Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD)
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.
Objectives
To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.
Search methods
We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.
Selection criteria
We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non‐serious, general behaviour, and quality of life.
Data collection and analysis
Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel‐group trials and first‐period data from cross‐over trials formed the basis of our primary analyses. We undertook separate analyses using end‐of‐last period data from cross‐over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.
Main results
We included 212 trials (16,302 participants randomised); 55 parallel‐group trials (8104 participants randomised), and 156 cross‐over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross‐over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male‐female ratio was 3:1. Most trials were carried out in high‐income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants.
Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.
Primary outcomes: methylphenidate versus placebo or no intervention may improve teacher‐rated ADHD symptoms (standardised mean difference (SMD) −0.74, 95% confidence interval (CI) −0.88 to −0.61; I² = 38%; 21 trials; 1728 participants; very low‐certainty evidence). This corresponds to a mean difference (MD) of −10.58 (95% CI −12.58 to −8.72) on the ADHD Rating Scale (ADHD‐RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD‐RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).
Secondary outcomes: methylphenidate may cause more adverse events considered non‐serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low‐certainty evidence). The TSA‐adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher‐rated general behaviour versus placebo (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials 792 participants; very low‐certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI −0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low‐certainty evidence).
Authors' conclusions
The majority of our conclusions from the 2015 version of this review still apply. Our updated meta‐analyses suggest that methylphenidate versus placebo or no‐intervention may improve teacher‐rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non‐serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear.
Due to the frequency of non‐serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials.
Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | CD009885 |
| Tidsskrift | Cochrane Database of Systematic Reviews |
| Vol/bind | 2023 |
| Udgave nummer | 3 |
| Antal sider | 923 |
| ISSN | 1465-1858 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
Funding: jointly funded by Ontario Mental Health Foundation (Grant No. 963-86/88) and Health and Welfare Canada (Grant No. 6606-3166-42)
Funding Information:
Funding: trial was supported by the Celgene Corporation
Funding Information:
Funding source: grant from the NIMH (MH62946). Dr. Pelham was funded by grants from the NIH (MH62946, MH69614, MH53554, MH69434, MH65899, MH78051, MH062946, NS39087, AA11873, DA12414, HD42080) and the Institute of Education Sciences (L03000665A). Dr. Fabiano was supported in part by a Ruth S. Kirschstein National Research Service Award Predoctoral Fellowship (1F31MH064243-01A1) and by the Department of Education, Institute of Education Sciences (R324J06024, R324B06045) Email correspondence with trial authors: April 2015. We emailed trial authors to request supplemental information but have not received a response
Funding Information:
Funding source: Noven Pharmaceuticals. Furthermore, Dr. Pelham was supported by grants from National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse; NIMH and National institute of Neurological Disorders and Stroke Email correspondence with trial authors: February-March 2014. We attempted to obtain supplemental information regarding randomisation, allocation concealment, washout period and efficacy and safety data from trial authors but without success
Funding Information:
Funding source: funded by NIMH and NIH. Placebo and MPH were supplied by CIBA-GEIGY Corporation, Summit, New Jersey Email correspondence with trial authors: November 2013. We received additional information regarding ethics approval, sample calculation, etc., from trial authors. However, it was not possible to receive all requested data, as the trial author no longer possessed raw data from the trial.
Funding Information:
Funding: the work was supported by the Smart Family Foundation.
Funding Information:
Funding source: Rhodes Pharmaceuticals […]. Medical writing assistance was provided by Linda Wagner, PharmD, from Excel Scientific Solutions and funded by Rhodes Pharmaceuticals LP Email correspondence with trial authors: September and November 2021. We contacted the trial authors for information regarding risk of bias and CSHQ data through personal email in September and November 2021, but no answer was received.
Funding Information:
Funding: National Institutes of Health (NIH) and National Institute of Mental Health (NIMH)
Funding Information:
Funding: this work was supported by the John and Maxine Bendheim Fellowship and by the Leon Lowenstein Foundation.
