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Open Access 01-12-2021 | Sildenafil | Protocol

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: Jessica Liauw, Katie Groom, Wessel Ganzevoort, Christian Gluud, Christopher J. D. McKinlay, Andrew Sharp, Laura Mackay, Chirag Kariya, Ken Lim, Peter von Dadelszen, Jacqueline Limpens, Janus C. Jakobsen, the STRIDER Consortium

Published in: Systematic Reviews | Issue 1/2021

Abstract

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 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.

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).

Available only for authorised users

Gordijn SJ, Beune IM, Thilaganathan B, et al. Consensus definition of fetal growth restriction: a Delphi procedure. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2016;48(3):333–339. doi:https://doi.org/10.1002/uog.15884 [doi].

Ganzevoort W, Thornton JG, Marlow N, et al. Comparative analysis of 2-year outcomes in GRIT and TRUFFLE trials. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2020;55(1):68–74. doi:https://doi.org/10.1002/uog.20354 [doi].

Malhotra A, Allison BJ, Castillo-Melendez M, Jenkin G, Polglase GR, Miller SL. Neonatal morbidities of fetal growth restriction: pathophysiology and impact. Frontiers in endocrinology. 2019;10:55. doi:https://doi.org/10.3389/fendo.2019.00055 [doi].

Monier I, Ancel PY, Ego A, et al. Gestational age at diagnosis of early-onset fetal growth restriction and impact on management and survival: a population-based cohort study. BJOG : an international journal of obstetrics and gynaecology. 2017;124(12):1899–1906. doi:https://doi.org/10.1111/1471-0528.14555 [doi].

Pels A, Knaven OC, Wijnberg-Williams BJ, et al. Neurodevelopmental outcomes at five years after early-onset fetal growth restriction: analyses in a Dutch subgroup participating in a European management trial. Eur J Obstet Gynecol Reprod Biol. 2019;234:63–70 doi: S0301-2115(19)30031-4 [pii].CrossRef

Villa PM, Marttinen P, Gillberg J, et al. Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study. PloS one. 2017;12(3):e0174399. doi:https://doi.org/10.1371/journal.pone.0174399 [doi].

Smith SD, Choudhury RH, Matos P, et al. Changes in vascular extracellular matrix composition during decidual spiral arteriole remodeling in early human pregnancy. Histology and histopathology. 2016;31(5):557–571. doi:https://doi.org/10.14670/HH-11-696 [doi].

Dilworth MR, Andersson I, Renshall LJ, et al. Sildenafil citrate increases fetal weight in a mouse model of fetal growth restriction with a normal vascular phenotype. PloS one. 2013;8(10):e77748. doi:https://doi.org/10.1371/journal.pone.0077748 [doi].

Oyston C, Stanley JL, Oliver MH, Bloomfield FH, Baker PN. Maternal administration of sildenafil citrate alters fetal and placental growth and fetal-placental vascular resistance in the growth-restricted ovine fetus. Hypertension (Dallas, Tex: 1979). 2016;68(3):760–767. doi:https://doi.org/10.1161/HYPERTENSIONAHA.116.07662 [doi].

10.

Paauw ND, Terstappen F, Ganzevoort W, Joles JA, Gremmels H, Lely AT. Sildenafil during pregnancy: a preclinical meta-analysis on fetal growth and maternal blood pressure. Hypertension (Dallas, Tex: 1979). 2017;70(5):998–1006. doi:10.1161/HYPERTENSIONAHA.117.09690 [doi].

11.

Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90(5):2550–5 doi:jc.2004-1831 [pii].CrossRef

12.

Goncalves-Rizzi VH, Possomato-Vieira JS, Nascimento RA, Caldeira-Dias M, Dias-Junior CA. Maternal hypertension and feto-placental growth restriction is reversed by sildenafil: evidence of independent effects of circulating nitric oxide levels. Eur J Pharmacol. 2018;822:119–27 doi: S0014-2999(18)30017-7 [pii].CrossRef

13.

Trapani A Jr, Goncalves LF, Trapani TF, Franco MJ, Galluzzo RN, Pires MM. Comparison between transdermal nitroglycerin and sildenafil citrate in intrauterine growth restriction: effects on uterine, umbilical and fetal middle cerebral artery pulsatility indices. Ultrasound in Obstetrics & Gynecology. 48(1):61–5.

