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

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 aggrega… | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search 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 View ORCID Profile M.E. Bruins , View ORCID Profile E.M. Bordewijk , View ORCID Profile A. Pels , View ORCID Profile A.T. Papageorghiou , View ORCID Profile S.J. Gordijn , View ORCID Profile J.C. Jakobsen , View ORCID Profile J. Wilkinson , View ORCID Profile B.W. Mol , View ORCID Profile K.M. Groom , View ORCID Profile W. Ganzevoort doi: https://doi.org/10.1101/2025.10.26.25338641 M.E. Bruins 1 Amsterdam Reproduction & Development Research Institute , Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, location University of Amsterdam , Meibergdreef 9, Amsterdam, The Netherlands 3 Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, Faculty of Medical Sciences , Groningen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for M.E. Bruins E.M. Bordewijk 1 Amsterdam Reproduction & Development Research Institute , Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, location University of Amsterdam , Meibergdreef 9, Amsterdam, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for E.M. Bordewijk A. Pels 1 Amsterdam Reproduction & Development Research Institute , Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, location University of Amsterdam , Meibergdreef 9, Amsterdam, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for A. Pels A.T. Papageorghiou 4 Oxford Maternal and Perinatal Health Institute, University of Oxford , Oxford, UK ; Nuffield Department of Women’s and Reproductive Health, University of Oxford , Oxford, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for A.T. Papageorghiou S.J. Gordijn 3 Department of Obstetrics and Gynaecology, University of Groningen, University Medical Center Groningen, Faculty of Medical Sciences , Groningen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for S.J. Gordijn J.C. Jakobsen 5 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Capital Region of Denmark , Denmark ; Department of Regional Health Research, The Faculty of Health Sciences, University of Southern Denmark , Denmark Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for J.C. Jakobsen J. Wilkinson 6 Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, Manchester Academic Health Science Centre, University of Manchester , Manchester, United Kingdom Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for J. Wilkinson B.W. Mol 7 Department of Obstetrics and Gynecology, Monash University , 246 Clayton Road, Clayton 3168 Victoria, Australia 2 Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, location University of Amsterdam , Meibergdreef 9, Amsterdam, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for B.W. Mol K.M. Groom 8 Liggins Institute, The University of Auckland , 85 Park Road, Grafton, Auckland, 1023, New Zealand Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for K.M. Groom W. Ganzevoort 1 Amsterdam Reproduction & Development Research Institute , Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Amsterdam University Medical Centers, location University of Amsterdam , Meibergdreef 9, Amsterdam, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for W. Ganzevoort For correspondence: j.w.ganzevoort{at}amsterdamumc.nl Abstract Full Text Info/History Metrics Supplementary material Preview PDF ABSTRACT Background Phosphodiesterase 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. Objective This 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. Methods Eligible 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. Discussion This 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) guidelines 1 . Corresponding PRISMA-P items are indicated in brackets following each section heading. INTRODUCTION Rationale {6} Fetal growth restriction (FGR) affects 5-10% of pregnancies 3 , 4 and is associated with adverse perinatal and long-term outcomes for the offspring. 5 , 6 The most common underlying pathophysiological mechanism is uteroplacental insufficiency. There are currently no effective treatments to ameliorate the adverse in utero environment associated with uteroplacental insufficiency and FGR. Phosphodiesterase type 5 (PDE-5) inhibitors were proposed as the first-ever in-utero treatment for FGR, using the nitric oxide pathway affecting vascular resistance to improve uteroplacental perfusion. This hypothesis was supported by animal studies 7 - 11 , human ex vivo 12 and small pre-clinical and clinical studies. 13 - 15 Over the past decade, multiple randomized controlled trials have been conducted to investigate the therapeutic potential of PDE-5 inhibitors for the treatment of FGR, yielding conflicting findings. Some meta-analyses have suggested improvements in birth weight and pregnancy prolongation. 