Impact of Indoor Air Quality and Breathing on Back and Neck Pain: A Systematic Review

Back pain and neck pain are important public health concerns and are among the most common and disabling conditions globally. However, the relationships among indoor air quality (IAQ), breathing parameters (pulmonary function, respiratory disorders), and back pain and neck pain have not been adequately assessed. The purpose of this study was to systematically review the literature about the impact of IAQ and breathing parameters on back pain and neck pain (PROSPERO ID: CRD42022380515). CINAHL, EMBASE, PEDRo, and PubMed databases were searched through January 19, 2023. Inclusion criteria for study eligibility were observational studies (except case reports) or randomized controlled trials (RCTs), published in peer-reviewed journals in the English language, human research, original research, examined the relationships between IAQ, or breathing parameters with back pain or neck pain. Review procedures were conducted and reported according to PRISMA recommendations. Empirical evidence statements were developed for observational studies, and grades of evidence statements were developed for RCTs. Sixty-seven eligible studies were found (54 observational studies and 13 RCTs) that enrolled 345,832 participants. None of the studies assessed the combined impact of IAQ and breathing parameters on back pain or neck pain. No level 1 studies were found, which precludes making strong statements about causality and strong recommendations about the efficacy of IAQ and breathing exercise interventions for reducing pain and disability related to back pain and neck pain. Evidence indicates that poor IAQ and respiratory disorders are related to an increased risk of back pain and neck pain. Conflicting evidence exists about the association between pulmonary function with back pain and neck pain. Evidence for breathing exercise interventions was mixed with numerous limitations. This review provides preliminary evidence on the relationships of IAQ and breathing parameters with back pain and neck pain, which can be used to guide future research and clinical implementation efforts. Assuming positive findings in subsequent research, a wide range of stakeholders involved with this complex human-building-environment interface can be equipped to address IAQ and breathing parameters, along with other established risk factors to help those suffering from back pain and neck pain.


Introduction And Background
Back pain and neck pain are important public health concerns and are among the most common, costly, and disabling conditions in the world [1][2][3][4][5][6]. In the global burden of disease (GBD) studies [2,6,7], low back pain (LBP) is the most common cause of years lived with disability (YLDs) and a leading cause of disabilityadjusted life years (DALYs), and neck pain is also problematic in terms of YLDs and DALYs. Most adults will experience disabling LBP or neck pain at some point in their lives [3,4], and symptoms and disability often persist for those who suffer initial episodes [4,5].
Numerous biopsychosocial risk factors have been identified for back pain and neck pain, such as age, previous history of the condition, obesity, sub-optimal fitness, low physical activity, psychological conditions, smoking, poor ergonomics, and awkward lifting [4,5]. Our recent systematic reviews found additional risk factors for back pain, neck pain, and other musculoskeletal disorders (MSDs) within the built environment that were not previously identified and classified as healthy building determinants (HBDs) [8,9]. For example, evidence was found to support an association between sub-optimal indoor air quality (IAQ) and increased risk of back pain and neck pain. However, the available evidence was primarily from lower-level studies; thus, conclusions about causality and intervention effectiveness could not be made. Others have found that various breathing parameters (e.g., pulmonary function, respiratory disorders) are associated with LBP and neck pain [10,11]. Yet, the inter-relationships of IAQ and breathing parameters on back pain and neck pain have not been adequately explored.
Among the various treatment options for back pain and neck pain, the clinical practice guidelines (CPGs) generally recommend therapeutic exercises to improve pain, disability, and function for managing these disorders [1, 3,12]. While many different types of exercises are available for the management of back pain and neck pain, no specific type has been shown to be clearly superior to others [13,14]. With some exceptions, such as directional preference exercises through mechanical diagnosis and therapy [15,16], exercises have generally been studied for heterogeneous groups of patients with LBP and neck pain [17]. Thus, the available evidence is unclear about how to match the right patient with the right intervention at the right time.
Given the relationships of IAQ and breathing parameters with back pain and neck pain, along with the lack of clarity on which exercises are best for specific patients, it is plausible that interventions aimed at improving IAQ and breathing parameters, along with the array of other established risk factors, may be useful for reducing the risk of these disorders in public, residential, and workplace environments. While our previous reviews did not find any RCTs examining the efficacy of IAQ interventions on various MSDs [8,9], a recent systematic review found preliminary evidence from small randomized controlled trials (RCTs) to support the efficacy of breathing exercises on short-term pain measures for LBP [18]. Another systematic review on this topic uncovered one small RCT that assessed the independent effect of breathing exercises compared to non-breathing exercise control for LBP [19]. Additionally, a systematic review of exercise for neck pain found one small RCT on breathing exercises that did not support efficacy of this intervention [13].
Conceivably, addressing both IAQ and breathing parameters at the same time within the human-buildingenvironment interface may be useful in reducing the risk of back pain and neck pain. For example, previous research indicates that poor IAQ contributes to tissue hypoxia [20] and is related to sick building syndrome [21], which is associated with MSDs [21]. Improving IAQ by addressing a building's air filtration and ventilation systems can decrease exposure to six common exterior air pollutants (i.e., ground-level ozone, particulate matter, carbon monoxide, lead, sulfur dioxide, nitrogen dioxide) that are known to affect human health [22]. Furthermore, disordered breathing is associated with abnormal carbon dioxide and oxygen physiology [23] and reduced functional movement quality [24], which is related to increased risk for MSDs [23,25]. Improving breathing patterns, such as the use of nose breathing and the light, slow, and deep technique [26,27], can enhance the body's ability to filter air and recover [26,27]. However, research on the combined effect of IAQ and breathing parameters on back pain and neck pain has not been systematically examined. The purpose of this study was to systematically review the literature on the impact of IAQ and breathing parameters on back pain and neck pain.