14.

Dastjerdi MV, Hosseini S, Bayani L. Sildenafil citrate and uteroplacental perfusion in fetal growth restriction. Journal of Research in Medical Sciences. 17(7):632–636.

15.

Trapani A, Jr., Goncalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial. Obstetrics & Gynecology. 128(2):253–259.

16.

Samangaya RA, Mires G, Shennan A, et al. A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia. Hypertension in Pregnancy. 28(4):369–382.

17.

Pels A, Kenny LC, Alfirevic Z, et al. STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials. BMC pregnancy and childbirth. 2017;17(1):440–017-1594-z. doi:https://doi.org/10.1186/s12884-017-1594-z [doi].

18.

Ganzevoort W, Alfirevic Z, von Dadelszen P, et al. STRIDER: sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction--a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Systematic reviews. 2014;3:23–4053-3-23. doi:https://doi.org/10.1186/2046-4053-3-23 [doi].

19.

Groom KM, McCowan LM, Mackay LK, et al. STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction. BJOG Int J Obstet Gynaecol. 2019;126(8):997–1006.

20.

Sharp A, Cornforth C, Jackson R, et al. Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial. The LancetChild & adolescent health. 2018;2(2):93–102 doi: S2352-4642(17)30173-6 [pii].

21.

Pels A, Derks J, Elvan-Taspinar A, et al. Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial. JAMA network open. 2020;3(6):e205323. doi:https://doi.org/10.1001/jamanetworkopen.2020.5323 [doi].

22.

Groom KM, Ganzevoort W, Alfirevic Z, Lim K, Papageorghiou AT, Consortium S. Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2018;52(3):295–296. doi:https://doi.org/10.1002/uog.19186 [doi].

23.

Ferreira R, Negrini R, Bernardo WM, Simoes R, Piato S. The effects of sildenafil in maternal and fetal outcomes in pregnancy: a systematic review and meta-analysis. PLoS One. 2019;14(7):e0219732. https://doi.org/10.1371/journal.pone.0219732.CrossRefPubMedPubMedCentral

24.

Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. JAMA. Apr 28 2015;313(16):1657–65. doi:https://doi.org/10.1001/jama.2015.3656

25.

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr Apr. 1978;92(4):529–34. https://doi.org/10.1016/s0022-3476(78)80282-0.CrossRef

26.

de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res. Jul 31 1992;49(1):1–6. doi:https://doi.org/10.1016/s0166-4328(05)80189-5

27.

Kiserud T, Piaggio G, Carroli G, et al. The World Health Organization fetal growth charts: a multinational longitudinal study of ultrasound biometric measurements and estimated fetal weight. PLoS medicine. 2017;14(1):e1002220. doi:https://doi.org/10.1371/journal.pmed.1002220 [doi].

28.

Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2019;366:l4898. doi:https://doi.org/10.1136/bmj.l4898 [doi].

29.

Tierney JF, Vale C, Riley R, et al. Individual participant data (IPD) meta-analyses of randomised controlled trials: guidance on their use. PLoS Med. Jul 2015;12(7):e1001855. https://doi.org/10.1371/journal.pmed.1001855.CrossRefPubMedPubMedCentral

30.

Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. Journal of clinical epidemiology. 2011;64(4):383–394. doi:https://doi.org/10.1016/j.jclinepi.2010.04.026 [doi].

31.

Guyatt GH, Oxman AD, Santesso N, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. Journal of clinical epidemiology. 2013;66(2):158–172. doi:https://doi.org/10.1016/j.jclinepi.2012.01.012 [doi].

32.

Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. Am J Obstet Gynecol. 1985;151(3):333–7 doi:0002-9378(85)90298-4 [pii].CrossRef

33.

Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. John Wiley & Sons; 2019.

34.

Keus F, Wetterslev J, Gluud C, van Laarhoven CJ. Evidence at a glance: error matrix approach for overviewing available evidence. BMC medical research methodology. 2010;10:90–2288-10-90. doi:https://doi.org/10.1186/1471-2288-10-90 [doi].

35.

Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC medical research methodology. 2014;14:120–2288–14-120. doi:https://doi.org/10.1186/1471-2288-14-120 [doi].

36.

StataCorp. Stata statistical software: release 16. College Station, TX: StatCorp LLC; 2019.

37.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88 doi:0197-2456(86)90046-2 [pii].CrossRef

38.

Demets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in medicine. 1987;6(3):341–350. doi:https://doi.org/10.1002/sim.4780060325 [doi].

39.

Hajdu SA, Rossi RM, DeFranco EA. Factors associated with maternal and neonatal interventions at the threshold of viability. Obstetrics and gynecology. 2020;135(6):1398–1408. doi:https://doi.org/10.1097/AOG.0000000000003875 [doi].

40.

Alfirevic Z, Stampalija T, Dowswell T. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. The Cochrane database of systematic reviews. 2017;6(6):CD007529. doi:https://doi.org/10.1002/14651858.CD007529.pub4 [doi].

41.

Kingdom JC, Audette MC, Hobson SR, Windrim RC, Morgen E. A placenta clinic approach to the diagnosis and management of fetal growth restriction. American journal of obstetrics and gynecology. 2018 2018;218(2S):S803-S817. doi:https://doi.org/10.1016/j.ajog.2017.11.575

42.

Trial Sequential Analysis. Copenhagen: Copenhagen Trial Unit; 2017. http://www.ctu.dk/tools-and-links/trial-sequential-analysis.aspx.

43.

Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for Trial Sequential Analysis (TSA). 2017(Journal, Electronic). http://www.ctu.dk/tsa/files/tsa_manual.pdf

44.

Imberger G, Thorlund K, Gluud C, Wetterslev J. False-positive findings in Cochrane meta-analyses with and without application of trial sequential analysis: an empirical review. BMJ open. 2016;6(8):e011890–2016-011890. doi:https://doi.org/10.1136/bmjopen-2016-011890 [doi].

45.

Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive--Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. International journal of epidemiology. 2009;38(1):287–298. doi:https://doi.org/10.1093/ije/dyn188 [doi].

46.

Thorlund K, Devereaux PJ, Wetterslev J, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? International journal of epidemiology. 2009;38(1):276–286. doi:https://doi.org/10.1093/ije/dyn179 [doi].

47.

Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61(1):64–75 doi: S0895-4356(07)00147-3 [pii].CrossRef

48.

Thorlund K, Anema A, Mills E. Interpreting meta-analysis according to the adequacy of sample size. An example using isoniazid chemoprophylaxis for tuberculosis in purified protein derivative negative HIV-infected individuals. Clinical epidemiology. 2010;2:57–66 doi:clep-2-057 [pii].PubMedPubMedCentral

49.

Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC medical research methodology. 2009;9:86–2288-9-86. doi:https://doi.org/10.1186/1471-2288-9-86 [doi].

50.

Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. Journal of clinical epidemiology. 2008;61(8):763–769. doi:https://doi.org/10.1016/j.jclinepi.2007.10.007 [doi].

51.

Nielsen EE, Nørskov AK, Lange T, et al. Assessing assumptions for statistical analyses in randomised clinical trials. BMJ evidence-based medicine. 2019;24(5):185–189. doi:https://doi.org/10.1136/bmjebm-2019-111174 [doi].

52.

Nørskov AK, Lange T, Nielsen EE, et al. Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how. BMJ evidence-based medicine. 2020;doi:https://doi.org/10.1136/bmjebm-2019-111268. bmjebm-2019-111268 [pii].

53.

Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC medical research methodology. 2017;17(1):162–017–0442-1. doi:https://doi.org/10.1186/s12874-017-0442-1 [doi].

54.

Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ (Clinical research ed). 2008;336(7650):924–926. doi:https://doi.org/10.1136/bmj.39489.470347.AD [doi].

Title: 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: Jessica Liauw
Katie Groom
Wessel Ganzevoort
Christian Gluud
Christopher J. D. McKinlay
Andrew Sharp
Laura Mackay
Chirag Kariya
Ken Lim
Peter von Dadelszen
Jacqueline Limpens
Janus C. Jakobsen
the STRIDER Consortium
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Sildenafil
Published in: Systematic Reviews / Issue 1/2021
Electronic ISSN: 2046-4053
DOI: https://doi.org/10.1186/s13643-021-01849-5

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Methods

Discussion

Systematic review registration

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Discussion

Systematic review registration

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