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The Epidemiology of Chronic Pain in Children and Adolescents: A Protocol for a Systematic Review Update

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-043675 review only Article Type: Protocol

Date Submitted by the 11-Aug-2020 Author:

Complete List of Authors: Langley, Charlotte; IWK Health Centre, Centre for Pediatric Pain Research Tutelman, Perri; Dalhousie University, Department of Psychology and Neuroscience; IWK Health Centre, Centre for Pediatric Pain Research Parker, Jennifer; IWK Health Centre, Centre for Pediatric Pain Research Chambers, Christine; Dalhousie University, Department of Psychology; IWK Health Centre, Centre for Pediatric Pain Research Finley, Allen; Dalhousie University, Department of Anesthesia, Pain Management & Perioperative Medicine; IWK Health Centre, Centre for Pediatric Pain Research Chapman, Darlene; IWK Health Centre, Health Sciences Library Jones, Gareth; University of Aberdeen, Epidemiology Group and Aberdeen Centre for Arthritis and Musculoskeletal Health Macfarlane, Gary; University of Aberdeen, Epidemiology Group and http://bmjopen.bmj.com/ Aberdeen Centre for Arthritis and Musculoskeletal Health Marianayagam, Justina; Patient Partner and Medical Student; Northern Ontario School of Medicine

Keywords: EPIDEMIOLOGY, PAEDIATRICS, PAIN MANAGEMENT

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3 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 4 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36

37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44

45 on September 23, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 1 1 2 3 The Epidemiology of Chronic Pain in Children and Adolescents: A Protocol for a 4 Systematic Review Update 5 6 1 1,2 1 1,2,3* 7 Charlotte L. Langley +, Perri R. Tutelman +, Jennifer A. Parker , Christine T. Chambers , 8 G. Allen Finley1,4, Darlene Chapman5, Gareth T. Jones6, Gary J. Macfarlane6, 9 Justina Marianayagam7 10 11 1IWK Health Centre, Centre for Pediatric Pain Research, Halifax, NS Canada; 2Dalhousie 12 13 3 14 University, Department of Psychology and Neuroscience, Halifax, Canada; Dalhousie 15 16 University, DepartmentFor of Pediatrics, peer Halifax, review Canada; 4Dalhousie only University, Department of 17 18 Anesthesia, Pain Management & Perioperative Medicine, Halifax, Canada; 5IWK Health Centre, 19 20 6 21 Health Sciences Library, IWK Health Centre; University of Aberdeen, Epidemiology Group and 22 23 Aberdeen Centre for Arthritis and Musculoskeletal Health, Aberdeen, Aberdeen, UK; 7Patient 24 25 Partner and Medical Student, Northern Ontario School of Medicine. 26 27 28 29 30 CLL and PRT contributed equally to this article 31 32

33 *Correspondence to: http://bmjopen.bmj.com/ 34 35 Dr. Christine T. Chambers 36 Centre for Pediatric Pain Research 37 IWK Health Centre (K8536) 38 5850/5980 University Ave 39 40 Halifax, NS B3K 6R8, Canada.

41 [email protected] on September 23, 2021 by guest. Protected copyright. 42 43 44 45 Word Count: 1770 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 2 1 2 3 ABSTRACT 4 5 6 Introduction: Chronic pain, defined as persistent or recurring pain lasting longer than three 7 8 months, is a common childhood problem and can profoundly impact children’s physical, 9 10 psychological, and social functioning. The last comprehensive systematic review estimating the 11 12 prevalence of chronic pain in children and adolescents was published in 2011. Since then, the 13 14 15 literature on pediatric chronic pain has grown substantially. This manuscript outlines a protocol 16 For peer review only 17 for an updated systematic review to provide updated estimates of the prevalence of various forms 18 19 of chronic pain in children and adolescence. The review will also examine the relationship 20 21 22 between sociodemographic and psychosocial factors related to chronic pain prevalence. 23 24 Methods and Analysis: This review will follow PRISMA guidelines. We will search EMBASE, 25 26 PubMed, CINAHL, and PsycINFO for observational studies published in English between 2009 27 28 29 and 2020 reporting population-based estimates of chronic non-disease-related pain prevalence in 30 31 children or adolescents (age  19 years). Two independent reviewers will screen the titles and 32 33 abstracts retrieved from the search based on predefined eligibility criteria. The full texts of http://bmjopen.bmj.com/ 34 35 36 relevant studies will then be assessed by two reviewers. Studies meeting inclusion criteria will be 37 38 categorized according to the type of pain investigated: headache only, abdominal pain only, back 39 40 pain only, musculoskeletal pain, combined pain, and other/general pain. Data will be extracted 41 on September 23, 2021 by guest. Protected copyright. 42 43 using customized forms and studies will be assessed for risk of bias using a 10-item tool 44 45 developed by Hoy et al. (2012). A narrative synthesis will summarize the prevalence estimates of 46 47 pediatric chronic pain and associated sociodemographic and psychosocial correlates. Meta- 48 49 analyses and meta-regressions will be performed if the data permit. 50 51 52 Ethics and dissemination: Ethical approval is not required. Findings will be disseminated 53 54 through publication in an academic journal, presentations at conferences, and in various media. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 3 1 2 3 PROSPERO registration number: Submitted to PROSPERO on July 22, 2020. Currently 4 5 6 awaiting registration number. 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 5 1 2 3 INTRODUCTION 4 5 6 Chronic pain, defined as persistent or recurring pain lasting longer than three months,[1] 7 8 is a common problem in childhood. Although numerous recent population-based studies have 9 10 provided estimates of the prevalence of chronic pain in children and adolescents, the reported 11 12 proportions have varied considerably across studies. For example, the prevalence of primary 13 14 15 headache disorders in children and adolescents in recent population-based studies has ranged 16 For peer review only 17 from 19.4-66.4%,[2,3] while estimates of the prevalence of functional gastrointestinal disorders 18 19 have varied from 4.6%-31.2%.[4,5] Due to the wide variability in the reported estimates, the 20 21 22 current epidemiology of chronic pain in children and adolescents is unclear. The uncertainty 23 24 regarding the number of children and adolescents impacted by chronic pain may limit the 25 26 appropriate allocation of clinical services for this population, which are crucial given the 27 28 29 pervasive and long-term consequences of chronic pain on young people. 30 31 Chronic pain can have a profound impact on children and adolescents. Children who 32 33 experience chronic pain are at increased risk for depression and anxiety,[6,7] school absences,[8] http://bmjopen.bmj.com/ 34 35 social isolation,[9] and poorer quality of life.[10] Approximately 5% of children with chronic 36 37 38 pain experience severe severe levels of pain which significantly impact their daily 39 40 functioning.[11] Unfortunately, a substantial majority of children with chronic pain become

41 on September 23, 2021 by guest. Protected copyright. 42 adults with chronic pain. In a study of adult patients with chronic pain, 80% of participants 43 44 45 reported their pain originated in childhood or adolescence.[12] The persistence of chronic pain 46 47 from childhood to adulthood has significant social and economic consequences. For instance, 48 49 children with chronic pain are at risk for opioid misuse[13] and psychiatric morbidity in 50 51 52 adulthood,[14] and pediatric chronic pain is associated with high rates of outpatient 53 54 appointments, emergency department visits, and hospitalizations all resulting in creased 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 6 1 2 3 healthcare costs.[15–17] The total annual cost of pediatric chronic pain in the United States is 4 5 6 estimated to be $19.5 billion.[16] The significant individual, social and economic burden of 7 8 pediatric chronic pain, and its persistence into adulthood, demonstrates the importance of 9 10 understanding the epidemiology of this disease in order to improve treatment and reduce the 11 12 impact that chronic pain has on the lives of children and adolescents. 13 14 15 The most recent, comprehensive review on the epidemiology of chronic pain in children and 16 For peer review only 17 adolescents was published 2011.[18] This review estimated that the median prevalence of 18 19 chronic pain in children and adolescents ranged from 11-38% depending on body site and study. 20 21 22 The prevalence of chronic pain was found to be higher in girls and prevalence proportions 23 24 increased with age.[18] The review identified several psychosocial correlates of chronic pain in 25 26 children and adolescents such as lower socio-economic status, anxiety, depression and low self- 27 28 29 esteem.[18] However, other correlates of chronic pain in children and adolescents, such as 30 31 sleep[19,20] and post-traumatic stress disorder,[21,22] have since been identified and were not 32 33 consistently examined at the population level at the time of the past review. The review also http://bmjopen.bmj.com/ 34 35 identified several gaps in the understanding of the epidemiology of chronic pain in children and 36 37 38 adolescents, including restricted age ranges and lack of longitudinal studies.[18] Furthermore, at 39 40 the time of the past review the quality of included studies was generally low to moderate and

