Short-term outcomes of phosphodiesterase type 5 inhibitors for fetal growth restriction: a study protocol for a systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis
Authors: Liauw Jessica , Groom Katie , Ganzevoort Wessel , Gluud Christian , McKinlay Christopher J. D. , Sharp Andrew , Mackay Laura , Kariya Chirag , Lim Ken , von Dadelszen Peter , Limpens Jacqueline , Jakobsen Janus C. ,   the STRIDER Consortium, Audibert Francois , Alfirevic Zarko , Baker Philip , Bujold Emmanuel , Chung Youkee , Cornforth Christine , Ganzevoort Wessel , Gordijn Sanne J. , Groom Katie , Gluud Christian , Jakobsen Janus C. , Johnstone Edward D. , Kariya Chirag , Kenny Louise , Lee Tang , Li Larry , Liauw Jessica , Lim Ken , Magee Laura , Mackay Laura , McCowan Lesley , McKinlay Chris , Mol Ben W. , Onland Wes , Papageorghiou Aris , Pels Anouk , Sharp Andrew , von Dadelszen Peter 
Published: December 2021

Background

Early onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality. Pre-clinical studies and a few small randomised clinical trials have suggested that phosphodiesterase type 5 (PDE-5) inhibitors may have protective effects against placental insufficiency in this context; however, robust evidence is lacking. The STRIDER Consortium conducted four randomised trials to investigate the use of a PDE-5 inhibitor, sildenafil, for the treatment of early onset fetal growth restriction. We present a protocol for the pre-planned systematic review with individual participant data meta-analysis, aggregate meta-analysis, and trial sequential analysis of these and other eligible trials. The main objective of this study will be to evaluate the effects of PDE-5 inhibitors on neonatal morbidity compared with placebo or no intervention among pregnancies with fetal growth restriction.

Methods

We will search the following electronic databases with no language or date restrictions: OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registersClinicaltrials.govand World Health Organisation International Clinical Trials Registry Platform (ICTRP). We will identify randomised trials of PDE-5 inhibitors in singleton pregnancies with growth restriction. Two reviewers will independently screen all citations, full-text articles, and abstract data. Our primary outcome will be infant survival without evidence of serious adverse neonatal outcome. Secondary outcomes will include gestational age at birth and birth weightz-scores. We will assess bias using the Cochrane Risk of Bias 2 tool. We will conduct aggregate meta-analysis using fixed and random effects models, Trial Sequential Analysis, and individual participant data meta-analysis using one- and two-stage approaches. The certainty of evidence will be assessed with GRADE.

Discussion

This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of PDE-5 inhibitors for the treatment of early onset fetal growth restriction.

Systematic review registration

PROSPERO (CRD42017069688).