The efficacy of sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction: the STRIDER RCT
Authors: Sharp Andrew , Cornforth Christine , Jackson Richard , Harrold Jane , Turner Mark A , Kenny Louise , Baker Philip N , Johnstone Edward D , Khalil Asma , von Dadelszen Peter , Papageorghiou Aris T , Vollmer Brigitte , Alfirevic Zarko 
Published: November 2024

Background
Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness.
Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes.

Methods
The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant.
The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age.

Results
Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil.
Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95).

Conclusion
Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction.

Trial registration
This trial is registered as ISRCTN39133303.

Funding
This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.