41 on September 23, 2021 by guest. Protected copyright. 42 methodological limitations, such as inconsistent definitions of pain between studies, made it 43 44 45 difficult to estimate overall prevalence proportions.[18] 46 47 The literature on pediatric pain is growing exponentially; a recent bibliometric analysis 48 49 revealed that there was nearly a 40-fold increase in the number of publications on pediatric pain 50 51 52 from 1975 to 2010.[23] Since the last comprehensive systematic review on the epidemiology of 53 54 chronic pain in children and adolescents,[18] numerous population-based studies estimating the 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 7 1 2 3 prevalence of various forms of pediatric chronic pain have been published.[24–26] A few recent 4 5 6 reviews estimating the prevlance of certain forms of chronic pain, such as functional abdominal 7 8 pain[27] and headache[28,29] have also been conducted. However, in order to appropriately 9 10 meet the clinical needs of children and adolescents with chronic pain, an updated review that 11 12 estimates the proportion of various forms of chronic pain and examines key sociodemographic 13 14 15 and psychosocial correlates of chronic pain in children and adolescents is needed. 16 For peer review only 17 This manuscript outlines a protocol for a systematic review to update a prior review 18 19 synthesizing the published literature on the prevalence of chronic pain in children and 20 21 22 adolescents. Specifically, the objectives of this review are to: 1) Provide updated estimates of the 23 24 prevalence of various forms of chronic pain (headache, abdominal pain, back pain, 25 26 musculoskeletal pain, combined pain, and other/general pain) in children and adolescence; 2) 27 28 29 Provide an updated examination of sociodemographic (e.g., age, sex, race) and psychosocial 30 31 (e.g., anxiety, depression, sleep) factors related to the prevalence of chronic pain in children; and 32 33 3) Assess study quality and identify gaps in the literature and areas for future research. http://bmjopen.bmj.com/ 34 35 METHODS AND ANALYSIS 36 37 38 This systematic review protocol was prepared in accordance with the Preferred Reporting 39 40 Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (see

41 on September 23, 2021 by guest. Protected copyright. 42 supplementary file 1).[30] The study protocol was submitted for registration with the 43 44 45 International Prospective Register of Systematic Reviews (PROSPERO) on July 22, 2020. In the 46 47 event of an amendment to this protocol, the date of the amendment, a description of the change 48 49 and the rationale will be documented and recorded in PROSPERO. The dates for this review are 50 51 52 May 14, 2020-April 1, 2021(expected). 53 54 Search strategy 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 8 1 2 3 We will search the following electronic databases: EMBASE, PubMed, CINAHL and 4 5 6 PsycINFO. The search terms will be comprised of three conceptual blocks: i) Pain terms (e.g., 7 8 musculoskeletal pain, back pain, headache, abdominal pain, recurrent pain); ii) Pediatric terms 9 10 (e.g., child, adolescent, boy, girl); and iii) Epidemiological terms (e.g., epidemiology, 11 12 prevalence, incidence, frequency). The searches will be restricted to English language articles, 13 14 15 human studies, and manuscripts published between January 2009-June 2020 (the original 16 For peer review only 17 systematic review[31] included studies published up until 2009). 18 19 Eligibility criteria 20 21 22 Studies will be eligible for inclusion if they meet the following criteria: 23 24 1. Observational studies (epidemiological, case-control, cross-sectional, retrospective and 25 26 prospective cohort studies) using a population-based sampling frame to estimate the 27 28 29 prevalence of chronic pain, defined as pain lasting 3 months or longer, in children or 30 31 adolescents (study sample age 19 years). 32 33 2. Studies published in peer-reviewed journals in English. http://bmjopen.bmj.com/ 34 35 36 Studies meeting the following criteria will be excluded: 37 38 1. Studies with sampling frames not deemed to be population-based. 39 40 2. Case studies, conference abstracts, dissertations, reviews, book chapters and qualitative 41 on September 23, 2021 by guest. Protected copyright. 42 43 studies. 44 45 3. Studies reporting on the prevalence of chronic pain in adults (sample age is exclusively 46 47 20 years) 48 49 50 4. Studies of non-human samples. 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 9 1 2 3 5. Studies exclusively examining the prevalence of disease- (e.g., cancer, arthritis) or 4 5 6 condition- (e.g., cerebral palsy, muscular dystrophy) related chronic pain in children and 7 8 adolescents. 9 10 Studies reporting on multiple populations (e.g., disease/condition and non-disease/condition- 11 12 related chronic pain, adults and children), where data on one or more sub-populations that fit the 13 14 15 eligibility criteria for this review can be separately identified, will be included and the relevant 16 For peer review only 17 data will be extracted. 18 19 Screening and Data Extraction 20 21 22 Literature search results will be transferred to Covidence systematic review management 23 24 software and duplicates will be removed. An initial title/abstract review of studies retrieved by 25 26 the search will be independently conducted by two members of the study team to determine 27 28 29 which studies potentially met the inclusion/exclusion criteria. Articles included from the 30 31 title/abstract review phase will then by reviewed in full by two reviewers. The two reviewers will 32 33 be blinded to each other’s decisions. Discrepancies regarding the eligibility of a study will be http://bmjopen.bmj.com/ 34 35 resolved by consensus, and if necessary, through discussion with a third reviewer. 36 37 38 Data will be extracted from included studies using customized forms. Extracted 39 40 information will include study design, location where the study was conducted, number of

41 on September 23, 2021 by guest. Protected copyright. 42 participants, participant demographics (e.g., age, sex, race), study sample (e.g., headache only, 43 44 45 abdominal pain only, back pain only, musculoskeletal pain, combined pain, and other/general.), 46 47 study methodology, prevalence proportion of chronic pain, and sociodemographic (e.g., age, sex, 48 49 race, parent education, household income) and psychosocial (e.g., anxiety, depression, sleep, 50 51 52 post-traumatic stress) predictors of chronic pain. In accordance with the PRISMA guidelines 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 10 1 2 3 [32], the number of studies meeting inclusion criteria will be recorded and the reason for 4 5 6 exclusion of those not included will be documented. 7 8 Quality Assessment 9 10 Two independent reviewers will assess study quality using the 10-item tool developed by 11 12 Hoy et al. (2012). This tool was developed to assess external and internal validity of prevalence 13 14 15 studies.[33] Response options for each item are either “yes” (indicating low risk of bias) or “no” 16 For peer review only 17 (indicating high risk of bias).[33] The tool will be adapted for this review if necessary. 18 19 Consensus will be reached by discussion between the reviewers. 20 21 22 Data Synthesis 23 24 A narrative synthesis will summarize the prevalence proportions of chronic pain in 25 26 children and adolescents in the following categories; headache only; abdominal pain only; back 27 28 29 pain only; musculoskeletal pain; combined pain; and other/general pain. Additionally, the 30 31 relationship between psychosocial factors (e.g., sleep, anxiety and depression) and 32 33 sociodemographic factors (e.g., sex, age, race and indicators of socio-economic status such as, http://bmjopen.bmj.com/ 34 35 but not limited to, household income, parental level of education and urban versus rural area of 36 37 38 residence) and chronic pain in children and adolescents will be reviewed. 39 40 Depending on the heterogeneity of included studies the prevalence proportions of chronic