Funding Information:
Funding source: research was funded by Eli Lilly and Company, Indianapolis, Indiana
Funding Information:
Funding source: supported by a local trust through a Tenovus Scotland initiative
Funding Information:
Funding: funded by National institute of Mental Health and National institutes of Health. Placebo and methylphenidate were supplied by CIBA-GEIGY Corporation, Summit, New Jersey
Funding Information:
Funding: The Netherlands Organization for Health Research and development (ZonMw, grant 836011014)
Funding Information:
Funding source: a grant from Ortho-McNeil Janssen Scientific Affairs to Dr. Abikoff
Funding Information:
Funding: sponsored by Novartis Pharmaceuticals Corporation
Funding Information:
Funding source: none, either external or internal. This project was supported in part by a Biomedical Research Support Grant (Number S07 RR05712), which was awarded to the first trial author by the Biomedical Research Support Grant Program, Division of Research Resources, NIH
Funding Information:
Funding source: grants from the Medical Research Council of Canada and by William T. Grant Foundation Faculty Scholar Program Email correspondence with trial authors: October 2013. Emailed last trial author twice to get supplemental information (protocol, ethics approval, data on side effects, etc.) but received no response. Therefore we included no data from this trial
Funding Information:
Funding: trial funded by Rhodes Pharmaceuticals LP.
Funding Information:
Funding: in part by funds from the Medical Research Council of Canada and the Research Institute of the Hospital for Sick Children
Funding Information:
Funding source: research was completed while Dr. Rubinsten was a post-doctoral fellow at the Hospital for Sick Children (HSC), in Toronto, Canada, and was supported by the Rothschild Fellowship from Israel. It was undertaken, in part, through funding received from the Canadian Institutes of Health (CIHR: grant #MOP 64312), a CIHR post-doctoral fellowship (A-CB), and the Canada Research Chairs Program (RT)
Funding Information:
Funding source: provided through a grant from the German Research Foundation (DFG grant: KFO112– TP5) Email correspondence with trial author: July 2015. Email sent to trial author to ask for additional information, but we have received no reply
Funding Information:
Funding: investigator-initiated trial sponsored by Novartis Pharmaceuticals, with additional support provided by the University of Illinois at Chicago (UIC) Center for Clinical and Translational Science (CCTS)
Funding Information:
Funding source: this work is supported by Orient Pharma Co, Ltd.
Funding Information:
Funding source: supported by a UMMS (University of Massachusetts Medical School) Small Grants Project Award
Funding Information:
Funding source: supported by funds from Neos Therapeutics, Inc
Funding Information:
Funding: Ms Kent was a summer medical student supported in part by the IWK Grace Research Foundation, Halifax, NovaScotia, and by the Pharmaceutical Manufacturers Association of Canada Studentship, Ottawa, Ontario
Funding Information:
Funding source: supported by Ortho-McNeil-Janssen Scientific Affairs, LLC. Phase IV trial
Funding Information:
Funding source: this work was supported by the John and Maxine Bendheim Fellowship and by the Leon Lowenstein Foundation Email correspondence with trial authors: March 2014. Sent an email to trial authors to request additional information but have not received a response
Funding Information:
• Phase 6 (parallel-group): sponsored by the NIMH, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Med-ical Center, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to J.K.G. Generic MPH was purchased by grant funds.
Funding Information:
Funding source: the NIMH, the General Clinical Research Center Program of the National Center for Research Resources, and the NIH, Department of Health and Human Services Correspondence with trial authors: August 2014. We contacted trial authors to request additional data. Trial authors no longer have access to the data
Funding Information:
Funding: supported by National Institute of Mental Health (NIMH) Grant, Number K23 MH066835
Funding Information:
Funding: National Institute of Mental Health Grant R01 MH63986
Funding Information:
Funding: this work is supported by Orient Pharma Co, Ltd.
Funding Information:
Funding source: NIMH Grant MH62946 and a Klingenstein Third Generation Foundation Fellowship in Child and Adolescent Depression Research Email correspondence with trial authors: August 2014. Obtained supplemental information regarding randomisation, allocation concealment and handling of missing data. Not possible to retrieve safety data
Funding Information:
Funding: clinical research was funded by KemPharm, Inc. Funding for editorial and writing assistance in the form of proofreading, copyediting, and fact-checking was provided by Corium, Inc.
Funding Information:
Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health and Emory University Research
Funding Information:
Funding: Biomedical Research Support Grant Program, Division of Research Resources, National Institutes of Health, and by the Emory University Research Fund
Funding Information:
Funding source: National Institute of Mental Health (NIMH) grant MH38118
Funding Information:
Funding: not declared. During the writing of this report, C Johnston was supported by a Doctoral Fellowship from the Social Sciences and Humanities Research Council of Canada.
Funding Information:
Funding source: grants from Le Fonds de la Recherche en Santé du Québec and the Canadian Institutes of Health Research.
Funding Information:
Funding source: grant from Richwood Pharmaceutical Company
Funding Information:
Funding source: this trial was supported by several grants from the NIMH, Bethesda, Maryland
Funding Information:
Funding source: grants from the Shire Richwood Pharmaceutical Company and NIMH (Grants MH53554, MH45576 and MH50467) Email correspondence with trial authors: April 2014. We requested additional information from trial authors but have not received a reply
Funding Information:
Funding source: grants from the National Institute on Drug Abuse, the NIMH, the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Child Health and Human Development Email correspondence with trial authors: September 2014. We contacted trial authors twice to ask for supplemental information/data but have received no response
Funding Information:
Funding source: supported by grant number MA 6913, from the Medical Research Council of Canada
Funding Information:
Funding source: trial was supported by the Celgene Corporation
Funding Information:
Funding: research part funded by the Neuropsychiatric Research Institute, Fargo, North Dakota, USA
Funding Information:
Funding: grants from the Medical Research Council of Canada and by William T Grant Foundation Faculty Scholar Program
Funding Information:
Funding source: data collection for the project was supported by the NIMH (Bethesda, MD) by R01MH074770 [Epstein] and K23MH083881 [Froehlich], while investigators’ time on the project was funded by NIMH K24MH064478 [Epstein], K23MH083027 [Brinkman], and R01MH070564 [Stein]).
Funding Information:
Funding source: in part by funds from the Medical Research Council of Canada and the Research Institute of the Hospital for Sick Children
Funding Information:
Funding source: Biomedical Research Support Grant Program, Division of Research Resources, NIH and Emory University Research Email correspondence with trial authors: October 2013. We received from trial authors additional information about ethics approval, planned outcomes and participants followed up. Unfortunately, it
Funding Information:
Funding source: Netherlands Organisation for Scientific Research (NWO) Grant 575-63-082
Funding Information:
Funding: grant from Noven Pharmaceuticals
Funding Information:
Funding source: in part by a NIMH grant. Ciba-Geigy provided medication and placebo.
Funding Information:
Funding source: "This study was funded by Novartis Pharmaceuticals Corporation and reports the following involvement: design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript" Email correspondence with trial authors: July 2014. Emailed trial authors to ask for additional information but have not received a reply
Funding Information:
Funding source: trial and medication/placebo were funded by a grant through Shire Pharmaceuticals. Shire had no role in design, collection, analysis, interpretation, writing or decision to submit Email correspondence with trial authors: March/April 2014. We contacted the first trial author twice to ask for supplemental data but have not received a response.
Funding Information:
Funding: this research was sponsored by NextWave Pharmaceuticals, a wholly owned subsidiary of Pfizer, Inc Email correspondence with trial authors: September and November 2021. We contacted the trial authors for information regarding risk of bias through personal email in September and November 2021, but no answer was received.
Funding Information:
Funding source: Ms Kent was a summer medical student supported in part by the IWK Grace Research Foundation, Halifax, NovaScotia, and by the Pharmaceutical Manufacturers Association of Canada Studentship, Ottawa, Ontario Email correspondence with trial authors: August 2013. We received additional information from trial authors, but they were not able to provide the additional data that we requested
Funding Information:
Funding source: research was supported by a grant from the Izaak Walton Killam IWK Health Centre in Halifax, Nova Scotia Email correspondence with trial authors: August-October 2013. We received supplemental information regarding additional data from trial authors, but we never received first-period data from the cross-overtrial.