Overview
The current review incorporated similar methods, evidence synthesis procedures, and reporting structure as our earlier reviews that examined HBDs and MSDs [8,9]. The current review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [28] and other resources [1, 12,[29][30][31][32][33][34] and was registered with PROSPERO (ID: CRD42022380515).

Information Sources
Studies were uncovered by searching CINAHL, EMBASE, PEDRo, and PubMed. The last author (JM) developed the search strategy, and the first author (EG) cross-checked it. The PubMed search strategy is shown in the Appendices, and CINAHL, EMBASE, and PEDRo were searched using a comparable databasespecific approach. To identify additional studies, hand searches of published reports available to the authors were conducted, and an examination of references within studies obtained from the primary search was performed [8,9].

Eligibility Criteria
Inclusion and exclusion criteria are depicted using the PICOTS method: P -patients/people, I -intervention, C -comparator, O -outcomes/variables, T -time/timing, S -setting [8,9,28]. P -Patients/people: Studies were included if they assessed humans ≥ 18 years of age with back pain, neck pain, or related MSDs (e.g., cervical radiculopathy, lumbar radiculopathy, sciatica). Back pain is defined as pain or associated symptoms in the thoracic spine region [35] or the lumbo-sacral spine region [36]. Neck pain is defined as pain or associated symptoms in the cervical spine region [35,37]. Studies were included that described all forms, severities, and durations of back pain and neck pain. Studies were excluded that only described systemic disorders (e.g., fibromyalgia) or neurological conditions (e.g., multiple sclerosis) [8,9]. I -Intervention: Studies were included if they examined IAQ or breathing parameters (pulmonary function, respiratory disorders). For the purpose of this review, IAQ consisted of air quality and ventilation HBDs, which are defined elsewhere [38]. Definitions for constructs related to IAQ are found elsewhere for healthy buildings [8,39], built environments [40], determinants of health [41], and HBDs [8]. For the purpose of this review, the breathing parameters of pulmonary function and respiratory disorders were included. Pulmonary function (i.e., lung function) is defined as "...how well the lungs work in helping a person breathe. During

Study Outcomes
For the included observational studies, the outcome measures were primarily descriptive and relational [8,9] and varied widely across study types, as well as the IAQ, breathing, and respiratory disorders. Outcomes for IAQ were mainly study-specific and not validated for general use. Outcomes for breathing were wideranging, many of which were validated pulmonary function tests (e.g., forced vital capacity). Outcomes for respiratory disorders were primarily prevalence and incidence. The observational studies also used various outcome measures for back and neck pain, such as validated patient-reported outcomes (e.g., Nordic musculoskeletal questionnaire) and administrative measures (e.g., work absenteeism), as well as studyspecific measures that have not been validated. For the RCTs, validated outcome measures for pain (e.g., visual analog scale), disability (e.g., Oswestry disability index), and pulmonary function tests (e.g., forced vital capacity) were used.

