Is Smoking Associated with Carpal Tunnel Syndrome? A Meta-Analysis

To date, the role of smoking in carpal tunnel syndrome (CTS) is unclear. The aim of this systematic review and meta-analysis was to assess the association between smoking and CTS. The literature searches were conducted in PubMed, Embase, and Scopus, from inception until October 2021. Three reviewers screened the titles, abstracts, and full-text articles and evaluated the methodological quality of the included studies. A random-effects meta-analysis was used, and heterogeneity across studies was examined using I2 statistic. A total of 31 (13 cross-sectional, 10 case-control, and 8 cohort) studies were qualified for meta-analysis. In a meta-analysis of cohort studies, the risk of CTS did not differ between current and never smokers (pooled hazard ratio (HR) 1.09, 95% CI 0.84–1.43), current and past/never smokers (HR 1.07, 95% CI 0.94–1.23), and past and never smokers (HR 1.12, 95% CI 0.83–1.49). Furthermore, a meta-analysis of case control studies found no difference in the risk of CTS between current and never smokers (pooled odds ratio (OR) 0.92, 95% CI 0.56–1.53), current and past/never smokers (OR 1.10, 95% CI 0.51–2.36), and past and never smokers (OR 0.91, 95% CI 0.59–1.39). However, a meta-analysis of cross-sectional studies showed the associations of ever (OR 1.36, 95% CI 1.08–1.72) and current smoking (OR 1.52, 95% CI 1.11–2.09) with CTS. However, the association between ever smoking and CTS disappeared after limiting the meta-analysis to higher quality studies or after adjusting for publication bias. The association between current smoking and CTS also attenuated after limiting the meta-analysis to studies that confirmed CTS by a nerve conduction study or studies with low attrition bias. This meta-analysis does not support an association between smoking and CTS. The association between smoking and CTS observed in cross-sectional studies could be due to biases and/or confounding factors.


Introduction
Compression of the median nerve at the carpal tunnel, known as carpal tunnel syndrome (CTS), is the most common entrapment neuropathy of the upper extremity [1][2][3]. The incidence of CTS varies between 88 and 105 cases per 100,000 person-years among men and between 193 and 232 cases per 100,000 person-years among women [4][5][6]. The etiology of CTS is multifactorial; often, both occupational and personal risk factors are involved. Its known risk factors include female gender, excess body mass, diabetes mellitus, rheumatoid arthritis, and thyroid disease [7][8][9][10][11][12][13]. Manual workers are at higher risk of CTS than non-manual workers [14]. Genetic factors might also play a role in CTS [15].
Smoking is a major health concern [16]. To date, the role of smoking in CTS remains unclear. Cigarette smoking is associated with reduced blood supply, oxidative stress, and systemic inflammation, which might impair the peripheral nerves and make them more vulnerable to compression neuropathies [17,18]. As found to be a neuroteratogen in

Inclusion and Exclusion Criteria
Three reviewers (K.L, S.H., and R.S.) independently screened the titles and abstracts of the references retrieved. Both population-and hospital-based case-control, cross-sectional, and cohort studies that reported quantitative results for the association between smoking and CTS symptoms confirmed by nerve conduction studies or clinical signs were included in the meta-analysis. Studies conducted among volunteers and CTS patients without a control group were excluded. Moreover, studies defined CTS based on self-reports, studies defined CTS by symptoms only, or nerve conduction studies only were excluded. Lastly, studies conducted among pregnant women, patients undergoing dialysis, or among patients with toxic oil syndrome were excluded from the review. Disagreements between the reviewers were resolved through discussion.

Data Extraction
Characteristics of the included studies and quantitative data were extracted by two reviewers (S.H. and K.L.) and checked by a third reviewer (R.S.). The following characteristics of the included studies were extracted: study population, age and gender distribution, sample size, smoking, outcome assessment, summary results, and adjustment for confounding factors.

Quality Assessment
Three reviewers (K.L., S.H., and R.S.) independently appraised the risk of bias of included studies. For methodological quality assessment, we used a checklist adapted from the Effective Public Health Practice Project tool [28]. We rated the quality of each study, according to five sources of bias: selection, performance, detection, confounding factors, and attrition (Appendix A Table A1). Disagreements between reviewers were resolved through discussion.

