STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early‐onset fetal growth restriction

Abstract

Objective To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction.Design A randomised placebo-controlled trial.Setting Thirteen maternal-fetal medicine units across New Zealand and Australia.Population Women with singleton pregnancies affected by fetal growth restriction at 22 +0 to 29 +6 weeks.Methods Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32 +0 weeks, birth or fetal death (whichever occurred first). Main Outcome MeasuresThe primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia.Results Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and newonset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75).Conclusions Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.Keywords Fetal growth restriction, intrauterine growth restriction, pre-eclampsia, sildenafil, small for gestational age, uterine artery Doppler.Tweetable abstract Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Maternal Sildenafil vs Placebo in Pregnant Women With Severe Early-Onset Fetal Growth Restriction

“…Moreover, no positive effects on the primary, secondary, or exploratory outcomes, as defined in the statistical analysis plan, 38 were seen. The results of the recently published STRIDER UK trial 39 as well as the (at that time unpublished) data of the STRIDER New Zealand/Australia trial 40 were included in the DSMB deliberations, as was foreseen in the DSMB…”

“…Our present finding of an increased incidence of pulmonary hypertension after antenatal sildenafil administration was not observed in the 2 other STRIDER trials. 39,40 This difference may be explained by definition differences, diagnostic strategies, or thresholds of suspicion. Our finding may indicate an important safety signal, and causality is a possibility because sildenafil targets the pulmonary vasculature.…”

Early‐onset fetal growth restriction: A systematic review on mortality and morbidity

“…Table A,B (see Supplementary material) shows the judgment of risk of bias of the individual studies. Two of the 5 included randomized controlled trials (RCT) were judged as “unknown” risk of bias. This judgment was mostly based on the fact that these studies were retrospectively registered and not blinded, and that some of the baseline criteria and outcomes were not reported for pregnancies that involved neonatal death.…”

Subcutaneous maternal resveratrol treatment increases uterine artery blood flow in the pregnant ewe and increases fetal but not cardiac growth

“…Clinical trials of maternal treatment with the vasodilator Sildenafil have shown either no improvement in fetal outcome measures (Groom et al . ; Sharp et al . ) or in the case of the Dutch trial, have been halted due to an increased risk of poor fetal outcomes (Groom et al .…”

“…Improving fetal substrate supply has been previously attempted in IUGR pregnancies. Clinical trials of maternal treatment with the vasodilator Sildenafil have shown either no improvement in fetal outcome measures (Groom et al 2019;Sharp et al 2019) or in the case of the Dutch trial, have been halted due to an increased risk of poor fetal outcomes (Groom et al 2018). However, before commencement of these human trials, Sildenafil treatment in a sheep model of IUGR was found to be detrimental to uteroplacental perfusion and fetal wellbeing (Miller et al 2009).…”