41 on September 23, 2021 by guest. Protected copyright. 42 pain will be calculated using median prevalence proportions and/or meta-analysis. When at least 43 44 45 two or more studies are comparable in terms of the study sample (e.g., category of chronic pain), 46 47 and methodology (e.g., operationalization of chronic pain), we will pool the effects to determine 48 49 the prevalence proportion of chronic pain across studies. Similarly, if studies have used similar 50 51 52 methods to examine the relationship between certain sociodemographic and/or psychosocial 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 11 1 2 3 variables in comparable chronic pain samples, we will conduct separate meta-regressions to 4 5 6 examine the relationship between these variables and chronic pain across studies. 7 8 Reporting of this systematic review will follow PRISMA guidelines.[34] A PRISMA 9 10 flow diagram will be included in the final manuscript of this review. 11 12 Ethics and Dissemination 13 14 15 Ethical approval will not be sought for this study, as no human subject participants will 16 For peer review only 17 be involved. A manuscript outlining the results of this review will be submitted for publication in 18 19 a peer-reviewed academic journal and for presentation at relevant academic conferences. Results 20 21 22 will be publicly disseminated through social media, news and media outlets, and newsletters and 23 24 blog posts, as appropriate. 25 26 IMPLICATIONS OF THE REVIEW 27 28 29 We anticipate that the results from this review will enhance our understanding of the 30 31 current burden of pediatric chronic pain which may help inform treatment and allocation of 32 33 clinical resources for this population. Furthermore, findings from this study will identify priority http://bmjopen.bmj.com/ 34 35 areas for research on the epidemiology of chronic pain to guide future research efforts. Through 36 37 38 our planned knowledge translation efforts, findings of the review will be disseminated not only 39 40 to clinicians and scientists, but also to patients and families, which may aid in public awareness

41 on September 23, 2021 by guest. Protected copyright. 42 and advocacy efforts. 43 44 45 PATIENT AND PUBLIC INVOLVEMENT 46 47 This protocol was designed in collaboration with a patient partner and co-author, JM. JM 48 49 will remain involved as a patient partner throughout all steps of the review. 50 51 52 CONTRIBUTORS 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 12 1 2 3 CTC conceived the study idea. CL, PRT and JAP designed the study protocol, data 4 5 6 extraction, and statistical analysis and wrote the first draft of the manuscript. DC, GAF, GTJ, 7 8 GJM and JM provided critical insights. All authors approved and contributed to the final 9 10 manuscript. 11 12 FUNDING 13 14 15 This work was supported by an operating grant from the Canadian Institutes of Health 16 For peer review only 17 Research (FRN167902) awarded to CTC. CTC is also supported by a Tier 1 Canada Research 18 19 Chair with infrastructure support from the Canada Foundation for Innovation. CL is supported by 20 21 22 an IWK Health Centre Summer Studentship [1025420]. PRT is supported by a Research Nova 23 24 Scotia Scholars Award, a Nova Scotia Graduate Scholarship, and an IWK Graduate Studentship 25 26 Award. 27 28 29 COMPETING INTERESTS 30 31 None declared. 32 33 PATIENT CONSENT FOR PUBLICATION http://bmjopen.bmj.com/ 34 35 Not required. 36 37 38 39 40

41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 13 1 2 3 REFERENCES 4 5 6 1 Treede R-D, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. PAIN 7 8 2015;156:1. doi:10.1097/j.pain.0000000000000160 9 10 2 Al-Hashel JY, Ahmed SF, Alroughani R. Prevalence and burden of primary headache 11 12 disorders in Kuwaiti children and adolescents: A community based study. Front Neurol 13 14 15 2019;10:793. doi:10.3389/fneur.2019.00793 16 For peer review only 17 3 Malik AH, Shah PA, Yaseen Y. Prevalence of primary headache disorders in school-going 18 19 children in Kashmir Valley (North-west India). Ann Indian Acad Neurol 2012;15:100–3. 20 21 22 doi:10.4103/0972-2327.100030 23 24 4 Zheng S, Fu W, Zhou J, et al. Prevalence and related factors of irritable bowel syndrome 25 26 among middle-school students in areas affected by Wenchuan earthquake: An 27 28 29 epidemiological study. J. Clin. Gastroenterol. 2012;46:345–6. 30 31 doi:10.1097/MCG.0b013e31824712d0 32 33 5 Demirceken FG, Kurt G, Dulkadir R, et al. Functional dyspepsia in children: A Turkish http://bmjopen.bmj.com/ 34 35 prospective survey in Kirikkale province. 2010. 36 37 38 6 Shelby GD, Shirkey KC, Sherman AL, et al. Functional abdominal pain in childhood and 39 40 long-term vulnerability to anxiety disorders. Pediatrics 2013;132:475–82.

41 on September 23, 2021 by guest. Protected copyright. 42 doi:10.1542/peds.2012-2191 43 44 45 7 Simons LE, Sieberg CB, Claar RL. Anxiety and impairment in a large sample of children 46 47 and adolescents with chronic pain. Pain Res Manag 2012;17:93–7. doi:10.1155/2012/420676 48 49 8 Logan DE, Gray LS, Iversen CN, et al. School Self-Concept in Adolescents With Chronic 50 51 52 Pain. J Pediatr Psychol 2017;42:892–901. doi:10.1093/jpepsy/jsx063 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 14 1 2 3 9 Maes M, Van den Noortgate W, Fustolo-Gunnink SF, et al. Loneliness in Children and 4 5 6 Adolescents With Chronic Physical Conditions: A Meta-Analysis. J Pediatr Psychol 7 8 2017;42:622–35. doi:10.1093/jpepsy/jsx046 9 10 10 Gold JI, Yetwin AK, Mahrer NE, et al. Pediatric Chronic Pain and Health-Related Quality of 11 12 Life. J Pediatr Nurs 2009;24:141–50. doi:10.1016/j.pedn.2008.07.003 13 14 15 11 Huguet A, Miró J. The Severity of Chronic Pediatric Pain: An Epidemiological Study. J Pain 16 For peer review only 17 2008;9:226–36. doi:10.1016/j.jpain.2007.10.015 18 19 12 Hassett AL, Hilliard PE, Goesling J, et al. Reports of chronic pain in childhood and 20 21 22 adolescence among patients at a tertiary care pain clinic. J Pain 2013;14:1390–7. 23 24 doi:10.1016/j.jpain.2013.06.010 25 26 13 Groenewald CB, Law EF, Fisher E, et al. Associations Between Adolescent Chronic Pain 27 28 29 and Prescription Opioid Misuse in Adulthood. J Pain 2019;20:28–37. 30 31 doi:10.1016/j.jpain.2018.07.007 32 33 14 Noel M, Groenewald CB, Beals-Erickson SE, et al. Chronic Pain in Adolescence and http://bmjopen.bmj.com/ 34 35 Internalizing Mental Health Disorders: A Nationally Representative Study. Pain 36 37 38 2016;157:1333–8. doi:10.1097/j.pain.0000000000000522 39 40 15 Ho IK, Goldschneider KR, Kashikar-Zuck S, et al. Healthcare Utilization and Indirect

41 on September 23, 2021 by guest. Protected copyright. 42 Burden among Families of Pediatric Patients with Chronic Pain. J Musculoskelet Pain 43 44 45 2008;16:155–64. doi:10.1080/10582450802161853 46 47 16 Groenewald CB, Essner BS, Wright D, et al. The economic costs of chronic pain among a 48 49 cohort of treatment-seeking adolescents in the United States. J Pain 2014;15:925–33. 50 51 52 doi:10.1016/j.jpain.2014.06.002 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 15 1 2 3 17 Tumin D, Drees D, Miller R, et al. Health Care Utilization and Costs Associated With 4 5 6 Pediatric Chronic Pain. J Pain 2018;19:973–82. doi:10.1016/j.jpain.2018.03.012 7 8 18 King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and 9 10 adolescents revisited: A systematic review. Pain 2011;152:2729–38. 11 12 doi:10.1016/j.pain.2011.07.016 13 14 15 19 Evans S, Djilas V, Seidman LC, et al. Sleep Quality, Affect, Pain, and Disability in Children 16 For peer review only 17 With Chronic Pain: Is Affect a Mediator or Moderator? J Pain 2017;18:1087–95. 18 19 doi:10.1016/j.jpain.2017.04.007 20 21 22 20 Murphy LK, Palermo TM, Tham SW, et al. Comorbid Sleep Disturbance in Adolescents 23 24 with Functional Abdominal Pain. Behav Sleep Med 2020;0:1–10. 25 26 doi:10.1080/15402002.2020.1781634 27 28 29 21 Noel M, Wilson AC, Holley AL, et al. Posttraumatic stress disorder symptoms in youth with 30 31 vs without chronic pain. Pain 2016;157:2277–84. doi:10.1097/j.pain.0000000000000642 32 33 22 Stahlschmidt L, Rosenkranz F, Dobe M, et al. Posttraumatic stress disorder in children and http://bmjopen.bmj.com/ 34 35 adolescents with chronic pain. Health Psychol 2020;39:463–70. doi:10.1037/hea0000859 36 37 38 23 Caes L, Boerner KE, Chambers CT, et al. A comprehensive categorical and bibliometric 39 40 analysis of published research articles on pediatric pain from 1975 to 2010. Pain.