16 , 17 However, the STRIDER trials 18 - 21 , considered high-quality studies, did not demonstrate any beneficial effects and described potential of harm, 20 , 22 We are currently further investigating these findings through a systematic review and a pre-planned individual participant data meta-analysis, which will incorporate data from all four STRIDER trials (publication in preparation). Strikingly, investigators from 14 other eligible trials did not respond to requests to contribute to the individual participant data meta-analysis. The lack of inclusion of these other trials is likely to explain the conflicting results seen as the investigation of PDE-5 inhibitors as a potential in-utero treatment for FGR evolves. The unwillingness to contribute data, alongside retraction and expression of concerns for some published trials raises concern regarding the quality and scientific integrity of some of the trials in this field. 23 , 24 Identifying studies at high risk of compromised integrity is crucial, as their inclusion in meta-analyses may influence the results, lead to unreliable conclusions, and potentially impact on clinical care that may be harmful. Given that some meta-analyses did not consider studies by their quality, trustworthiness and integrity, there is a need to evaluate the impact of including or excluding such studies. This approach will help to generate reliable and clinically meaningful evidence. Objectives {7} The objective of this review is to conduct an aggregate data meta-analysis of randomised controlled trials on exploring the short-term effects of PDE-5 inhibitors, in comparison to placebo or no treatment, for the treatment of FGR. We will include a detailed analysis on trustworthiness of individual trials and evaluate the aggregate effects of based on trustworthiness. METHODS This study will perform an aggregate data meta-analysis of randomized controlled trials identified through a previous systematic review, alongside a comprehensive assessment of the trustworthiness of each included trial. The trials to be included have been identified through an earlier systematic review conducted as part of an individual participant data meta-analysis. 2 For clarity, the eligibility criteria, information sources and selection process are outlined below. Eligibility criteria {8} Study type: randomized clinical trials Participants: women with singleton pregnancies affected by FGR (as defined by individual trials) Intervention: any PDE-5 inhibitor at any dose and by any route of administration with the intention of multiple dose administration Control: placebo or no intervention Information sources {9} Databases OVID MEDLINE, OVID EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and the clinical trial registers Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP) from 1946 to present. Grey literature We included conference abstracts published in these databases. We did not hand search conference proceedings. We cross-checked the reference lists and the cited articles of relevant papers for additional relevant trials. 2 We also included references cited in systematic review reports on the same or similar topic and from online searches on the topic. Date of searches Literature searches on the databases were conducted on 18 November 2019, with subsequent updates on 17 September 2020 and 25 September 2024. Grey literature was searched until March 2025. Search strategy {10} The full search strategy is provided in Supplementary Appendix B. Selection process {11b} Paired independent reviewers screened all titles and abstracts, advancing any citation deemed potentially eligible by either reviewer to full-text review. Full-text reviews were conducted independently by different paired reviewers. Discrepancies were resolved through discussion and, if necessary, by involving a third investigator. Data management {11a} Records retrieved from database searches were managed in EndNote, where duplicates were removed. Title and abstract screening was performed using Rayyan or Microsoft Excel. Full-text was documented using standardized forms in Excel. Quality assessments and extracted data will be documented in the same way. Data collection process {11c} Data on trial characteristics and outcomes will be extracted from the published articles. For trials in which individual participant data are available but outcomes were not reported in the publication, aggregate-level data will be derived from the individual participant data using SPSS software. Data extraction will be conducted using an artificial intelligence-based data extraction tool, which will import the information into a standardized Excel form. All extracted data will then be manually verified by a single human reviewer to ensure accuracy. Data integrity assessments will be conducted in parallel with data extraction, following a predefined structured plan (below). Results will be documented in Excel. Data items {12} Trial characteristics First author Title of the study Year of publication Inclusion criteria (including diagnosis of FGR and gestational age at inclusion) Exclusion criteria Control Intervention Third arm (if applicable) Co-intervention Intervention – sample size Control – sample size Outcomes among all pregnancies Gestational age at birth Birth weight (grams) Maternal preeclampsia (as defined by individual trials) Stillbirth Outcomes among liveborn Intraventricular haemorrhage (Papile grade 3 or 4, or as defined by individual trials) Cystic periventricular leukomalacia (grade two or more, or as defined by individual trials) Bronchopulmonary dysplasia (as defined by individual trials) Necrotising enterocolitis requiring surgery (as defined by individual trials) Retinopathy of prematurity requiring treatment (as defined by individual trials) Neonatal and infant death For data integrity assessments The following checks and methodological references for the data integrity assessments are based on the scoping review by Bordewijk et al . and the INSPECT-SR (INveStigating ProblEmatic Clinical Trials in Systematic Reviews) tool. 25 (available via: https://osf.io/b74wj ). Trial characteristics Trial registry Data availability and transparency (based on the willingness of authors to share individual participant data) Single or multicenter trial Number of participants included Number of participants lost to follow up Timespan of recruitment Journal of publication of the results Date received by journal Date start recruitment Date trial registry Author characteristics Retractions or expressions of concern involving any of the authors of the included paper (if so, the reason) using Retraction Watch Database 26 Number of published randomized controlled trials authored or co-authored by the first author of the included paper Search with Google Scholar for similar articles or abstracts by the same author group Statistical methods Statistical analyses will be conducted independently by two reviewers. Plausibility and correctness of reported statistics Reproducibility of the P-values as reported by the authors Reproducibility of the effect sizes and confidence intervals Distribution of the P-values of the baseline characteristics, split for continuous and dichotomous tests Other Internal consistency Registry concordance Chronological plausibility Plagiarism check Duplication of numbers with other publications Image duplication Feasibility and plausibility (governance, methodology, execution, results, reporting) Outcomes and prioritization {13} Primary outcome 2 Mortality (defined as either stillbirth, neonatal or infant mortality) Secondary outcomes Cerebral intraventricular haemorrhage (Papile grade 3 or 4 27 , or as defined by individual trials) Cystic periventricular leukomalacia (grade two or more 28 , or as defined by individual trials) Bronchopulmonary dysplasia (as defined by individual trials) Necrotising enterocolitis requiring surgery (as defined by individual trials) Retinopathy of prematurity requiring treatment (as defined by individual trials) Maternal preeclampsia Exploratory outcomes Gestational age at birth Birth weight (grams) Stillbirth Neonatal and infant death (among liveborn infants, as defined as by individual trials) Quality assessment Multiple types of quality assessments will be conducted for all eligible trials. Risk of bias {14} Risk of bias will be assessed using version 2 of the Cochrane tool for assessing risk of bias in randomised trials (RoB 2) 29 . The tool assesses five domains 1) bias arising from the randomization process 2) bias due to deviations from intended interventions 3) bias due to missing outcome data 4) bias in measurement of the outcome and 5) bias in selection of the reported result. Individual trials will be classified as: Low risk Some concerns High risk Trustworthiness Trustworthiness and data integrity will be checked using the INSPECT-SR (INveStigating ProblEmatic Clinical Trials in Systematic Reviews) tool 30 (available via: https://osf.io/b74wj ). INSPECT-SR includes 21 checks in four domains 1) inspecting post-publication notices (3 checks), 2) inspecting conduct, governance, and transparency (5 checks), 3) inspecting text and figures (2 checks), 4) inspecting results in the study (11 checks). Individual trials will be classified as: No concerns Some concerns Serious concerns In addition, it will be assessed using the Trustworthiness Screening Tool developed by the Cochrane Pregnancy and Childbirth Group 31 . The tool assesses four domains 1) research governance 2) plausibility of baseline characteristics 3) feasibility and 4) plausibility of results. Individual trials will be classified as: Excluded Awaiting classification Included Lastly, statistics will be checked using an existing spreadsheet that recalculates P-values based on reported means, standard deviations (t-tests) and absolute numbers (chi-square tests). Baseline characteristics will also be assessed for statistically significant differences. Notifying the authors If indicators of integrity issues are identified, the primary contact of the trial will be notified by email, requesting clarification of unclear aspects of the methodology or results. If an inadequate or no response is received, a letter requesting an investigation and, depending on the result of the investigation, retraction will be sent to the journal in which the article was published. Examples of both letters are included in the Supplementary Appendix C. Subgroups based on quality assessments Based on the results of the INSPECT-SR, subgroups (no concerns, some concerns or serious concerns) will be defined for the aggregate data meta-analysis. Data synthesis {15} Criteria under which trial data will be quantitatively synthesised {15a} All available data will be included in the meta-analysis, which will be conducted without the application of predefined eligibility thresholds. Statistical approach {15b} In accordance with our original protocol 2 , the aggregate data meta-analyses will be conducted according to the Cochrane Handbook of Systematic Reviews of Interventions 32 , Keus et al. 33 , and the eight-step assessment proposed by Jakobsen et al 34 . Subgroup analyses will be performed based on the results of the trustworthiness and integrity assessments (see Quality assessment). Intervention effects will be assessed using both random-effects and fixed-effect meta-analyses for each treatment comparison, with the analysis with the highest P-value being used as main result. 32 - 34 A P-value of 0.02 or less will be considered statistically significant. 34 Heterogeneity among trials will be identified by visual inspection of forest plots and by calculating the I 2 value. 32 Data from intention-to-treat population will be used where possible. However, for participants with missing outcome data, analysis will be based on the available data, without imputing missing values. In a multiple-arm trial, if two or more intervention groups are relevant and included as separate comparisons in the same meta-analysis, and they share a common control group, the control group should be split (e.g. halved) to avoid double counting participants. However, if only one intervention group is relevant to the review or meta-analysis, the study can be treated as a standard two-arm trial, and the full control group can be used without adjustment 32 . Descriptive statistics (mean, standard deviation (SD), numbers and proportions) will be used to describe the patient and intervention related characteristics. Binary outcomes will be reported as risk ratios and absolute risk differences with 95% confidence intervals, while continuous outcomes will be reported as mean differences with standard deviations or as medians with interquartile ranges. The statistical analysis will be performed using the current version of R. Additional analyses {15c} The impact of missing data will be assessed in prespecified sensitivity analyses 2 using the ‘best-worst-case’ scenario and the ‘worst-best-case’ scenario. 34 In case of continuous outcomes, standard deviations will be imputed from P-values according to the Cochrane Handbook for Systematic Reviews of Intervention. 30 If it was not possible to calculate the standard deviation from the P value or the confidence intervals, the highest standard deviation from the other trials that included the relevant outcome will be imputed. Clinical interpretations will be limited to trials meeting trustworthiness criteria. Meta-analyses including trials that do not meet these criteria will be conducted exclusively to explore their potential effect on the overall results. Meta-bias {16} Where more than 10 trials are included, we will visually inspect funnel plots to assess for reporting bias. 2 Confidence in cumulative evidence {17} Confidence in cumulative evidence will not be formally assessed using GRADE, as this review does not focus on evaluating intervention effects or clinical outcomes, but instead aims to investigate the impact of data integrity on subgroup analyses. ADMINISTRATIVE INFORMATION Registration {2} PROSPERO (CRD42017069688) Author contributions {3b} All authors contributed to the development of the protocol. WG conceptualized the review question. WG and MB designed the methodology, which was refined with input from all authors. WG and KMG were involved in the design of the search strategy. EMB designed the data integrity assessments. MEB drafted the initial version of the protocol with contributions from all authors. Amendments {4} The search strategy was conducted in advance in accordance with a previously published protocol, that included individual participant data meta-analysis, as well as aggregate data meta-analysis 2 . Authors of eligible trials were approached to contribute to the individual participant data meta-analysis. However, the majority of authors did not respond to the invitation to share data. This prompted a study plan for a structured analysis of the trustworthiness of all eligible published trials. The current study will report on the aggregate data meta-analysis, with some minor amendments that have been incorporated into the current version of the protocol and are described in Supplementary Appendix A. Due to limited data availability, the prespecified outcomes have been revised to improve the feasibility of the study and ensure the potential for meaningful analysis. Additionally, a further investigation will be conducted to assess the trustworthiness and scientific integrity of the included trials. The results of this assessment will be incorporated as subgroups in the aggregate data meta-analysis. Support {5} This study will be conducted without financial support. DECLARATIONS Author approval All authors have seen and approved the manuscript. Competing interests KMG and WG led STRIDER trials in New Zealand/Australia and the Netherlands, respectively. All authors except MEB, EMB, JW and JCJ are members of the STRIDER Consortium. Data availability statement Not applicable as no new data is generated. Funding statement This study will be conducted without financial support. Footnotes M.E. Bruins, m.e.bruins{at}amsterdamumc.nl E.M. Bordewijk, e.m.bordewijk{at}amsterdamumc.nl A. Pels, a.pels{at}amsterdamumc.nl A.T. Papageorghiou, aris.papageorghiou{at}wrh.ox.ac.uk S.J. Gordijn, s.j.gordijn{at}umcg.nl J.C. Jakobsen, Janus.jakobsen{at}ctu.dk J. 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