Empirical Evidence Statements -Observational Studies
Empirical evidence statements from observational studies for the relationships of IAQ, pulmonary function, and respiratory disorders with back pain and neck pain are detailed in Table 1. This review found evidence to support significant weak relationships between IAQ and back pain, based on 12 studies for back pain and seven studies for neck pain. Namely, poor IAQ is related to an increased risk of back pain and neck pain. Similarly, this review found evidence to support significant moderate relationships between various respiratory disorders and back pain and neck pain, based on 22 studies for back pain and six studies for neck pain. That is, the presence of respiratory disorders is associated with an increased risk of back pain and neck pain. On the contrary, this review found conflicting evidence about the relationships between pulmonary function and back pain and neck pain, based on eight studies for back pain and 11 studies for neck pain. Many studies examining these relationships reported mixed results among various pulmonary function measures. That is, some results support a relationship between pulmonary function and back pain and neck pain, while some results do not support a relationship.

Outcome Back Pain Neck Pain
Indoor Air Quality Weak evidence from 12 studies indicates that poor indoor air quality is associated with an increased risk of back pain. Yes: [69,88,91,100,103].
Weak evidence from 7 studies indicates that poor indoor air quality is associated with an increased risk of neck pain.
Conflicting evidence from 11 studies exists about the association between pulmonary function and neck pain.

Grade of Evidence Statements -RCTs
The grade of evidence statements from RCTs assessing the efficacy of breathing exercise interventions on back pain and neck pain is detailed in Table 2. For back pain, moderate evidence from two RCTs indicates that breathing exercises alone, compared to control, may be useful to improve pain outcomes. Conflicting evidence from seven RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pain outcomes. Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on disability outcomes. Conflicting evidence from seven RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on disability outcomes. Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on pulmonary function outcomes. Conflicting evidence from four RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pulmonary outcomes.

Pain
Moderate evidence from two RCTs indicates that breathing exercises alone, compared to control, may be useful to improve pain outcomes. Yes: [48,55]. Mixed: none. No: none. Conflicting evidence from seven RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pain outcomes. Yes: [72,94,98]. Mixed: [80].
Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on pain outcomes. Yes: none. Mixed: none. No: [74]. Conflicting evidence from two RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pain outcomes. Yes: [50]. Mixed: none. No: [62].

Disability
Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on disability outcomes. Yes: none. Mixed: none. No: [55]. Conflicting evidence from seven RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on disability outcomes. Yes: [72,92,98]. Mixed: none. No: [80,89,94,96].
Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on disability outcomes. Yes: none. Mixed: none. No: [74]. Insufficient evidence from one RCT is available to assess the efficacy of adding breathing exercises to another intervention compared to that intervention alone on disability outcomes. Yes: [50]. Mixed: none. No: none.

Pulmonary
Function Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on pulmonary function outcomes. Yes: [48]. Mixed: none. No: none.
Conflicting evidence from four RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pulmonary outcomes. Yes: [72]. Mixed: [92,96,98]. No: none.
No evidence is available to assess the efficacy of breathing exercises alone compared to control on pulmonary function outcomes. Moderate evidence from two RCTs indicates that adding breathing exercises to another intervention compared to that intervention alone may be useful to improve pulmonary function outcomes. Yes: [50,62]. Mixed: none. No: none. The available evidence on breathing exercise interventions for neck pain was likewise mixed. Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on pain outcomes. Conflicting evidence from two RCTs exists about the efficacy of adding breathing exercises to another intervention compared to that intervention alone on pain outcomes. Insufficient evidence from one RCT is available to assess the efficacy of breathing exercises alone compared to control on disability outcomes. Insufficient evidence from one RCT is available to assess the efficacy of adding breathing exercises to another intervention compared to that intervention alone on disability outcomes. No evidence is available to assess the efficacy of breathing exercises alone compared to control on pulmonary function outcomes. Moderate evidence from two RCTs indicates that adding breathing exercises to another intervention compared to that intervention alone may be useful to improve pulmonary function outcomes.
For IAQ, insufficient evidence from one RCT is available to assess the efficacy of an IAQ intervention compared to control on pain and pulmonary function outcomes for back pain. No evidence is available to assess the efficacy of IAQ interventions on disability outcomes for back pain. Moreover, no evidence is available to assess the efficacy of IAQ interventions on pain, disability, and pulmonary function outcomes for neck pain.