41 on September 23, 2021 by guest. Protected copyright. 42 2016;157:302–13. doi:10.1097/j.pain.0000000000000403 43 44 45 24 Oswari H, Alatas FS, Hegar B, et al. Functional abdominal pain disorders in adolescents in 46 47 Indonesia and their association with family related stress. BMC Pediatr 2019;19:342–5. 48 49 doi:10.1186/s12887-019-1682-5 [doi] 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 16 1 2 3 25 Aartun E, Hartvigsen J, Wedderkopp N, et al. Spinal pain in adolescents: prevalence, 4 5 6 incidence, and course: a school-based two-year prospective cohort study in 1,300 Danes aged 7 8 11–13. BMC Musculoskelet Disord 2014;15:187. doi:10.1186/1471-2474-15-187 9 10 26 Arruda MA, Arruda R, Guidetti V, et al. Psychosocial adjustment of children with migraine 11 12 and tension-type headache - a nationwide study. Headache 2015;55 Suppl 1:39–50. 13 14 15 doi:10.1111/head.12510 16 For peer review only 17 27 Korterink JJ, Diederen K, Benninga MA, et al. Epidemiology of Pediatric Functional 18 19 Abdominal Pain Disorders: A Meta-Analysis. PLOS ONE 2015;10:e0126982–e0126982. 20 21 22 doi:10.1371/journal.pone.0126982 23 24 28 Albers L, von Kries R, Heinen F, et al. Headache in School Children: Is the Prevalence 25 26 Increasing? Curr Pain Headache Rep 2015;19:4. doi:10.1007/s11916-015-0477-0 27 28 29 29 Wöber-Bingöl Ç. Epidemiology of migraine and headache in children and adolescents 30 31 topical collection on childhood and adolescent headache. Curr Pain Headache Rep 32 33 2013;17:1–11. doi:10.1007/s11916-013-0341-z http://bmjopen.bmj.com/ 34 35 30 Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and 36 37 38 meta-analysis protocols (PRISMA-P) 2015 statement. Rev Espanola Nutr Humana Diet 39 40 2016;20:148–60. doi:10.1186/2046-4053-4-1

41 on September 23, 2021 by guest. Protected copyright. 42 31 King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and 43 44 45 adolescents revisited: A systematic review. Pain 2011;152:2729–38. 46 47 doi:10.1016/j.pain.2011.07.016 48 49 32 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 50 51 52 meta-analyses: The PRISMA statement. PLoS Med. 2009;6. 53 54 doi:10.1371/journal.pmed.1000097 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 17 1 2 3 33 Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: Modification 4 5 6 of an existing tool and evidence of interrater agreement. J Clin Epidemiol 2012;65:934–9. 7 8 doi:10.1016/j.jclinepi.2011.11.014 9 10 34 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 11 12 meta-analyses: The PRISMA statement. PLoS Med. 2009;6. 13 14 15 doi:10.1371/journal.pmed.1000097 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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1 2 3 Additional file 1: PRISMA-P (Preferred Reporting Items for Systematic review and Meta- 4 Analysis Protocols) 2015 checklist: recommended items to address in a systematic review 5 6 protocol 7 8 PRISMA Protocol Checklist 9 Section and Item Checklist Reporting. 10 topic No Page No 11 12 ADMINISTRATIVE INFORMATION 13 Title: 14 15 16 Identification 1aForIdentify peer the report review as a protocol of a onlysystematic review 1 17 Update 1b If the protocol is for an update of a previous systematic 1,3 18 review, identify as such 19 20 Registration 2 If registered, provide the name of the registry (e.g., 3 21 PROSPERO) and registration number 22 Authors: 23 24 25 Contact 3a Provide name, institutional affiliation, and e-mail address of 1 26 all protocol authors; provide physical mailing address of 27 corresponding author 28 Contributions 3b Describe contributions of protocol authors and identify the 12 29 30 guarantor of the review 31 Amendments 4 If the protocol represents an amendment of a previously 7 32 completed or published protocol, identify as such and list

33 changes; otherwise, state plan for documenting important http://bmjopen.bmj.com/ 34 protocol amendments 35 Support: 36 37 38 Sources 5a Indicate sources of financial or other support for the review 12 39 40 Sponsor 5b Provide name for the review funder and/or sponsor Role of N/A

41 sponsor/ funder on September 23, 2021 by guest. Protected copyright. 42 Role of 5c Describe roles of funder(s), sponsor(s), and/or institution(s), N/A 43 44 sponsor or if any, in developing the protocol 45 funder 46 INTRODUCTION 47 Rationale 6 Describe the rationale for the review in the context of what is 5-7 48 already known 49 Objectives 7 Provide an explicit statement of the question(s) the review 7 50 51 will address with reference to participants, interventions, 52 comparators, and outcomes (PICO) 53 METHODS 54 Eligibility 8 Specify the study characteristics (e.g., PICO, study design, 8-9 55 criteria setting, time frame) and report characteristics (e.g., years 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 20 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from

1 2 3 considered, language, publication status) to be used as criteria 4 for eligibility for the review 5 6 Information 9 Describe all intended information sources (e.g., electronic 7,8 7 8 sources databases, contact with study authors, trial registers, or other 9 grey literature sources) with planned dates of coverage 10 11 Search 10 Present draft of search strategy to be used for at least one To be 12 Strategy electronic database, including planned limits, such that it included in 13 could be repeated final 14 manuscript 15 16 Study For peer review only 17 Records 18 11a Describe the mechanism(s) that will be used to manage 9 19 records and data throughout the review 20 11b State the process that will be used for selecting studies (e.g., 9-11 21 22 two independent reviewers) through each phase of the review 23 (i.e., screening, eligibility, and inclusion in meta-analysis) 24 11c Describe planned method of extracting data from reports 9-11 25 (e.g., piloting forms, done independently, in duplicate), any 26 processes for obtaining and confirming data from 27 investigators 28 Data items 12 List and define all variables for which data will be sought 9,10 29 30 (e.g., PICO items, funding sources), any pre-planned data 31 assumptions and simplifications 32 Outcomes 13 List and define all outcomes for which data will be sought, 9-11 33 and including prioritization of main and additional outcomes, with http://bmjopen.bmj.com/ 34 prioritization rationale 35 Risk of bias 14 Describe anticipated methods for assessing risk of bias of 10 36 37 in individual individual studies, including whether this will be done at the 38 studies outcome or study level, or both; state how this information 39 will be used in data synthesis 40 Data 41 synthesis on September 23, 2021 by guest. Protected copyright. 42 15a Describe criteria under which study data will be 10,11 43 44 quantitatively synthesized 45 15b If data are appropriate for quantitative synthesis, describe 10,11 46 planned summary measures, methods of handling data, and 47 methods of combining data from studies, including any 48 planned exploration of consistency (e.g., I 2 , Kendall’s tau) 49 15c Describe any proposed additional analyses (e.g., sensitivity or 10,11 50 51 subgroup analyses, meta-regression) 52 15d If quantitative synthesis is not appropriate, describe the type 10 53 of summary planned 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 20 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from

1 2 3 Meta-bias(es) 16 Specify any planned assessment of meta-bias(es) (e.g., N/A 4 publication bias across studies, selective reporting within 5 6 studies) 7 Confidence in 17 Describe how the strength of the body of evidence will be N/A 8 cumulative assessed (e.g., GRADE) 9 evidence 10 11 12 13 From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart 14 L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis 15 protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647. 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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The Epidemiology of Chronic Pain in Children and Adolescents: A Protocol for a Systematic Review Update

Journal: BMJ Open ManuscriptFor ID peerbmjopen-2020-043675.R1 review only Article Type: Protocol

Date Submitted by the 28-Dec-2020 Author:

Complete List of Authors: Tutelman, Perri; Dalhousie University, Department of Psychology and Neuroscience; IWK Health Centre, Centre for Pediatric Pain Research Langley, Charlotte; IWK Health Centre, Centre for Pediatric Pain Research Chambers, Christine; Dalhousie University, Department of Psychology; IWK Health Centre, Centre for Pediatric Pain Research Parker, Jennifer; IWK Health Centre, Centre for Pediatric Pain Research Finley, Allen; Dalhousie University, Department of Anesthesia, Pain Management & Perioperative Medicine; IWK Health Centre, Centre for Pediatric Pain Research Chapman, Darlene; IWK Health Centre, Health Sciences Library Jones, Gareth; University of Aberdeen, Epidemiology Group and Aberdeen Centre for Arthritis and Musculoskeletal Health Macfarlane, Gary; University of Aberdeen, Epidemiology Group and http://bmjopen.bmj.com/ Aberdeen Centre for Arthritis and Musculoskeletal Health Marianayagam, Justina; Patient Partner and Medical Student; Northern Ontario School of Medicine

Primary Subject Paediatrics Heading:

Secondary Subject Heading: Epidemiology

Keywords: EPIDEMIOLOGY, PAEDIATRICS, PAIN MANAGEMENT on September 23, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 21 BMJ Open

1 2

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45 on September 23, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 1 1 2 3 The Epidemiology of Chronic Pain in Children and Adolescents: A Protocol for a 4 Systematic Review Update 5 6 1,2 1 1,2,3* 1 7 Perri R. Tutelman , Charlotte L. Langley , Christine T. Chambers , Jennifer A. Parker , G. 8 Allen Finley1,4, Darlene Chapman5, Gareth T. Jones6, Gary J. Macfarlane6, 9 Justina Marianayagam7 10 11 1IWK Health Centre, Centre for Pediatric Pain Research, Halifax, NS Canada; 2Dalhousie 12 13 3 14 University, Department of Psychology and Neuroscience, Halifax, Canada; Dalhousie 15 16 University, DepartmentFor of Pediatrics, peer Halifax, review Canada; 4Dalhousie only University, Department of 17 18 Anesthesia, Pain Management & Perioperative Medicine, Halifax, Canada; 5IWK Health Centre, 19 20 6 21 Health Sciences Library, IWK Health Centre; University of Aberdeen, Epidemiology Group and 22 23 Aberdeen Centre for Arthritis and Musculoskeletal Health, Aberdeen, Aberdeen, UK; 7Patient 24 25 Partner and Medical Student, Northern Ontario School of Medicine. 26 27 28 29 *Correspondence to: 30 31 Dr. Christine T. Chambers 32 Centre for Pediatric Pain Research 33 IWK Health Centre (K8536) http://bmjopen.bmj.com/ 34 5850/5980 University Ave 35 Halifax, NS B3K 6R8, Canada 36 37 [email protected] 38 39 40 41 Word Count: 1892 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 2 1 2 3 ABSTRACT 4 5 6 Introduction: Chronic pain, defined as persistent or recurring pain or pain lasting longer than 7 8 three months, is a common childhood problem and can profoundly impact children’s physical, 9 10 psychological, and social functioning. The last comprehensive systematic review estimating the 11 12 prevalence of chronic pain in children and adolescents was published in 2011. Since then, the 13 14 15 literature on pediatric chronic pain has grown substantially. This manuscript outlines a protocol 16 For peer review only 17 for an updated systematic review to provide updated estimates of the prevalence of various forms 18 19 of chronic pain in children and adolescence. The review will also examine the relationship 20 21 22 between sociodemographic and psychosocial factors related to chronic pain prevalence. 23 24 Methods and Analysis: This review will follow PRISMA guidelines. We will search EMBASE, 25 26 PubMed, CINAHL, and PsycINFO for observational studies published in English between 2009 27 28 29 and 2020 reporting population-based estimates of chronic non-disease-related pain prevalence in 30 31 children or adolescents (age  19 years). Two independent reviewers will screen the titles and 32 33 abstracts retrieved from the search based on predefined eligibility criteria. The full texts of http://bmjopen.bmj.com/ 34 35 36 relevant studies will then be assessed by two reviewers. Studies meeting inclusion criteria will be 37 38 categorized according to the type of pain investigated: headache only, abdominal pain only, back 39 40 pain only, musculoskeletal pain, combined pain, general pain, and other pain. Data will be 41 on September 23, 2021 by guest. Protected copyright. 42 43 extracted using customized forms and studies will be assessed for risk of bias using a 10-item 44 45 tool developed by Hoy et al. (2012). A narrative synthesis will summarize the prevalence 46 47 estimates of pediatric chronic pain and associated sociodemographic and psychosocial correlates. 48 49 Meta-analyses and meta-regressions will be performed if the data permit. 50 51 52 Ethics and dissemination: Ethical approval is not required. Findings will be disseminated 53 54 through publication in an academic journal, presentations at conferences, and in various media. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 3 1 2 3 PROSPERO registration number: CRD42020198690 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 5 1 2 3 INTRODUCTION 4 5 6 Chronic pain, often defined as persistent or recurring pain or pain lasting longer than 7 8 three months,[1] is a common problem in childhood. Although numerous recent population- 9 10 based studies have provided estimates of the prevalence of chronic pain in children and 11 12 adolescents, the reported proportions have varied considerably across studies. For example, the 13 14 15 prevalence of primary headache disorders in children and adolescents in recent population-based 16 For peer review only 17 studies has ranged from 19.4-66.4%,[2,3] while estimates of the prevalence of functional 18 19 gastrointestinal disorders have varied from 4.6%-31.2%.[4,5] Due to the wide variability in the 20 21 22 reported estimates, the current epidemiology of chronic pain in children and adolescents is 23 24 unclear. The uncertainty regarding the number of children and adolescents impacted by chronic 25 26 pain may limit the appropriate allocation of clinical services for this population, which are 27 28 29 crucial given the pervasive and long-term consequences of chronic pain on young people. 30 31 Chronic pain can have a profound impact on children and adolescents. Children who 32 33 experience chronic pain are at increased risk for depression and anxiety,[6,7] school absences,[8] http://bmjopen.bmj.com/ 34 35 social isolation,[9] and poorer quality of life.[10] Approximately 5% of children with chronic 36 37 38 pain experience severe levels of pain which significantly impact their daily functioning.[11] 39 40 Unfortunately, many children with chronic pain become adults with chronic pain. In a

41 on September 23, 2021 by guest. Protected copyright. 42 prospective study of pediatric patients with functional abdominal pain, 35% continued to report 43 44 45 recurrent abdominal symptoms when reassessed in adulthood.[12] Similarly, in 14-year follow 46 47 up study of adolescents with frequent headaches, 19% continued to report weekly headaches in 48 49 young adulthood.[13] These rates are similar to retrospective reports of chronic pain in childhood 50 51 52 by adults with chronic pain. In a study of adult patients with chronic pain, 17% of participants 53 54 reported their pain originated in childhood or adolescence. [14] 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 6 1 2 3 The persistence of chronic pain from childhood to adulthood has significant social and 4 5 6 economic consequences. For instance, children with chronic pain are at risk for opioid 7 8 misuse[15] and psychiatric morbidity in adulthood,[16] and pediatric chronic pain is associated 9 10 with high rates of outpatient appointments, emergency department visits, and hospitalizations all 11 12 resulting in creased healthcare costs.[17–19] The total annual cost of pediatric chronic pain in 13 14 15 the United States is estimated to be $19.5 billion.[18] The significant individual, social and 16 For peer review only 17 economic burden of pediatric chronic pain, and its persistence into adulthood, demonstrates the 18 19 importance of understanding the epidemiology of this disease in order to improve treatment and 20 21 22 reduce the impact that chronic pain has on the lives of children and adolescents. 23 24 The most recent, comprehensive review on the epidemiology of chronic pain in children and 25 26 adolescents was published 2011.[20] This review estimated that the median prevalence of 27 28 29 chronic pain in children and adolescents ranged from 11-38% depending on pain type and varied 30 31 substantially across studies. The prevalence of chronic pain was found to be higher in girls and 32 33 prevalence proportions increased with age.[20] The review identified several psychosocial http://bmjopen.bmj.com/ 34 35 correlates of chronic pain in children and adolescents such as lower socio-economic status, 36 37 38 anxiety, depression and low self-esteem.[20] However, other correlates of chronic pain in 39 40 children and adolescents, such as sleep[21,22] and post-traumatic stress disorder,[23,24] have