Statistical Analysis
Odds ratio for cross-sectional and case-control studies and risk ratio for prospective cohort studies were estimated for those studies reporting descriptive results, such as the number of CTS cases in smokers and non-smokers or number of smokers in CTS cases and controls. The Woolf confidence interval was calculated for the estimated odds ratios [29]. Since the prevalence of CTS is less than 5%, we did not convert odds ratios to risk ratios for the meta-analysis of prospective cohort studies. With a prevalence of less than 5%, the odds ratio is identical to risk ratio. A random-effects meta-analysis was used to combine the estimates of studies, and the I 2 statistic was used to assess the presence of heterogeneity across the studies [30,31]. Subgroup analyses were conducted with regard to methodological quality of included studies. A funnel plot was used for exploring publication bias, and Egger's regression test was used for examining funnel plot asymmetry. Due to small number of studies included in the meta-analyses, only presence or absence of bias in one quality domain was used for subgroup analysis. Furthermore, the trim and fill method was used to adjust for missing studies, due to publication bias [32,33]. Stata version 17 (StataCorp LP, College Station, TX, USA) was used for the meta-analyses.

Results
A total of 733 records were identified. After removing duplicates, 644 were screened. Of these, 591 were excluded based on titles and abstracts, and 53 full-text reports were assessed for eligibility. Of these, 22 reports were excluded with reasons ( Figure 1). Finally, 31 studies, consisting of 13 cross-sectional studies [10,[34][35][36][37][38][39][40][41][42][43][44][45], 10 case-control studies [11,[46][47][48][49][50][51][52][53][54], and 8 cohort studies [22,[24][25][26][27][55][56][57], were included in the meta-analysis. The characteristics and quality of the included studies are reported in Appendix A Tables A2-A4. A meta-analysis of cross-sectional studies showed a higher prevalence of CTS among ever smokers, compared with never smokers (OR 1.36, 95% CI 1.08-1.72, Figure 2), as well as among current smokers, compared with past/never smokers (OR 1.52, 95% CI 1.11-2.09). Of note, a small (n = 379) cross-sectional study examined the association between number of packs per years smoked and CTS, but no association was found [44]. In the sensitivity analyses, the association between ever smoking and CTS disappeared after limiting the meta-analysis to higher quality studies or adjusting for publication bias ( Table 2). The association between current smoking and CTS was not due to publication bias, selection bias, or confounding factors. The association did not remain statistically significant when the meta-analysis was limited to the studies with CTS confirmed by a nerve conduction study or to those studies with low attrition bias. A meta-analysis of cross-sectional studies showed a higher prevalence of CTS among ever smokers, compared with never smokers (OR 1.36, 95% CI 1.08-1.72, Figure 2), as well as among current smokers, compared with past/never smokers (OR 1.52, 95% CI 1.11-2.09). Of note, a small (n = 379) cross-sectional study examined the association between number of packs per years smoked and CTS, but no association was found [44]. In the sensitivity analyses, the association between ever smoking and CTS disappeared after limiting the meta-analysis to higher quality studies or adjusting for publication bias ( Table  2). The association between current smoking and CTS was not due to publication bias, selection bias, or confounding factors. The association did not remain statistically significant when the meta-analysis was limited to the studies with CTS confirmed by a nerve conduction study or to those studies with low attrition bias.
A meta-analysis of case control studies showed no associations of ever, past, and current smoking with CTS ( Figure 3). The pooled OR was 0.92 (95% CI 0.56-1.53, three studies) for current smoking, compared with never smoking, 1.10 (95% CI 0.51-2.36, six studies) for current smoking, compared with past/never smoking, and 0.91 (95% CI 0.59-1.39, three studies) for past smoking, compared with never smoking.
A meta-analysis of prospective cohort studies showed that the incidence of CTS does not differ between current and never smokers (hazard ratio [HR] 1.09, 95% CI 0.84-1.43, two studies, Figure 4), current and past/never smokers (HR 1.07, 95% CI 0.94-1.23, five A meta-analysis of case control studies showed no associations of ever, past, and current smoking with CTS ( Figure 3). The pooled OR was 0.92 (95% CI 0.56-1.53, three studies) for current smoking, compared with never smoking, 1.10 (95% CI 0.51-2.36, six studies) for current smoking, compared with past/never smoking, and 0.91 (95% CI 0.59-1.39, three studies) for past smoking, compared with never smoking.
A meta-analysis of prospective cohort studies showed that the incidence of CTS does not differ between current and never smokers (hazard ratio [HR] 1.09, 95% CI 0.84-1.43, two studies, Figure 4), current and past/never smokers (HR 1.07, 95% CI 0.94-1.23, five studies), and past and never smokers (HR 1.12, 95% CI 0.83-1.49, two studies). Only one cohort study compared ever smokers with never smokers (HR 1.48, CI 1.12-1.96). One prospective cohort study (n = 8703) explored the association of the number of pack-years smoked and hospitalization for CTS [58]. Among men, pack-years > 10 was associated with hospitalization for CTS but not pack-years ≤ 10, after adjustment for body mass index, socioeconomic status, and diabetes. Among women, both pack-years ≤ 10 and pack-years > 10 were associated with hospitalization for CTS.
cohort study compared ever smokers with never smokers (HR 1.48, CI 1.12-1.96). One prospective cohort study (n = 8703) explored the association of the number of pack-years smoked and hospitalization for CTS [58]. Among men, pack-years > 10 was associated with hospitalization for CTS but not pack-years ≤ 10, after adjustment for body mass index, socioeconomic status, and diabetes. Among women, both pack-years ≤ 10 and packyears > 10 were associated with hospitalization for CTS.

