafil has also been proposed as a potential therapeutic strategy to maintain placental function in pre-eclampsia [15].…”

Investigational noncardiovascular uses of phosphodiesterase-5 inhibitors

“…There is conflicting evidence on the efficacy of sildenafil in intrauterine growth retardation, but no detrimental effects were found [107] There is also conflicting evidence about sildenafil in sheep models: one study reported hypoxia, hypotension, and tachycardia in animals with induced IUGR and in control fetuses [116]; another study reported dose-related increases in fetal weight in both control and nutrient-restricted ewes, and increased delivery of amino acids and polyamines to IUGR fetuses [117] 12.2.2 Conception and preservation of pregnancy Intravaginal sildenafil (also at 25 mg four times daily) has been employed in cases of recurrent miscarriage, which has been linked to various factors including NO-mediated release of tumor necrosis factor-a (TNF-a) from natural killer (NK) cells.…”

“…Data on the safety of this experimental use are limited, but no adverse effects have been reported from preclinical models or human case reports [107].…”

“…A review of clinical and preclinical reports shows conflicting evidence of efficacy in IUGR but no detrimental effects [107]. In a study in sheep with IUGR and fetal hypoxia induced by single umbilical artery ligation, sildenafil actually led to worsening hypoxia, hypotension and tachycardia in both IUGR and control fetuses [116].…”

Sildenafil vaginal suppositories: preparation, characterization,in vitroandin vivoevaluation

“…Recently, sildenafil, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine, a type 5-specific phosphodiesterase (PDE) inhibitor, has been reported to improve uterine blood flow in women following intravaginal (IVG) administration 1,4,[12][13][14][15] . This increased blood flow has lead to estrogen-induced proliferation of the endometrial lining in patients with poor endometrial development resulting in successful pregnancy 4,13 .…”