Is There a Relationship Between Smoking and Stricture Recurrence After the Urethroplasty? a Systematic Review and Meta-Analysis CURRENT STATUS: UNDER REVIEW

Some retrospective studies have noted that smoking is a possible risk factor for recurrence of restenosis after urethroplasty, but not all of them are consistent. Therefore a meta-analysis is needed. graft and stricture until Jan 30, 2020. The quality of included studies was assessed by Newcastle-Ottawa Scale (NOS) system. Hazard ratio (HR), odds ratio (OR), relative risk (RR) with 95% confidence interval (CI) were extracted or re-calculated from included studies. Meta-analysis was performed with Stata 15.0 based on univariate and multivariate data separately. Sensitivity analysis was performed to test stability of meta-analysis. I 2 was calculated to evaluate heterogeneity. Publication biases were assessed by egger’s and begg’s tests. Funnel plots of univariate analysis and multivariate analysis were also offered. The analysis results of two stages were consistent. 9 2279 pooled and the result


Abstract
Background Some retrospective studies have noted that smoking is a possible risk factor for recurrence of restenosis after urethroplasty, but not all of them are consistent. Therefore a meta-analysis is needed.

Method
Pubmed, Web of Science, Embase, Cochrane databases were searched with key words: "urethroplasty", "buccal mucosa graft urethroplasty", "oral mucosa graft urethroplasty", "excision and primary anastomosis urethroplasty", "urethral stricture recurrence" until Jan 30, 2020. The quality of included studies was assessed by Newcastle-Ottawa Scale (NOS) system. Hazard ratio (HR), odds ratio (OR), relative risk (RR) with 95% confidence interval (CI) were extracted or re-calculated from included studies. Meta-analysis was performed with Stata 15.0 based on univariate and multivariate data separately. Sensitivity analysis was performed to test stability of meta-analysis. I 2 was calculated to evaluate heterogeneity. Publication biases were assessed by egger's and begg's tests. Funnel plots of univariate analysis and multivariate analysis were also offered.

Results
12 studies with 3443 patients were involved into this meta-analysis. The analysis results of two stages were consistent. In the univariate meta-analysis stage, 9 studies with 2279 patients were pooled and the result indicated that smoking might promote stricture recurrence (RR=1.46, 95%CI: 1.11-1.93, P=0.008). In the multivariate meta-analysis stage, based on adjusted estimate, 7 studies with 2074 patients were pooled and the result indicated that smoking might promote stricture recurrence (RR=1.39, 95%CI: 1.04-1.85, P=0.026). There was no significant heterogeneity in both univariate and multivariate stage.

Conclusion
This meta-analysis of current evidence indicates that smoking may prompt stricture recurrence after the urethroplasty. Quitting smoking may be a good option for patients undergoing urethroplasty surgery.
3 Background When urologists deal with the urethral stricture patients by urethroplasty, one of the most worrying situations is the stricture recurrence. In order to find out the possible causes of postoperative stricture recurrence, many retrospective studies have been conducted, and many risk factors such as length of stricture [1][2][3], previous urethroplasty history [2,[4][5][6], direct visual internal urethrotomy (DVIU) history have been reported [2,3,7,8]. However, in addition to these risk factors that have a strong role in promoting stricture recurrence, there are still some risk factors that are relatively mild or need a long time for stricture promotion, which can only be described by a large sample size of clinical research.
In 2010, a study pointed out that tobacco consumption may lead to stricture recurrence after urethroplasty [9]. However, in many subsequent retrospective studies, whether in univariate analysis or multivariate analysis, the role of smoking in the stricture recurrence after the urethroplasty has not been uniformly described.
In this study, a meta-analysis based on the univariate and multivariate results was conducted to obtain a stable assessment of the relationship between smoking and stricture recurrence after the urethroplasty.

Literature search and inclusion criteria
This meta-analysis was carried out according to the principle of preferred reporting items for systematic reviews and meta-analysis (PRISMA). We searched Pubmed, Embase, Web of Science and Cochrane Library to identify relevant studies. The latest search date was February 1, 2020. The searching key words included urethroplasty, smoking, smoker, tobacco consumption and stricture recurrence. Furthermore, reference part of every candidate literature was manually screened to find possible data source.
Detailed inclusion criteria were as follows: Patients were treated with onlay with buccal mucosa or penile fasciocutaneous flap or oral mucosa or any other type of substitution urethroplasty, anastomotic urethroplasty or any combined urethroplasty techniques for anterior or posterior urethral strictures. Odds ratio (OR), hazard ratio (HR) with 95% confidence interval (CI) of risk factors should be offered. Exclusion criteria were complied as follow: Reviews, meta-analysis, letters, comments, case serials and conference abstract were excluded. Studies didn't contain regression information or enough data which could be used for secondary analysis were excluded.

Research Quality Evaluation
All included studies were evaluated by Newcastle-Ottawa Scale (NOS) system and the evaluation procedure was performed by two independent reviewers. According to the NOS, 7-9 score studies were thought as high-level quality, 5-6 score studies were thought as moderate-level and < 5 score studies were low-level quality. Low-level quality studies shouldn't be involved in the meta-analysis.

Meta-analysis
In this study, based on univariate and multivariate analysis results, the relationship between smoking and stricture recurrence was pooled in meta-analysis. All analysis was powered by Stata 15.0 software (Stata corporation, College Station TX, USA). Statistical significance was defined as P < 0.05 in this study. Pooled estimate larger than 1 indicated that smoking would make patients more vulnerable to stricture recurrence. Heterogeneity was evaluated by I 2 . When I 2 was larger than 50%, heterogeneity could be significant. If significant heterogeneity was detected, random effect model should be applied. To identity the potential factors which contributed to heterogeneity, metaregression analysis was performed. Subgroup analysis based on meta-regression was also performed to get detailed information. Furthermore, sensitivity analysis was performed to test stability of metaanalysis results and publication-bias was tested by Egger's and Begg's tests. Funnel plots were used for publication-bias visual identification.

Univariate analysis
In terms of univariate analysis, there are 9 studies containing 2279 patients exploring the association between smoking and stricture recurrence after urethroplasty. According to the overall meta-analysis result, smoking can make patients more vulnerable to stricture recurrence (RR = 1.46, 95%CI: 1.11-1.93, P = 0.008) with no significant heterogeneity found (I2 = 28.6%, p = 0.190) (Fig. 2). No significant publication bias was found according to the Egger's test (t = 0.92, P = 0.389) and Begg's test (z = 0.00, P = 1.00) and was showed in funnel plot (Fig. 3). Sensitivity analysis showed that the results were not significantly changed by eliminating the study one by one (Fig. 4).

Multivariate analysis
Based on multivariate analysis, the the association between smoking and stricture recurrence after urethroplasty was explored in 7 studies containing 2074 studies. According to the overall metaanalysis result, smoking can make patients more vulnerable to stricture recurrence (RR = 1.39, 95%CI: 1.04-1.85, P = 0.026) with no significant heterogeneity found (I2 = 27.5%, p = 0.290) (Fig. 5).

Discussion
Urethral stricture is a kind of pathological stricture of urethra, which can limit fluid transportation.
Since the male urethra is significantly longer than the female urethra, and the posterior urethra is hidden in the pelvis, urethral stricture can always bring many troubles to patients and urologists.
Urethral stricture is a common urinary disease for the male. There are 229-627 cases in every 100000 people, and in some susceptible groups, such as elderly men, the prevalence rate is as high as 0.6% [18]. As one of the main methods to treat urethral stricture, there are many ways to implement urethroplasty, including primary anastomosis and substitution implantation. However, although many different surgical methods have been developed for different stricture degree, length and location, the total success rate is still only 72% − 94% [11,14,16]. Therefore, it is very important to find out the risk factors of recurrence of urethral stricture after urethroplasty and to prevent them.
Some risk factors such as the length of stricture and etiology have attracted the attention of urologists, but other factors such as tobacco consumption has not been evaluated carefully [1,3,8,19] This meta-analysis revealed that tobacco consumption can make the chance of stricture recurrence significantly increased based on both univariate and multivariate analysis. In the multivariate analysis stage, the sensitivity analysis result was not exactly stable, this indicated that more multivariate analysis studies and adjusted estimate between smoking and stricture recurrence were required.
There are many proven relationships between smoking and urinary diseases. Smoking can promote the development of bladder cancer, which has been proved by many studies [20,21]. The possible reasons why smoking is an independent risk factor for bladder cancer are various and some studies mentioned that the substances produced by tobacco burning, when metabolized into urine, will have a great influence on the DNA of bladder urothelial cells, which will lead to cell death and local inflammation [22]. This procedure may also be implied on urothelial cells. Persistent local inflammation in the epithelium of the urethra at the site of urethroplasty, caused by irritation of substances in the urine, may lead to recurrence of urethral stricture. Furthermore, for patients who receive oral mucosa graft Urethroplasty (OMGU), smoking history will make the general state of oral mucosa worse, leading to poor graft survival after OMGU operation, and ultimately leading to the increase of stenosis recurrence rate [9,23].
In many current urological guidelines, the effect of smoking on the stricture recurrence after urethroplasty is not mentioned [24]. According to the results of this meta-analysis, urologists should guide urethroplasty patients to quit smoking before and after the operation to improve the overall success rate of the operation.
Some potential limitations of this study should be presented. First, although there were some prospective data involved, all the included studies are retrospective studies. Second, although it was recognized in statistical methodology [25,26], it is still possible to bring some additional bias by combining HR and OR to get RR estimates. Third, since smoking can directly damage oral mucosa, so OMGU patients with smoking history may have higher recurrence ratio, however, in this meta-

Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate
All analyses were based on previous published studies. Thus  Forest plot of crude estimate meta-analysis between smoking and stricture recurrence.    Forest plot of adjusted estimate meta-analysis between smoking and stricture recurrence.