Discussion
The findings of the current review add to the body of knowledge on the impact of IAQ and breathing parameters on back pain and neck pain. When the current review is considered along with other recent efforts, the available evidence provides a comprehensive preliminary assessment of this topic that can be used to inform future research and implementation initiatives. Overall, this review found 67 studies (54 observational studies and 13 RCTs) on relationships of IAQ or breathing parameters with back pain or neck pain. More than half (39/67) of these studies were published over the past decade (since 2014) and were conducted in a wide range of countries, settings, and populations, which suggests that the interest in this topic is growing. The uncovered studies provide preliminary evidence on the relationships of IAQ or breathing parameters with back pain and neck pain, which can be used to guide future research and clinical implementation efforts. Key findings are as follows: 1. None of the uncovered studies assessed the combined impact of IAQ and breathing parameters on back pain or neck pain.
2. Evidence indicates that IAQ and respiratory disorders are associated with back pain and neck pain, which is consistent with previous work.

3.
Conflicting evidence exists about the association between pulmonary function with back pain and neck pain.
4. Evidence for breathing exercise interventions is mixed with numerous limitations, which precludes making strong recommendations for or against their use for reducing pain and disability related to back pain and neck pain.
Contrary to our assumptions before conducting this review, no studies were found that examined the combined impact of IAQ and breathing parameters on back pain and neck pain. Furthermore, our anecdotal observations outside of this review suggest that no clinical programs or commercial initiatives have implemented strategies to address both factors in people with back pain and neck pain. We speculate that a primary reason to explain no research or program implementation efforts is the lack of awareness and disconnect among the diverse stakeholders involved with decision-making about these relationships. As we previously described [8], the stakeholder sectors include (1) healthcare (e.g., patients, clinicians, managed care organizations), (2) real estate (e.g., tenants, owners, investors, property managers, engineers, architects), (3) occupational (e.g., employees, employers), (4) policy (e.g., regulatory, licensing, credentialing), and (5) public health (e.g., public health officials and organizations). Considering the large magnitude of tackling the combined impact of IAQ and breathing parameters on back pain and neck pain, it is possible that each stakeholder is working in silos and approaching the problem with their unique point of view. In our opinion, a better approach would be working together to address known risk factors with a common goal of reducing the adverse effects of back pain and neck pain. We acknowledge that reaching a consensus among so many interested parties is challenging because it is impossible for a specific stakeholder group to be well-versed in the field at large. Moreover, stakeholder-specific biases and conflicts of interest add other barriers. Some of these explanations have been mentioned as problematic for the overall management of LBP [178]. Regardless, the findings of the current review can serve to enhance awareness and provide a framework to help guide future efforts.
For the observational studies, the findings about IAQ in the current review confirm those from our previous review [8], which indicates that poor IAQ is associated with an increased risk of back pain and neck pain. While more studies were found in the current review (13 in the current review vs. 10 in a previous review), the uncovered studies were primarily lower level, and the updated findings continue to support a weak association. The findings on the association of respiratory disorders with back pain are mostly consistent with another review on this topic [10]. Namely, the presence of respiratory disorders is associated with an increased risk of back pain. We did not find another review to compare findings about the association of respiratory disorders with neck pain. The current review found conflicting evidence about the associations between pulmonary function and back pain and neck pain. Namely, some results support a relationship between poor pulmonary function and elevated risk of back pain and neck pain, while other results do not support a relationship. These findings are generally consistent with other reviews on this topic [11,179,180].
For the intervention trials, the current review found only one RCT that assessed the efficacy of an IAQ intervention on the prevalence of back pain during the past month and no RCTs on neck pain; therefore, evidence is insufficient to make clinical recommendations. For comparison, our previous reviews did not find any RCTs assessing IAQ interventions for back pain, neck pain, or other MSDs [8,9].
The 12 RCTs uncovered in the current review assessed the efficacy of breathing exercises on pain intensity and disability related to back pain or neck pain. These RCTs were small, generally included short-term outcomes, enrolled heterogeneous groups of patients with non-specific LBP, and used a wide variety of breathing exercise types with minimal overlap across the studies. Therefore, considering the limitations and heterogeneity of the available evidence, the clinical recommendations (as shown in Table 2) about breathing exercises resulting from these RCTs should be used with caution. Conclusions from our current review differ from a previous systematic review on breathing exercises for back pain [18]. For example, the current review found moderate evidence from two RCTs, suggesting that breathing exercises alone compared to control may be useful to improve pain outcomes, and conflicting evidence from seven RCTs about the efficacy of adding breathing exercises to other interventions on pain outcomes. The previous review found evidence from seven RCTs to support the efficacy of breathing exercises to improve pain outcomes for back pain. A possible explanation for these differences is that we stratified the clinical recommendations by use of breathing exercises alone or in combination with other interventions, while the previous review did not. Further, the previous review included RCTs that we did not, such as RCTs without comparisons between groups for relevant outcomes [144], and RCTs in which the independent effects of breathing exercise could not be determined [133,134].
For neck pain, the current review found three RCTs on breathing exercises, which had mixed findings for pain, disability, and pulmonary function outcomes. For comparison, the current review and a previous review [13] found one small RCT on breathing exercises that did not support the efficacy of this intervention for pain outcomes [74].
The current review has limitations that need to be addressed in future research. For example, the combined impact of IAQ and breathing on back pain or neck pain was not assessed in any study. The available evidence was mostly from lower-level studies, and no level 1 studies (e.g., high-quality RCTs) were found, which limited assessment of causality of the observed IAQ breathing parameters, back pain, and neck pain relationships. Several pairwise comparisons had minimal studies to formulate empirical evidence statements or the grade of evidence statements. Comparisons among the studies were challenging, and meta-analysis was not possible because of the previously described limitations of the available evidence. In addition, the studies did not assess the interrelationships of numerous factors that may affect back pain and neck pain development, recovery, and prognosis, such as those reflecting what is put into the building (e.g., ergonomics, biopsychosocial factors) rather than the building itself [8,9].
The RCTs on breathing exercises uncovered in the current review had additional limitations that negatively impact generalizability. For example, the RCTs also enrolled people with heterogeneous types of back pain and neck pain without considering precise diagnostic or treatment classifications. Nearly all (11/12) of the RCTs only assessed short-term outcomes. The breathing exercises delivered among the RCTs were heterogenous and unstandardized. The RCTs also did not report if the participants achieved proper breathing patterns through the administered exercises. Moreover, none of the RCTs analyzed the relationships among breathing parameters, exercise adherence, and clinical outcomes (e.g., pain, disability). Finally, none of the RCTs assessed implementation factors, such as those described for the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) and consolidated framework for implementation research (CFIR) models [181].
A full examination of causality about the relationships of IAQ and breathing parameters with back pain and neck pain using Hill's criteria [182] was not possible since the studies found in the current review were generally lower level (i.e., no level 1 studies were uncovered). Regardless, it is biologically plausible that addressing IAQ and breathing parameters could be useful to mitigate risk factors for back pain and neck pain, as mentioned in the introduction of this manuscript. Thus, this review, along with our other reviews [8,9], provides a comprehensive initial framework on this topic that can be used to inform future research and implementation initiatives. While the available evidence from the RCTs was generally inconclusive, the combined body of evidence from the observational studies and RCTs can be used to create awareness among the diverse groups impacted by the human-building-environment interface involving IAQ, breathing, and back and neck pain.
Assuming positive findings in subsequent research, various stakeholders may benefit from the implementation of strategies to mitigate IAQ and breathing parameter risk factors related to back pain and neck pain. For healthcare stakeholders, these strategies, especially if combined with established interventions, may improve the recovery, function, quality of life, and performance of people suffering from back pain and neck pain. For occupational stakeholders, these multi-modal interventions could enhance employee productivity and reduce lost work time [183,184]. For real estate professionals, enhancements to IAQ and other HBDs could result in monetary benefits [39,185], higher tenant satisfaction and retention [8,9], and lower risk of liability related to injury or poor health [8,9]. For policymakers, the implementation of client-centered practices and policies to improve indoor environmental quality related to IAQ and breathing parameters could be influential in attenuating the global burden of human disability [8,9]. Conflicting evidence exists about the association between pulmonary function with back pain and neck pain.

Conclusions
(4) Evidence for breathing exercise interventions is mixed with numerous limitations, which precludes making strong recommendations for or against their use for reducing pain and disability related to back pain and neck pain.
Overall, no level 1 studies were found, which precludes making strong statements about causality and strong recommendations about the efficacy of IAQ and breathing exercise interventions for reducing pain and disability related to back pain and neck pain. Regardless, the uncovered studies provided preliminary evidence on the relationships of IAQ and breathing parameters with back pain and neck pain, which can be used to guide future research and clinical implementation efforts. Assuming positive findings in subsequent research, a wide range of stakeholders involved with this complex human-building-environment interface can be equipped to address IAQ and breathing parameters along with other established risk factors to help those suffering from back pain and neck pain. 2023     Chi-square. Prevalence of MSK symptoms was greater in workers exposed to lead compared to non-exposed controls in the neck, upper back, and low back (neckexposed: 14%, controls: 4%, p = 0.015) (upper back -exposed: 7%, controls: 0%, p = 0.021) (low back -exposed: 33%, controls: 0%, p = 0.0008

2011
Cross-sectional Mohan et al. [90], 2018 Noormohammadpour et al. [91], 2017 Cross-sectional Park et al. [95], 2014 Park et al. [97], 2020 Retrospective Park et al. [99], 2023 Cross-sectional Pisinger et al. [100], 2011 Cross-sectional Rasmussen-Barr et al. [101], 2019 Prospective Rathinaraj et al. [102], Ravibabu et al. [103], Roussel et al. [104], Shah et al. [105], 2019 Smith et al. [106], 2006 Cross-sectional Smith et al. [107], 2009 Prospective Ulger [109], 2021 Cross-sectional Wickstrom et al. [110], Wirth et al. et al. [111], Wright et al. [112], 1995 Cross-sectional Yalcinkaya et al. [113], Yeung et al. [114], 2011 Cross-sectional  (4) Were all the subjects selected or recruited from the same or similar populations (including the same time period)? Were inclusion and exclusion criteria for being in the study prespecified and applied uniformly to all participants? (5) Was a sample size justification, power description, or variance and effect estimates provided? (6) For the analyses in this paper, were the exposure(s) of interest measured prior to the outcome(s) being measured? (7) Was the timeframe sufficient so that one could reasonably expect to see an association between exposure and outcome if it existed? (8) For exposures that can vary in amount or level, did the study examine different levels of the exposure as related to the outcome (e.g., categories of exposure, or exposure measured as continuous variable)? (9) Were the exposure measures (independent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? (10) Was the exposure(s) assessed more than once over time? (11) Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants? (12) Were the outcome assessors blinded to the exposure status of participants? (13) Was the loss to follow-up after baseline 20% or less? (14) Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)? NA: Not Applicable. N: No. NR: Not Reported. Y: Yes. Overall Quality Rating: 0-4: Poor (high risk of bias) 5-9: Fair (between low and high risk of bias) 10-14: Good (low risk of bias). Ahmadnezhad et al. [48], 2020

Author, Year
Anwar et al. [50], 2022 Gholami-Borujeni et al. [55], 2021 Dareh-Deh et al. [62], Diaz et al. [66], 2007 Ghavipanje et al. [72], Hallman et al. [74], Kavya et al. [80], 2020 Mehling et al. [89], Oh et al. [92], 2020 Otadi et al. [94], 2021 Park et al. [96], 2019 Park et al. [98], 2022 Study quality determined by the NIH quality assessment tool for controlled intervention studies, with 14 items: (1) Was the study described as randomized, a randomized trial, a randomized clinical trial, or an RCT? (2) Was the method of randomization adequate (i.e., use of randomly generated assignment)? (3) Was the treatment allocation concealed (so that assignments could not be predicted)? (4) Were study participants and providers blinded to treatment group assignment? (5) Were the people assessing the outcomes blinded to the participants' group assignments? (6) Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, co-morbid conditions)? (7 Was the overall drop-out rate from the study at endpoint 20% or lower of the number allocated to treatment? (8) Was the differential drop-out rate (between treatment groups) at endpoint 15 percentage points or lower? (9) Was there high adherence to the intervention protocols for each treatment group? (10) Were other interventions avoided or similar in the groups (e.g., similar background treatments)? (11) Were outcomes assessed using valid and reliable measures, implemented consistently across all study participants? (12) Did the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power? (13) Were outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)? (14) Were all randomized participants analyzed in the group to which they were originally assigned, i.e., did they use an intention-to-treat analysis? NA: Not Applicable. N: No. NR: Not Reported. Y: Yes. Overall Quality Rating: 0-4: Poor (high risk of bias) 5-9: Fair (between low and high risk of bias) 10-14: Good (low risk of bias).  Table 3 Selection process 8

Section and
Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

2, 3
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.  Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

3, 4 13b
Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions. 3, 4 13c Describe any methods used to tabulate or visually display results of individual studies and syntheses.
3, 4, Tables 1, 2,   Supplementary   Tables 4, 5 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If metaanalysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

13e
Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
not applicable as noted on page 4 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. not applicable as noted on page 4 Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
not applicable as noted on page 4 Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. 4

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. 4, 5, Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. 5, 6, Figure 1 Study characteristics 17 Cite each included study and present its characteristics.

5, 6
Supplementary Tables 4, 5 Risk of bias in studies 18 Present assessments of risk of bias for each included study. For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.