Biochemical role of intravaginal sildenafil citrate as a novel antiabortive agent in unexplained recurrent spontaneous miscarriage: first clinical study of four case reports from Egypt

Abstract

Many factors have been implicated in the pathogenesis of unexplained recurrent spontaneous miscarriage (URSM). The objective of this preliminary clinical study was to verify whether intravaginal sildenafil citrate tablets (25 mg intravaginally, 4 times/day for 24 days) are effective as a novel treatment of threatened miscarriage in patients with a history of URSM (n=4). We also evaluated changes in the concentrations of some antioxidants, the percent expression of cells positive for tumor necrosis factor-alpha (TNF-alpha), CD56+T-cells [CD3+CD56+ natural killer cells (NKT cells) (cluster differentiation 3, 56 NKT cells)], which express one of the NK cell markers, and uterine artery pulsatility index (PI). We compared these results with healthy women in their first trimester of pregnancy (FTP n=4). Sildenafil improved the measured antioxidants concentrations [total antioxidant capacity (TAC), glutathione S-transferase (GSH-S-T) and catalase (CAT), superoxide dismutase (SOD)], and improved oxidative stress by reducing malondialdehyde (MDA) and nitric oxide (NO) in the four patients under investigation. The improvement in antioxidants was close to concentrations seen in women in their FTP. The four patients had progressed to their third trimester of pregnancy using this novel application. The percentage of [CD3+CD56+ NKT cells] and TNF-alpha in peripheral blood was higher in URSM patients compared to women in their FTP. However, concentrations were greatly reduced and improved after sildenafil administration. We demonstrated that intravaginal sildenafil citrate tablets can reduce vasoconstriction by increasing blood flow through relaxation of uterine arteries as indicated from measured PI in URSM patients. We conclude that intravaginal sildenafil citrate tablets used as suppositories might be a novel, interesting, safe antiabortive option in the treatment of threatened miscarriage in patients with a history of URSM. We are the first to report this novel clinical application in four case reports in Egypt.