41 on September 23, 2021 by guest. Protected copyright. 42 since been identified and were not consistently examined at the population level at the time of 43 44 45 the past review. The review also identified several gaps in the understanding of the epidemiology 46 47 of chronic pain in children and adolescents, including restricted age ranges and lack of 48 49 longitudinal studies.[20] Furthermore, at the time of the past review the quality of included 50 51 52 studies was generally low to moderate and methodological limitations, such as inconsistent 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 7 1 2 3 definitions of pain between studies, made it difficult to estimate overall prevalence 4 5 6 proportions.[20] 7 8 The literature on pediatric pain is growing exponentially; a recent bibliometric analysis 9 10 revealed that there was nearly a 40-fold increase in the number of publications on pediatric pain 11 12 from 1975 to 2010.[25] Since the last comprehensive systematic review on the epidemiology of 13 14 15 chronic pain in children and adolescents,[20] numerous population-based studies estimating the 16 For peer review only 17 prevalence of various forms of pediatric chronic pain have been published.[26–28] A few recent 18 19 reviews estimating the prevlance of certain forms of chronic pain, such as functional abdominal 20 21 22 pain[29] and headache[30,31] have also been conducted. However, in order to appropriately 23 24 meet the clinical needs of children and adolescents with chronic pain, an updated review that 25 26 estimates the proportion of various forms of chronic pain and examines key sociodemographic 27 28 29 and psychosocial correlates of chronic pain in children and adolescents is needed. 30 31 This manuscript outlines a protocol for a systematic review to update a prior review 32 33 synthesizing the published literature on the prevalence of chronic pain in children and http://bmjopen.bmj.com/ 34 35 adolescents. Specifically, the objectives of this review are to: 1) Provide updated estimates of the 36 37 38 prevalence of various forms of chronic pain (headache, abdominal pain, back pain, 39 40 musculoskeletal pain, combined pain, general pain, and other pain) in children and adolescents;

41 on September 23, 2021 by guest. Protected copyright. 42 2) Provide an updated examination of sociodemographic (e.g., age, sex, race) and psychosocial 43 44 45 (e.g., anxiety, depression, sleep) factors related to the prevalence of chronic pain in children and 46 47 adolescents; and 3) Assess study quality and identify gaps in the literature and areas for future 48 49 research. 50 51 52 METHODS AND ANALYSIS 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 8 1 2 3 This systematic review protocol was prepared in accordance with the Preferred Reporting 4 5 6 Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines (see 7 8 supplementary file 1).[32] The study protocol was registered with the International Prospective 9 10 Register of Systematic Reviews (PROSPERO) on September 3, 2020. In the event of an 11 12 amendment to this protocol, the date of the amendment, a description of the change and the 13 14 15 rationale will be documented and recorded in PROSPERO. The dates for this review are May 14, 16 For peer review only 17 2020-April 1, 2021(expected). 18 19 Search strategy 20 21 22 We will search the following electronic databases: EMBASE, PubMed, CINAHL and 23 24 PsycINFO. The search terms will be comprised of three conceptual blocks: i) Pain terms (e.g., 25 26 musculoskeletal pain, back pain, headache, abdominal pain, recurrent pain); ii) Pediatric terms 27 28 29 (e.g., child, adolescent, boy, girl); and iii) Epidemiological terms (e.g., epidemiology, 30 31 prevalence, frequency). The searches will be restricted to English language articles, human 32 33 studies, and manuscripts published between January 2009-June 2020 (the original systematic http://bmjopen.bmj.com/ 34 35 review[20] included studies published up until 2009). 36 37 38 Eligibility criteria 39 40 Studies will be eligible for inclusion if they meet the following criteria:

41 on September 23, 2021 by guest. Protected copyright. 42 1. Observational studies using a population-based sampling frame to estimate the 43 44 45 prevalence of chronic pain in children or adolescents (study sample age 19 years). 46 47 2. Studies examining the prevalence of chronic pain in children and adolescents, defined as 48 49 pain with a minimum duration of at least 3 months or pain that is described as chronic, 50 51 52 persistent, or recurrent. This definition was selected to align with current 53 54 conceptualizations of chronic pain [1] while allowing for flexibility to accommodate 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 9 1 2 3 established diagnostic criteria for common childhood chronic pain conditions (e.g., 4 5 6 functional abdominal pain [33] and migraine [34]). 7 8 3. Studies published in peer-reviewed journals in English. 9 10 Studies meeting the following criteria will be excluded: 11 12 1. Studies with sampling frames not deemed to be population-based. 13 14 15 2. Case studies, conference abstracts, dissertations, reviews, book chapters and qualitative 16 For peer review only 17 studies. 18 19 3. Studies reporting on the prevalence of chronic pain in adults (sample age is exclusively 20 21 22 20 years) 23 24 4. Studies of non-human samples. 25 26 5. Studies examining the prevalence of chronic pain in specific sub-populations, such as 27 28 29 children and adolescents with chronic illnesses (e.g., cancer, arthritis) or other health 30 31 conditions (e.g., cerebral palsy, muscular dystrophy). 32 33 Studies reporting on multiple populations (e.g., adults and children), where data on one or http://bmjopen.bmj.com/ 34 35 36 more sub-populations that fit the eligibility criteria for this review can be separately identified, 37 38 will be included and the relevant data will be extracted. 39 40 Screening and Data Extraction 41 on September 23, 2021 by guest. Protected copyright. 42 43 Literature search results will be transferred to Covidence systematic review management 44 45 software and duplicates will be removed. An initial title/abstract review of studies retrieved by 46 47 the search will be independently conducted by two members of the study team to determine 48 49 which studies potentially met the inclusion/exclusion criteria. Articles included from the 50 51 52 title/abstract review phase will then be reviewed in full by two reviewers. The two reviewers will 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 10 1 2 3 be blinded to each other’s decisions. Discrepancies regarding the eligibility of a study will be 4 5 6 resolved by consensus, and if necessary, through discussion with a third reviewer. 7 8 Data will be extracted from included studies using customized forms. Extracted 9 10 information will include study design, location where the study was conducted, number of 11 12 participants, participant demographics (e.g., age, sex, race), study sample (e.g., headache only, 13 14 15 abdominal pain only, back pain only, musculoskeletal pain, combined pain, general pain, and 16 For peer review only 17 other pain), study methodology, prevalence proportion of chronic pain, and sociodemographic 18 19 (e.g., age, sex, race, parent education, household income) and psychosocial (e.g., anxiety, 20 21 22 depression, sleep, post-traumatic stress) predictors of chronic pain. In accordance with the 23 24 PRISMA guidelines [35], the number of studies meeting inclusion criteria will be recorded and 25 26 the reason for exclusion of those not included will be documented. 27 28 29 Quality Assessment 30 31 Two independent reviewers will assess study quality using the 10-item tool developed by 32 33 Hoy et al. (2012). This tool was developed to assess external and internal validity of prevalence http://bmjopen.bmj.com/ 34 35 studies.[36] Response options for each item are either “yes” (indicating low risk of bias) or “no” 36 37 38 (indicating high risk of bias).[36] The tool will be adapted for this review if necessary. 39 40 Consensus will be reached by discussion between the reviewers.

41 on September 23, 2021 by guest. Protected copyright. 42 Data Synthesis 43 44 45 A narrative synthesis will summarize the prevalence proportions of chronic pain in 46 47 children and adolescents in the following categories; headache only; abdominal pain only; back 48 49 pain only; musculoskeletal pain; combined pain; general pain; and other pain. Additionally, the 50 51 52 relationship between psychosocial factors (e.g., sleep, anxiety, and depression) and 53 54 sociodemographic factors (e.g., sex, age, race and indicators of socio-economic status such as, 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 11 1 2 3 but not limited to, household income, parental level of education and urban versus rural area of 4 5 6 residence) and chronic pain in children and adolescents will be reviewed. 7 8 Depending on the heterogeneity of included studies the prevalence proportions of chronic 9 10 pain will be calculated using median prevalence proportions and/or meta-analysis. When at least 11 12 two or more studies are comparable in terms of the study sample (e.g., category of chronic pain), 13 14 15 and methodology (e.g., operationalization of chronic pain), we will pool the effects to determine 16 For peer review only 17 the prevalence proportion of chronic pain across studies. Similarly, if studies have used similar 18 19 methods to examine the relationship between certain sociodemographic and/or psychosocial 20 21 22 variables in comparable chronic pain samples, we will conduct separate meta-regressions to 23 24 examine the relationship between these variables and chronic pain across studies. 25 26 Reporting of this systematic review will follow PRISMA guidelines.[37] A PRISMA 27 28 29 flow diagram will be included in the final manuscript of this review. 30 31 Ethics and Dissemination 32 33 Ethical approval will not be sought for this study, as no human subject participants will http://bmjopen.bmj.com/ 34 35 be involved. A manuscript outlining the results of this review will be submitted for publication in 36 37 38 a peer-reviewed academic journal and for presentation at relevant academic conferences. Results 39 40 will be publicly disseminated through social media, news and media outlets, and newsletters and

