Title: A randomised controlled trial of sildenafil therapy for severe early-onset intrauterine growth restriction
Funder: Department of Health (England)

Abstract: The process of human placentation is complex and poorly understood. Inadequate placental invasion into the uterine myometrium has been associated with intra-uterine growth restriction (IUGR) pre-eclampsia and recurrent pregnancy loss. The normal physiological process of spiral artery remodelling includes the removal of the nitric oxide (NO)-producing endothelium the internal elastic lamina and the NO-responsive muscularis layers to the depth of the inner third of the myometrium. In normal pregnancies the removal of these layers by extravillous trophoblast (EVT) converts the narrow bore high resistance low flow circulation to a wide bore low resistance high flow circulation which is then unresponsive to normal regional vascular control. In some pregnancies this process is incomplete. In this scenario the NO-modulating/modulated elements of endothelium and muscularis remain partially intact in all vessels and fully intact in some. It is this intact tissue that is responsive to a NO donor. Early-onset IUGR in the absence of a genetic abnormality or congenital infection is the result of such abnormal placentation. Currently there is no antenatal treatment for early-onset ‘idiopathic’ IUGR; management strategies involve intensive fetal surveillance with elective delivery performed when there is evidence of presumed fetal acidosis/distress. At gestational ages remote from term such iatrogenic delivery is associated with significant perinatal mortality and morbidity. Intact survival is less than 25% for an infant weighing 600g born at 25 completed weeks’ gestation and still only approximately 50% up to 28 weeks’ gestation. Our animal studies in the catechol-O-methyl transferase knockout mouse demonstrated the ability of the NO-donor Sildenafil citrate (Viagra®) to increase uterine artery vasodilation thereby decreasing uterine artery resistance and hence ameliorating IUGR. In humans we showed that sildenafil significantly reduced vasoconstriction and improved relaxation of IUGR small arteries. In a placebo-controlled randomised trial sildenafil was given to 17 pregnant women with pre-eclampsia with 18 women receiving placebo. Maternal outcomes were not improved but there was a non-significant increase in median birth weight of 367g in babies born by mothers who received sildenafil without significant side-effects. We have also used sildenafil in a cohort of 10 women with severe early-onset IUGR as compassionate therapy. Compared with 17 sildenafil-naïve IUGR pregnancies sildenafil improved daily fetal growth velocity. The oldest Sildenafil-exposed fetus is now a 5 year old girl who is ahead of her developmental milestones despite being born at 27 weeks gestation weighing 425g. Therefore we believe that there are sufficient preliminary data to conduct a randomised trial in this context targeting the fetus as a patient. This study will be carried out in 9 large maternity units in England and 6 hospitals in Ireland (Perinatal Ireland Consortium) with a total of 116000 births per annum. All women carrying a singleton fetus diagnosed with IUGR before 30+0 weeks defined as an estimated fetal weight or abdominal circumference below the 10th centile with abnormal umbilical artery Doppler (absent or reversed flow) will be invited to participate. We anticipate that around 50%s of eligible women will agree to participate; 112 women will be randomised in 24 months to receive either oral sildenafil or matching placebo until delivery or 32+0 weeks of gestation whichever comes first. The whole study will last 36 months; the first 6 months will be spent to set up the study followed by 24 months for recruitment 3 months for post-randomisation follow-up and 3 months for final analysis and write-up.The study will have 90% power to test the hypothesis that sildenafil exposed fetuses because of improved utero-placental and fetal circulation will be delivered on average 7 days later compared to those exposed to placebo (alfa 5% SD 11 days). In these severe cases such a prolongation of gestation is considered clinically significant. Nevertheless this difference will be truly important only if associated with a long term benefit for the baby. It is recognised however that this study will not have the power to demonstrate such an impact on long term health of the IUGR babies; this will addressed by the prospective individual patient data meta-analysis (IPD) of several randomised studies that are currently being planned in New Zealan Canada and the Netherlands. In addition to clinically important outcomes we will evaluate the functional effects of Sildenafil on maternal and placental circulation and consequently on the fetus by serial monitoring of materal blood pressure and pulse and serial Doppler and colour flow ultrasound studies of feto-placental circulation. We also plan to elucidate the precise mechanism and location of action of sildenafil in pregnancy by investigating the effects of sildenfil therapy on omental (representative of the wider maternal systemic vasculature) myometrial (uterine vasculature) and chorionic plate artery (placental vasculature) reactivity. We will store placental tissue obtained after birth and if sildenafil is found to be clinically effective we will seek additional funding to assess placental morphology and perform stereological analysis. It has been agreed that the British Columbia Women’s Hospital CTU (Vancouver Canada) will act as the worldwide Trial Coordinating Centre for all primary efficacy studies and subsequent individual patient (IPD) meta-analysis of effectiveness long term follow up and safety data. It is recognised that additional funding for the long term follow up will have to be sought separately once the evidence of efficacy has been demonstrated.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH