University of Leicester
Browse
17TLCHILD0261_Alfirevic final Dec 5.pdf (732.05 kB)

Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial

Download (732.05 kB)
journal contribution
posted on 2018-04-05, 10:58 authored by Andrew Sharp, Christine Cornforth, Richard Jackson, Jane Harrold, Mark A. Turner, Louise C. Kenny, Philip N. Baker, Edward D. Johnstone, Asma Khalil, Peter von Dadelszen, Aris T. Papageorghiou, Zarko Alfirevic, Umber Agarwal, Elaine Willis, Silvia Mammarella, Geraldine Masson, Joe Aquilina, Elena Greco, Sally Higgins, Dimuthu Vinayagam, Louise Shaw, Louise Stephens, David Howe, Abby Rand, Shalini Patni, Tommy Mousa, Asma Rabab, Helen Russell, Therese Hannon, Andrea Fenn, Mark Kilby, Tara Selman, Anna David, Rebecca Spencer, Kelly Cohen, Andrew Breeze, Alastair McKelvey, Lawrence Impey, Christos Loannou, Sarah Stock, Liona Poon, Dharmintra Pasupathy, Louise Webster, George Bugg
Background Severe early-onset fetal growth restriction can lead to a range of adverse outcomes including fetal or neonatal death, neurodisability, and lifelong risks to the health of the affected child. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates the actions of nitric oxide, which leads to vasodilatation of the uterine vessels and might improve fetal growth in utero. Methods We did this superiority, placebo-controlled randomised trial in 19 fetal medicine units in the UK. We used random computer allocation (1:1) to assign women with singleton pregnancies between 22 weeks and 0 days' gestation and 29 weeks and 6 days' gestation and severe early-onset fetal growth restriction to receive either sildenafil 25 mg three times daily or placebo until 32 weeks and 0 days' gestation or delivery. We stratified women by site and by their gestational age at randomisation (before week 26 and 0 days or at week 26 and 0 days or later). We defined fetal growth restriction as a combination of estimated fetal weight or abdominal circumference below tenth 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. This study is registered with BioMed Central, number ISRCTN 39133303. Findings Between Nov 21, 2014, and July 6, 2016, we recruited 135 women and randomly assigned 70 women to sildenafil and 65 women to placebo. We found no difference in the median randomisation to delivery interval between women assigned to sildenafil (17 days [IQR 7–24]) and women assigned to placebo (18 days [8–28]; p=0·23). Livebirths (relative risk [RR] 1·06, 95% CI 0·84 to 1·33; p=0·62), fetal deaths (0·89, 0·54 to 1·45; p=0·64), neonatal deaths (1·33, 0·54 to 3·28; p=0·53), and birthweight (−14 g,–100 to 126; p=0·81) did not differ between groups. No differences were found for any other secondary outcomes. Eight serious adverse events were reported during the course of the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Interpretation Sildenafil did not prolong pregnancy or improve pregnancy outcomes in severe early-onset fetal growth restriction and therefore it should not be prescribed for this indication outside of research studies with explicit participants' consent.

Funding

We are also grateful to Sharp Clinical Services and University of British Columbia (UBC) for supporting the provision of masked investigational medicinal products to research sites and to staff of pharmacy and research and development departments in all of the participating hospitals. We would also like to thank UBC for the development and support of the STRIDER randomisation and electronic data capture systems and Liverpool Clinical Laboratories, Royal Liverpool University, and Broadgreen Hospital Trust for doing the Elecsys sFlt-1 and PlGF analyses. STRIDER was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, award number 12/62/109. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales. The trial was sponsored by the University of Liverpool and Liverpool Women's Hospital.

History

Citation

The Lancet Child and Adolescent Health, 2018, 2 (2), pp. 93-102

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES

Version

  • VoR (Version of Record)

Published in

The Lancet Child and Adolescent Health

Publisher

Elsevier

eissn

2352-4642

Copyright date

2017

Available date

2018-04-05

Publisher version

https://www.sciencedirect.com/science/article/pii/S2352464217301736?via=ihub

Notes

For the protocol see https://doi.org/10.1186/2046-4053-3-23 This online publication has been corrected. The corrected version first appeared at thelancet.com/child-adolescent on Dec 11, 2017

Language

en

Usage metrics

    University of Leicester Publications

    Categories

    Keywords

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC