Sildenafil citrate: A novel therapy for intrauterine growth restriction

Abstract

Intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity, mortality and adverse long term health consequences, yet no treatments are available which can improve fetal growth and wellbeing in utero. As utero-placental insufficiency (increased resistance to uterine artery blood flow with reduced utero-placental perfusion) is an important cause of IUGR, agents that vasodilate the utero-placental circulation are potential therapies. Sildenafil citrate, a phosphodiesterease inhibitor with vasodilatory properties, is a potential new therapy for IUGR. Small animal studies suggest that sildenafil can increase fetal growth, but presently evidence of its efficacy in larger animals, and an understanding of the mechanism/s through which sildenafil affects growth are lacking. The two aims of this thesis are to assess the effect of sildenafil on 1) fetal growth in large and small animal models of IUGR; and 2) maternal myometrial / uterine artery ex vivo function in animal models of IUGR and human pregnancies complicated by IUGR. Methods Two different animal models of IUGR were used: uterine artery embolisation in the pregnant ewe, and gene knockout (endothelial nitric oxide synthase knockout and catechol-o-methyltransferase knockout) ± maternal weight gain in mice. In both studies, pregnant animals were randomised to sildenafil or vehicle treatment during pregnancy. Myometrial arteries were collected from uterine biopsies taken at delivery from women randomised to sildenafil or placebo as part of the ‘sildenafil treatment for dismal prognosis early onset IUGR’ trial. Wire myography was used to assess ex vivo perfusion function in uterine (mouse) or myometrial arteries (sheep, human). Results The lambs of sildenafil treated ewes had a weight that was intermediate between the IUGR vehicle treated and the normal growth control lambs. In the murine study, sildenafil was associated with increased fetal growth. Sildenafil treatment was not associated with changes in uterine or myometrial artery function in animal studies. Data pertaining to human myometrial artery ex vivo could not be analysed at the time of thesis submission due to treatment concealment in an ongoing clinical trial. Conclusion Sildenafil increases fetal growth independent of changes in uterine or myometrial artery function in animal models of IUGR. This suggests that in human pregnancy, sildenafil treatment will not only be useful for the treatment of IUGR caused by utero-placental insufficiency, but also of IUGR due to other causes.