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

Jessica Liauw ,Jacqueline Limpens ,Christine Cornforth ,Louise Kenny ,Christopher J.d Mckinlay ,Wes Onland ,Tang Lee ,Christian Gluud ,Philip N Baker ,Laura A Magee ,Chirag Kariya ,François Audibert ,Larry Li ,Laura K Mackay ,Wessel Ganzevoort ,Anouk Pels ,Peter Von Dadelszen ,A.t Papageorghiou ,Sanne J Gordijn ,Žarko Alfirević ,Janus Christian Jakobsen ,Kenneth Lim ,Youkee Chung ,Lesley Mccowan ,Ben Willem J Mol ,Christopher J D Mckinlay ,Edward Johnstone ,Emmanuel Bujold ,Katie Groom ,Andrew Sharp

doi:10.1186/s13643-021-01849-5

Abstract

BackgroundEarly 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.MethodsWe 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 registers Clinicaltrials.gov and 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 weight z-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.DiscussionThis 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 registrationPROSPERO (CRD42017069688).

Highlights

Onset fetal growth restriction secondary to placental insufficiency can lead to severe maternal and neonatal morbidity and mortality
Liauw et al Systematic Reviews (2021) 10:305. This pre-defined protocol will minimise bias during analysis and interpretation of results, toward the goal of providing robust evidence regarding the use of phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of early onset fetal growth restriction
In a further randomised clinical trial in women with preeclampsia, PDE-5 inhibitor use was associated with prolongation of pregnancy by 4 days when compared with placebo [15], while another randomised clinical trial showed no effect on pregnancy prolongation [16]

Summary

Methods

We will conduct the systematic review according to this protocol and report any deviations from it in the published review under ‘Differences between protocol and review’. We will extract data on trial eligibility criteria, study methods, participant characteristics, intervention details, outcomes assessed, and primary results for the effects of PDE-5 inhibitors on fetal growth. We will adjust for and perform subgroup analyses for the following potential confounders of the association between early onset growth restriction and perinatal mortality or severe neonatal morbidity, determined at the time of trial inclusion: (1) gestational age; (2) abdominal circumference; (3) estimated fetal weight; (4) umbilical artery Doppler waveform status; (5) uterine artery Doppler waveform status; (6) hypertensive disorder of pregnancy status; (7) abnormal or normal PLGF level, as defined by individual trials; (8) whether or not the trial was a STRIDER trial; (9) daily dose of PDE-5 inhibitor used; (10) type of PDE-5 inhibitor used; (11) trial-level risk of bias assessment; and (12) trial industry sponsorship. We will deal with missing data according to previously recommended methods [53]

Discussion

Background

Findings