Funding Information:
Funding source: Funding and operating grant from the Canadian Institute of Health Research and funding from the Canada Research Chairs Programme Email correspondence with trial authors: December 2013. Not able to get supplemental information from trialauthors
Funding Information:
Funding: grant from the Canadian Psychiatric Research Foundation and a post-doctoral fellowship by the Ontario Mental Health Foundation
Funding Information:
Funding: in part by the Ontario Mental Health Foundation and the National Health Research and Development Program, Health Canada Email correspondence with trial authors: June 2014. Emailed trial authors twice to request supplemental information/data but have received no response.
Funding Information:
Funding: supported by a grant from Shire-Richwood Pharmaceuticals, Incorporated - manufacturer of Adderall - and from the National Institute of Mental Health (NIMH)
Funding Information:
• Phase 5 (cross-over): sponsored by the NIMH, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Medical Cen-ter, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to J.K.G. Generic MPH was purchased by grant funds
Funding Information:
Funding source: in part by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grants and the University of Southern California Faculty Research and Innovation Fund.
Funding Information:
Funding: research was funded by Eli Lilly and Company, Indianapolis, Indiana
Funding Information:
Funding source: supported by the Medical Center Rehabilitation Hospital Foundation and the School of Medicine, University North Dakota; the Veterans Hospital; the Dakota Clinic; and The Neuropsychiatric Institute, Fargo, North Dakota Email correspondence with trial authors: September 2013. Emailed trial author requesting additional information about the trial and data. Dr. Cook referred to his Ph.D. dissertation, which we managed to get.
Funding Information:
Funding: in part, by the Ontario Mental Health Foundation and the National Health Research and Development Program, Health Canada
Funding Information:
Funding source: this trial was supported in part by a research grant from the Tourette Syndrome Association Incorporated, and by Public Health Service (PHS) grant number MH45358 from NIMH Email correspondence with trial authors: April 2014. We obtained supplemental information from trial authors
Funding Information:
Any withdrawals due to AEs: yes. 1; exacerbation of borderline personality disorder and ADHD requiring hospitalisation Funding source: research grants from Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil) (Grant 471761=03-6) and Hospital de Clinicas de Porto Alegre (GPPG 03-325). Aripiprazole was provided by Bristol-Myers Squibb without restriction.
Funding Information:
Funding: grant number MH072263 from National Institute of Mental Health (NIMH)
Funding Information:
• Phase 8 (discontinuation): sponsored by the NIMH, Columbia/New York State Psychiatric Institute, Johns Hopkins University, Columbia University, University of California Irvine, Duke University Med-ical Center, New York University Child Study Center and University of California Los Angeles, Arizona Institute of Mental Health Research to J.K.G. Generic MPH was purchased by grant funds
Funding Information:
Funding source: during the conduct of this research, Dr. Pelham was supported by grants from the NIMH (MH48157, MH47390, MH45576, MH50467, MH53554, MH62946), NIAAA (AA06267, AA11873), National Institute on Drug Abuse (NIDA) (DA05605, DA12414), National Institute of Neurological Disorders and Stroke (NINDS) (NS39087), National Institute for Environmental Studies (NIES) (ES05015) and National Institute of Child Health and Human Development (NICHHD) (HD42080) Email correspondence with trial authors: December 2013. We emailed trial authors to request additional information about trial sample and side effects. Trial authors replied to say that the data are no longer available. Data from this trial could not be used in meta-analyses
Funding Information:
Funding: Health Canada grant
Funding Information:
Funding: grant from the National Institute of Mental Health (MH62946). Dr Pelham was funded by grants from the National Institutes of Health (MH62946, MH69614, MH53554, MH69434, MH65899, MH78051, MH062946, NS39087, AA11873, DA12414, HD42080) and the Institute of Education Sciences (L03000665A). Dr Fabiano was supported in part by a Ruth S Kirschstein National Research Service Award Predoctoral Fellowship (1F31MH064243-01A1) and by the Department of Education, Institute of Education Sciences (R324J06024, R324B06045).
Funding Information:
Funding source: a University of Utah Biomedical Sciences Research Grant and a grant from the University Research Committee Email correspondence with trial authors: May 2014. We obtained supplemental information from trial authors (Magnusson 2014c [pers comm])
Funding Information:
Funding source: Canadian Psychiatric Research Foundation and the Medical Research Council of Canada.