Discussion
In this meta-analysis, we found no association between smoking and CTS in case control or cohort studies. Only a meta-analysis of cross-sectional studies showed an association between smoking and CTS. The results of the current meta-analysis are consistent with those of a previous systematic review and meta-analysis of studies published up to 2014 [21]. Limiting the meta-analysis of cross-sectional studies to higher quality research did not support an association between smoking and CTS.
The lack of uniformity in using a comparison group for current smoking across the included studies reduced the statistical power of this meta-analysis. A meta-analysis of cross-sectional studies did not show a significant difference in the prevalence of CTS between current and never smokers, but showed a significant difference between current and past/never smokers. Furthermore, most of the studies included in the current metaanalysis did not assess the association between the number of cigarettes smoked per day and CTS.
Recent studies have identified the relationship between workload factors and CTS [26,59,60]. Occupational biomechanical factors, such as forceful handgrip, repetitive wrist extension and flexion, extreme wrist postures, and use of vibratory tools, play a role in the causation of CTS [26,[59][60][61]. In this meta-analysis, we found an association between smoking and CTS in cross-sectional studies; however, some of these studies did not adjust their estimates for work-related factors. It would be worth noting that bluecollar workers are more likely to smoke [62]. It is possible that the association between smoking and CTS in cross-sectional studies is confounded by work-related factors. In the sensitivity analysis of cross-sectional studies, the association between smoking and CTS was attenuated after limiting the meta-analysis to higher quality studies. It is likely that the association between CTS and smoking observed in cross-sectional studies is not a true association. It may be due to biases and/or confounding factors.
With respect to the meta-analysis of case control studies, we found no association of ever, past, or current smoking with CTS. It is possible that hospital-based controls have influenced the outcomes, as most of the included studies in this meta-analysis used hospital-based controls [11,[47][48][49]51,52]. Only one case control study used both populationand hospital-based control groups [54]. In particular, there was a higher proportion of current smokers among hospital controls (29%) than population-based controls (19%).
Hospital-based controls are likely to have other latent or undiagnosed diseases. Many studies have shown that the prevalence of CTS is significantly higher, for example, among patients with postmastectomy lymphedema or chronic hemodialysis than among the general population [63][64][65][66]. Using hospital patients as a control group may underestimate the true association between smoking and CTS.
The studies included in the current meta-analysis had some limitations. Smoking was assessed subjectively, rather than objectively, which makes it prone to recall bias. Study participants may underreport their tobacco consumption [67]. Another possible explanation for underreporting is that smoking tends to be a habitual and almost unconscious habit [68]. Some of the included studies did not control their estimates for the known risk factors of CTS. The observed association in cross-sectional studies can partly be due to confounding factors. Furthermore, most of the included studies did not collect data on the number of cigarettes smoked per day, number of years spent smoking, and duration of smoking cessation. Thus, we were not able to explore a dose-response relationship between smoking and CTS.

Conclusions
In this meta-analysis, we found no association between smoking and CTS in the metaanalyses of case control and cohort studies. Smoking was associated with CTS only in a meta-analysis of cross-sectional studies. However, limiting the meta-analysis to higher quality cross-sectional studies did not support an association between smoking and CTS. It is likely that the association between smoking and CTS observed in cross-sectional studies is not a true association.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Table A1. Quality assessment.

Selection bias
Sampling method of the study population, representativeness, response rate, difference between responders and non-responders, investigation, and control of variables, in case of difference between responders and non-responders Weak: Target population defined as representative of the general population or subgroup of the general population (specific age group, women, men, specific geographic area, and specific occupational group), and response rate is above 80%.
Moderate: Target population defined as somewhat representative of the general population, a restricted subgroup of the general population, response rate 60-79%. Strong: Target population defined as "self-referred"/volunteers, response rate less than 60%.