41 on September 23, 2021 by guest. Protected copyright. 42 blog posts, as appropriate. 43 44 45 IMPLICATIONS OF THE REVIEW 46 47 We anticipate that the results from this review will enhance our understanding of the 48 49 current burden of pediatric chronic pain which may help inform treatment and allocation of 50 51 52 clinical resources for this population. Furthermore, findings from this study will identify priority 53 54 areas for research on the epidemiology of chronic pain to guide future research efforts. Through 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 12 1 2 3 our planned knowledge translation efforts, findings of the review will be disseminated not only 4 5 6 to clinicians and scientists, but also to patients and families, which may aid in public awareness 7 8 and advocacy efforts. 9 10 PATIENT AND PUBLIC INVOLVEMENT 11 12 This protocol was designed in collaboration with a patient partner and co-author, JM. JM 13 14 15 will remain involved as a patient partner throughout all steps of the review. 16 For peer review only 17 CONTRIBUTORS 18 19 CTC conceived the study idea. CL, PRT, and JAP designed the study protocol, data 20 21 22 extraction, and statistical analysis and wrote the first draft of the manuscript. CTC, DC, GAF, 23 24 GTJ, GJM and JM provided critical insights at all stages. All authors approved and contributed 25 26 to the final manuscript. 27 28 29 FUNDING 30 31 This work was supported by an operating grant from the Canadian Institutes of Health 32 33 Research (FRN167902) awarded to CTC and funding from the Dalhousie Medical Research http://bmjopen.bmj.com/ 34 35 Foundation (DMRF). CTC is the senior author and is supported by a Tier 1 Canada Research 36 37 38 Chair with infrastructure support from the Canada Foundation for Innovation. CL is supported by 39 40 an IWK Health Centre Summer Studentship [1025420]. PRT is supported by a Research Nova

41 on September 23, 2021 by guest. Protected copyright. 42 Scotia Scholars Award, a Nova Scotia Graduate Scholarship, and an IWK Graduate Studentship 43 44 45 Award and is a trainee member of Pain Child Health (PICH). 46 47 COMPETING INTERESTS 48 49 None declared. 50 51 52 PATIENT CONSENT FOR PUBLICATION 53 54 Not required. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 13 1 2 3 DATA AVAILABILITY STATEMENT 4 5 6 Data sharing not applicable as no datasets were generated and/or analysed for this 7 8 protocol. 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 14 1 2 3 REFERENCES 4 5 6 1 Treede R-D, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. PAIN 7 8 2015;156:1. doi:10.1097/j.pain.0000000000000160 9 10 2 Al-Hashel JY, Ahmed SF, Alroughani R. Prevalence and burden of primary headache 11 12 disorders in Kuwaiti children and adolescents: A community based study. Front Neurol 13 14 15 2019;10:793. doi:10.3389/fneur.2019.00793 16 For peer review only 17 3 Malik AH, Shah PA, Yaseen Y. Prevalence of primary headache disorders in school-going 18 19 children in Kashmir Valley (North-west India). Ann Indian Acad Neurol 2012;15:100–3. 20 21 22 doi:10.4103/0972-2327.100030 23 24 4 Zheng S, Fu W, Zhou J, et al. Prevalence and related factors of irritable bowel syndrome 25 26 among middle-school students in areas affected by Wenchuan earthquake: An 27 28 29 epidemiological study. J. Clin. Gastroenterol. 2012;46:345–6. 30 31 doi:10.1097/MCG.0b013e31824712d0 32 33 5 Demirceken FG, Kurt G, Dulkadir R, et al. Functional dyspepsia in children: A Turkish http://bmjopen.bmj.com/ 34 35 prospective survey in Kirikkale province. 2010. 36 37 38 6 Shelby GD, Shirkey KC, Sherman AL, et al. Functional abdominal pain in childhood and 39 40 long-term vulnerability to anxiety disorders. Pediatrics 2013;132:475–82.

41 on September 23, 2021 by guest. Protected copyright. 42 doi:10.1542/peds.2012-2191 43 44 45 7 Simons LE, Sieberg CB, Claar RL. Anxiety and impairment in a large sample of children 46 47 and adolescents with chronic pain. Pain Res Manag 2012;17:93–7. doi:10.1155/2012/420676 48 49 8 Logan DE, Gray LS, Iversen CN, et al. School Self-Concept in Adolescents With Chronic 50 51 52 Pain. J Pediatr Psychol 2017;42:892–901. doi:10.1093/jpepsy/jsx063 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 15 1 2 3 9 Maes M, Van den Noortgate W, Fustolo-Gunnink SF, et al. Loneliness in Children and 4 5 6 Adolescents With Chronic Physical Conditions: A Meta-Analysis. J Pediatr Psychol 7 8 2017;42:622–35. doi:10.1093/jpepsy/jsx046 9 10 10 Gold JI, Yetwin AK, Mahrer NE, et al. Pediatric Chronic Pain and Health-Related Quality of 11 12 Life. J Pediatr Nurs 2009;24:141–50. doi:10.1016/j.pedn.2008.07.003 13 14 15 11 Huguet A, Miró J. The Severity of Chronic Pediatric Pain: An Epidemiological Study. J Pain 16 For peer review only 17 2008;9:226–36. doi:10.1016/j.jpain.2007.10.015 18 19 12 Walker LS, Dengler-Crish CM, Rippel S, et al. Functional abdominal pain in childhood and 20 21 22 adolescence increases risk for chronic pain in adulthood. PAIN 2010;150:568–572. 23 24 doi:10.1016/j.pain.2010.06.018 25 26 13 Larsson B, Sigurdson JF, Sund AM. Long-term follow-up of a community sample of 27 28 29 adolescents with frequent headaches. J Headache Pain 2018;19:79. doi:10.1186/s10194- 30 31 018-0908-5 32 33 14 Hassett AL, Hilliard PE, Goesling J, et al. Reports of chronic pain in childhood and http://bmjopen.bmj.com/ 34 35 adolescence among patients at a tertiary care pain clinic. J Pain 2013;14:1390–7. 36 37 38 doi:10.1016/j.jpain.2013.06.010 39 40 15 Groenewald CB, Law EF, Fisher E, et al. Associations Between Adolescent Chronic Pain

41 on September 23, 2021 by guest. Protected copyright. 42 and Prescription Opioid Misuse in Adulthood. J Pain 2019;20:28–37. 43 44 45 doi:10.1016/j.jpain.2018.07.007 46 47 16 Noel M, Groenewald CB, Beals-Erickson SE, et al. Chronic Pain in Adolescence and 48 49 Internalizing Mental Health Disorders: A Nationally Representative Study. Pain 50 51 52 2016;157:1333–8. doi:10.1097/j.pain.0000000000000522 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 16 1 2 3 17 Ho IK, Goldschneider KR, Kashikar-Zuck S, et al. Healthcare Utilization and Indirect 4 5 6 Burden among Families of Pediatric Patients with Chronic Pain. J Musculoskelet Pain 7 8 2008;16:155–64. doi:10.1080/10582450802161853 9 10 18 Groenewald CB, Essner BS, Wright D, et al. The economic costs of chronic pain among a 11 12 cohort of treatment-seeking adolescents in the United States. J Pain 2014;15:925–33. 13 14 15 doi:10.1016/j.jpain.2014.06.002 16 For peer review only 17 19 Tumin D, Drees D, Miller R, et al. Health Care Utilization and Costs Associated With 18 19 Pediatric Chronic Pain. J Pain 2018;19:973–82. doi:10.1016/j.jpain.2018.03.012 20 21 22 20 King S, Chambers CT, Huguet A, et al. The epidemiology of chronic pain in children and 23 24 adolescents revisited: A systematic review. Pain 2011;152:2729–38. 25 26 doi:10.1016/j.pain.2011.07.016 27 28 29 21 Evans S, Djilas V, Seidman LC, et al. Sleep Quality, Affect, Pain, and Disability in Children 30 31 With Chronic Pain: Is Affect a Mediator or Moderator? J Pain 2017;18:1087–95. 32 33 doi:10.1016/j.jpain.2017.04.007 http://bmjopen.bmj.com/ 34 35 22 Murphy LK, Palermo TM, Tham SW, et al. Comorbid Sleep Disturbance in Adolescents 36 37 38 with Functional Abdominal Pain. Behav Sleep Med 2020;0:1–10. 39 40 doi:10.1080/15402002.2020.1781634