Funding Information:
Funding: trial was internally funded by the medical school
Funding Information:
Funding: this trial was supported by funds from Neos Therapeutics, Inc, PI.
Funding Information:
Funding source: research grants from the Tourette Syndrome Association and the NIMH
Funding Information:
Funding: Medical Research Council of Canada, National Health Research Development Program of Canada and the Department of Psychiatry, The Hospital for Sick Children, Toronto. Placebo pills were provided by Ciba Geigy, Canada, Ltd Conflicts of interest: 2 trial authors have reported working as consultants for pharmaceutical companies, and 1 has furthermore received industry-sponsored research grants.
Funding Information:
Funding source: investigator-initiated trial sponsored by Novartis Pharmaceuticals, with additional support provided by the University of Illinois at Chicago, Center for Clinical and Translational Science.
Funding Information:
Funding: National Institute of Mental Health (NIMH) Research Center grant P50MH077248, “Translational Research to Enhance Cognitive Control”
Funding Information:
Funding source: supported by NIMH grant, Number K23 MH066835
Funding Information:
Funding: Netherlands Organisation for Scientific Research (NWO) Grant 575-63-082
Funding Information:
Thanks also to the Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark; Region Zealand Research Foundation, Denmark; and the Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital — Rigshospitalet, Copenhagen, Denmark, for funding and enabling the review.
Funding Information:
Funding: supported by grants from the National Institute of Mental Health (NIMH) and from the National Institute on Drug Abuse (NIDA)
Funding Information:
Funding source: this work was supported in part by a grant from the Fond de Recherche du Québec and the Canadian Institutes of Health Research. Weam Fageera is a recipient of a PhD scholarship from the Ministry of Education of Saudi Arabia.
Funding Information:
Funding: Novartis Pharma GmbH, Germany. Trial aimed at showing efficacy of Ritalin LA with purpose of obtaining marketing authorisation Conflicts of interest: almost all trial authors have received grants, research support or other kinds of financial support from the medical industry.
Funding Information:
Sponsor: Fund for Scientific Research Flanders (Fonds Wetenschappelijk Onderzoek (FWO); FWO MAND 2013 - 11U8316N 5 W)
Funding Information:
We thank Trine Lacoppidan Kæstel, Research Librarian, at the Psychiatric Research Unit, Region Zealand, Denmark, for helping with searches and descriptions of measurement scales. We thank Anne Fink for helping with the review. We are grateful to the many authors who kindly responded to our requests for further information on the trials in which they were involved. Thanks also to the Psychiatric Research Unit, Region Zealand Psychiatry, Roskilde, Denmark; Region Zealand Research Foundation, Denmark; and the Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital — Rigshospitalet, Copenhagen, Denmark, for funding and enabling the review. We also wish to warmly thank Geraldine McDonald (Co-ordinating Editor), Joanne Duffield (Managing Editor), Sarah Davies (Assistant Managing Editor), and Margaret Anderson (Information Specialist) of Cochrane Developmental, Psychosocial and Learning Problems for providing help and support. Cochrane Developmental, Psychosocial and Learning Problems supported the authors in the development of this update. The following people conducted the editorial process for this article. Sign-off Editor (final editorial decision): Geraldine Macdonald, University of Bristol; Managing Editor (provided editorial guidance to authors, edited the article): Joanne Duffield, Queen's University Belfast; Deputy Managing Editor (conducted editorial policy checks and supported editorial team): Sarah Davies, University of Bristol; Information Specialist (search review): Margaret Anderson, Queen's Univeristy Belfast; and Copy Editor (copy editing and production): Denise Mitchell, Cochrane Evidence, Production and Methods Directorate. Sign-off Editor (final editorial decision): Geraldine Macdonald, University of Bristol; Managing Editor (provided editorial guidance to authors, edited the article): Joanne Duffield, Queen's University Belfast; Deputy Managing Editor (conducted editorial policy checks and supported editorial team): Sarah Davies, University of Bristol; Information Specialist (search review): Margaret Anderson, Queen's Univeristy Belfast; and Copy Editor (copy editing and production): Denise Mitchell, Cochrane Evidence, Production and Methods Directorate.
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