Investigating the quality, trustworthiness and integrity of published randomized trials on phosphodiesterase type 5 inhibitors for the treatment of fetal growth restriction and their impact on study findings: protocol for a systematic review with aggregate data meta-analysis and data integrity assessments

BackgroundPhosphodiesterase type 5 (PDE-5) inhibitors have been proposed as a potential in-utero treatment to improve uteroplacental perfusion in pregnancies with fetal growth restriction. Randomized controlled trials (RCTs) have shown conflicting results, with concerns about the integrity of several trials. ObjectiveThis protocol outlines a systematic review and aggregate data meta-analysis of RCTs investigating the short-term effects of PDE-5 inhibitors versus placebo or no treatment in pregnancies affected by FGR. We will assess the trustworthiness and scientific integrity of included trials and evaluate their impact on pooled outcomes. MethodsEligible trials were identified through a literature search. Primary outcome is mortality (stillbirth, neonatal or infant death). Secondary outcomes include severe neonatal morbidities and maternal preeclampsia. Risk of bias will be assessed using the Cochrane Risk of Bias 2 tool. Trustworthiness will be evaluated using the INSPECT-SR tool, the Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool and additional statistical analyses. In the aggregate data meta-analysis, trials will be classified into subgroups based on the results from the INSPECT-SR tool. If concerns about trial conduct or reporting arise, authors will be contacted; unresolved issues may be referred to the journal. DiscussionThis review will critically assess the trustworthiness of randomized trials on PDE-5 inhibitors for FGR and summarize the available evidence. This protocol is written in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines1. Corresponding PRISMA-P items are indicated in brackets following each section heading.