41 on September 23, 2021 by guest. Protected copyright. 42 23 Noel M, Wilson AC, Holley AL, et al. Posttraumatic stress disorder symptoms in youth with 43 44 45 vs without chronic pain. Pain 2016;157:2277–84. doi:10.1097/j.pain.0000000000000642 46 47 24 Stahlschmidt L, Rosenkranz F, Dobe M, et al. Posttraumatic stress disorder in children and 48 49 adolescents with chronic pain. Health Psychol 2020;39:463–70. doi:10.1037/hea0000859 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 17 1 2 3 25 Caes L, Boerner KE, Chambers CT, et al. A comprehensive categorical and bibliometric 4 5 6 analysis of published research articles on pediatric pain from 1975 to 2010. Pain. 7 8 2016;157:302–13. doi:10.1097/j.pain.0000000000000403 9 10 26 Oswari H, Alatas FS, Hegar B, et al. Functional abdominal pain disorders in adolescents in 11 12 Indonesia and their association with family related stress. BMC Pediatr 2019;19:342–5. 13 14 15 doi:10.1186/s12887-019-1682-5 [doi] 16 For peer review only 17 27 Aartun E, Hartvigsen J, Wedderkopp N, et al. Spinal pain in adolescents: prevalence, 18 19 incidence, and course: a school-based two-year prospective cohort study in 1,300 Danes aged 20 21 22 11–13. BMC Musculoskelet Disord 2014;15:187. doi:10.1186/1471-2474-15-187 23 24 28 Arruda MA, Arruda R, Guidetti V, et al. Psychosocial adjustment of children with migraine 25 26 and tension-type headache - a nationwide study. Headache 2015;55 Suppl 1:39–50. 27 28 29 doi:10.1111/head.12510 30 31 29 Korterink JJ, Diederen K, Benninga MA, et al. Epidemiology of Pediatric Functional 32 33 Abdominal Pain Disorders: A Meta-Analysis. PLOS ONE 2015;10:e0126982–e0126982. http://bmjopen.bmj.com/ 34 35 doi:10.1371/journal.pone.0126982 36 37 38 30 Albers L, von Kries R, Heinen F, et al. Headache in School Children: Is the Prevalence 39 40 Increasing? Curr Pain Headache Rep 2015;19:4. doi:10.1007/s11916-015-0477-0

41 on September 23, 2021 by guest. Protected copyright. 42 31 Wöber-Bingöl Ç. Epidemiology of migraine and headache in children and adolescents 43 44 45 topical collection on childhood and adolescent headache. Curr Pain Headache Rep 46 47 2013;17:1–11. doi:10.1007/s11916-013-0341-z 48 49 32 Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and 50 51 52 meta-analysis protocols (PRISMA-P) 2015 statement. Rev Espanola Nutr Humana Diet 53 54 2016;20:148–60. doi:10.1186/2046-4053-4-1 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from 18 1 2 3 33 Hyams JS, Di Lorenzo C, Saps M, et al. Childhood Functional Gastrointestinal Disorders: 4 5 6 Child/Adolescent. Gastroenterology 2016;150:1456-1468.e2. 7 8 doi:10.1053/j.gastro.2016.02.015 9 10 34 Headache Classification Committee of the International Headache Society (IHS). The 11 12 International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38:1–211. 13 14 15 doi:10.1177/0333102417738202 16 For peer review only 17 35 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 18 19 meta-analyses: The PRISMA statement. PLoS Med. 2009;6. 20 21 22 doi:10.1371/journal.pmed.1000097 23 24 36 Hoy D, Brooks P, Woolf A, et al. Assessing risk of bias in prevalence studies: Modification 25 26 of an existing tool and evidence of interrater agreement. J Clin Epidemiol 2012;65:934–9. 27 28 29 doi:10.1016/j.jclinepi.2011.11.014 30 31 37 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and 32 33 meta-analyses: The PRISMA statement. PLoS Med. 2009;6. http://bmjopen.bmj.com/ 34 35 doi:10.1371/journal.pmed.1000097 36 37 38 39 40

1 2 3 Additional file 1: PRISMA-P (Preferred Reporting Items for Systematic review and Meta- 4 Analysis Protocols) 2015 checklist: recommended items to address in a systematic review 5 6 protocol 7 8 PRISMA Protocol Checklist 9 Section and Item Checklist Reporting. 10 topic No Page No 11 12 ADMINISTRATIVE INFORMATION 13 Title: 14 15 16 Identification 1aForIdentify peer the report review as a protocol of a onlysystematic review 1 17 Update 1b If the protocol is for an update of a previous systematic 1,3 18 review, identify as such 19 20 Registration 2 If registered, provide the name of the registry (e.g., 3 21 PROSPERO) and registration number 22 Authors: 23 24 25 Contact 3a Provide name, institutional affiliation, and e-mail address of 1 26 all protocol authors; provide physical mailing address of 27 corresponding author 28 Contributions 3b Describe contributions of protocol authors and identify the 12 29 30 guarantor of the review 31 Amendments 4 If the protocol represents an amendment of a previously 8 32 completed or published protocol, identify as such and list

41 sponsor/ funder on September 23, 2021 by guest. Protected copyright. 42 Role of 5c Describe roles of funder(s), sponsor(s), and/or institution(s), N/A 43 44 sponsor or if any, in developing the protocol 45 funder 46 INTRODUCTION 47 Rationale 6 Describe the rationale for the review in the context of what is 5-7 48 already known 49 Objectives 7 Provide an explicit statement of the question(s) the review 7 50 51 will address with reference to participants, interventions, 52 comparators, and outcomes (PICO) 53 METHODS 54 Eligibility 8 Specify the study characteristics (e.g., PICO, study design, 8-9 55 criteria setting, time frame) and report characteristics (e.g., years 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from

1 2 3 considered, language, publication status) to be used as criteria 4 for eligibility for the review 5 6 Information 9 Describe all intended information sources (e.g., electronic 8 7 8 sources databases, contact with study authors, trial registers, or other 9 grey literature sources) with planned dates of coverage 10 11 Search 10 Present draft of search strategy to be used for at least one To be 12 Strategy electronic database, including planned limits, such that it included in 13 could be repeated final 14 manuscript 15 16 Study For peer review only 17 Records 18 11a Describe the mechanism(s) that will be used to manage 9 19 records and data throughout the review 20 11b State the process that will be used for selecting studies (e.g., 9-11 21 22 two independent reviewers) through each phase of the review 23 (i.e., screening, eligibility, and inclusion in meta-analysis) 24 11c Describe planned method of extracting data from reports 9-11 25 (e.g., piloting forms, done independently, in duplicate), any 26 processes for obtaining and confirming data from 27 investigators 28 Data items 12 List and define all variables for which data will be sought 9,10 29 30 (e.g., PICO items, funding sources), any pre-planned data 31 assumptions and simplifications 32 Outcomes 13 List and define all outcomes for which data will be sought, 9-11 33 and including prioritization of main and additional outcomes, with http://bmjopen.bmj.com/ 34 prioritization rationale 35 Risk of bias 14 Describe anticipated methods for assessing risk of bias of 10 36 37 in individual individual studies, including whether this will be done at the 38 studies outcome or study level, or both; state how this information 39 will be used in data synthesis 40 Data 41 synthesis on September 23, 2021 by guest. Protected copyright. 42 15a Describe criteria under which study data will be 10,11 43 44 quantitatively synthesized 45 15b If data are appropriate for quantitative synthesis, describe 10,11 46 planned summary measures, methods of handling data, and 47 methods of combining data from studies, including any 48 planned exploration of consistency (e.g., I 2 , Kendall’s tau) 49 15c Describe any proposed additional analyses (e.g., sensitivity or 10,11 50 51 subgroup analyses, meta-regression) 52 15d If quantitative synthesis is not appropriate, describe the type 10,11 53 of summary planned 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 21 BMJ Open: first published as 10.1136/bmjopen-2020-043675 on 16 February 2021. Downloaded from

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml