Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis

Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis Fan He, Chenglin tang, Fuyu Yang, Defei Chen, junjie Xiong, yu Zou, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3888064/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Apr, 2024 Read the published version in World Journal of Surgical Oncology → Version 1 posted 10 You are reading this latest preprint version Abstract Background Temporary ileostomy (TI) has proven effective in reducing the severity of anastomotic leakage after rectal cancer surgery; however, some ileostomies fail to reverse over time, leading to conversion into a permanent stoma (PS). In this study, we aimed to investigate the preoperative risk factors and cumulative incidence of TI non-closure after sphincter-preserving surgery for rectal cancer. Materials and Methods We conducted a meta-analysis after searching the Embase, Web of Science, PubMed, and MEDLINE databases from their inception until November 2023. We collected all published studies on the risk factors related to TI non-closure after sphincter-preserving surgery for rectal cancer. Results A total of 1610 studies were retrieved, and 13 studies were included for meta-analysis, comprising 3026 patients. The results of the meta-analysis showed that the identified risk factors included older age (p = 0.03), especially > 65 years of age (p = 0.03), male sex (p = 0.009), American Society of Anesthesiologists score ≥ 3 (p = 0.004), comorbidity (p = 0.001), and distant metastasis (p < 0.001). Body mass index, preoperative hemoglobin, preoperative albumin, preoperative carcinoma embryonic antigen, tumor location, neoadjuvant chemoradiotherapy, smoking, history of abdominal surgery, and open surgery did not significantly change the risk of TI non-closure Conclusion We identified five preoperative risk factors for TI non-closure after sphincter-preserving surgery for rectal cancer. This information enables surgeons to identify high-risk groups before surgery, inform patients about the possibility of PS in advance, and consider performing protective colostomy or Hartmann surgery. Temporary ileostomy Risk factors Rectal cancer Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 INTRODUCTION Anastomotic leak (AL) is the most serious complication following rectal cancer surgery, with an incidence of 3%-20%. 1–3 Among these cases, 10%-35% require reoperation, 4 and approximately 2% of patients die after AL. 5 Moreover, AL may increase the risk of local tumor recurrence after rectal cancer surgery. 6,7 Protective temporary ileostomy (TI) is the simplest and most effective treatment to reduce the severity of AL. 8,9 Fecal diversion can significantly reduce the incidence of AL, shorten hospital stay, and reduce the rate of emergency reoperation. Simultaneously, should AL occur, the associated peritonitis symptoms and systemic inflammatory response are markedly reduced. 9,10 Therefore, many surgeons routinely incorporate TI into sphincter-preserving surgery for rectal cancer. However, an ileostomy is associated with specific complications such as parastomal hernia, intestinal obstrcutions, periostomy dermatitis, high-output dehydration, acute renal impairment, and electrolyte balance disturbance. 11,12 In addition, several studies 13–16 have shown that 6–23% of TI will not be reversed due to tumor recurrence, anastomosis-related complications, and poor anal function recovery, resulting in the formation of a permanent stoma (PS). This outcome is closely related to preoperative clinical decision-making. In contrast, studies 17 have shown that ileostomy should be the procedure of choice for short-term temporary stoma, but colostomy is more suitable for patients who need long-term or permanent stoma. In patients with ileostomy, electrolyte disturbance and chronic renal impairment due to high output dehydration and peristomy dermatitis are significantly higher than colostomy, which significantly affects quality of life (QoL) in patients with persistent stoma status. 18–20 Therefore, early identification of high-risk patients unable to reverse TI is crucial for preoperative consultation and surgical planning, with colostomy or Hartmann surgery offering potential benefits for long-term prognosis. While several studies have explored the causes of TI non-closure, systematic and comprehensive assessments of preoperative risk factors and cumulative incidence of TI non-closure following rectal cancer surgery are still lacking. The objective of this study was to explore the preoperative risk factors and cumulative incidence of TI non-closure and conversion to PS after sphincter-preserving surgery for rectal cancer, utilizing a systematic review and meta-analysis. METHODS This systematic review and meta-analysis adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA, Supplementary Digital Content 1.) 21 and Assessing the Methodological Quality of Systematic Reviews (AMSTAR). 22 Additionally, it was registered with the International Center for Prospective Systems Review (PROSPERO: CRD42023476511). Search strategy and selection criteria Comprehensive searches were conducted on Web of Science, Embase, PubMed, and MEDLINE databases for articles published in English while simultaneously viewing the references of papers. The search strategy included the following keywords: "ileostomy," "permanent stoma," "non-closure", "nonreversal," "no closure," and "rectal cancer" (Supplementary Table 1). The search covered the period from the inception of the database to November 2023, as well as the language was limited to English. All identified literature was imported into Endnote 20 software for screening. Selection criteria Inclusion criteria: ( 1 ) study design: prospective or retrospective cohort study; ( 2 ) study participants: patients with rectal cancer who underwent sphincter-preserving surgery for rectal cancer and TI; and ( 3 ) study content: exploration of preoperative risk factors for TI non-closure after rectal cancer surgery. Exclusion criteria: ( 1 ) letters, meetings, comments, trial protocols, and articles that were not available in full text; ( 2 ) studies that did not provide raw data; and ( 3 ) studies with higher quality and more detailed data selected for studies with repeated cases. Study selection and data extraction The pulled studies were imported into Endnote20 software for initial screening by reviewing the title and abstract. The remaining study underwent a second screening by reviewing the full text to determine the studies that were included in the meta-analysis. All steps were conducted by two authors, and in cases of disagreement, a third author was consulted. The following elements were extracted, ( 1 ) study characteristics: author, publication year, study area, study period, and study type, number of cases, sex ratio, grouping method, and age. ( 2 ) risk factors: sex, age, body mass index (BMI), comorbidities, American Society of Anesthesiologists (ASA) score, smoking, tumor location, metastasis, surgical method, history of abdominal surgery, neoadjuvant chemotherapy (NCT) and neoadjuvant radiotherapy (NRT), preoperative hemoglobin (Hb), preoperative albumin (Alb), and preoperative carcinoma embryonic antigen (CEA). In cases of a lack of information, we made efforts to contact the author by email or phone. Quality assessment The Newcastle-Ottawa Scale (NOS) was used to evaluate retrospective cohort studies and assess the risk of bias of each study in the following three areas: patient representation, exposure and outcome determination, and adequacy of follow up. The total NOS score ranges from 0 to 9, and studies with scores ≥ 7 are considered high-quality studies, those with scores 4–6 are considered moderate-quality studies, and those with scores ≤ 3 are considered low-quality studies. Quality evaluation was carried out by two authors, and differences were resolved through discussion. Statistical analysis RevMan 5.3 statistical software provided by the Cochrane Collaboration was used to perform the meta-analysis. Data are reported as the combined weighted mean difference (WMD) for continuous variables and odds ratio (OR) for categorical variables. If the data in the original study were not represented as mean and standard deviation (SD), conversion to mean or SD was performed before meta-analysis. 23,24 All effect sizes were expressed as 95% confidence interval (CI). I² was used to analyze the heterogeneity of the studies. A funnel plot was used to determine whether bias existed in the results. If there was publication bias or other biases, a sensitivity analysis of the results was performed to determine whether the results were stable and reliable. RESULTS Selection of the included studies A total of 1605 studies in English were initially retrieved, and five additional studies were supplemented from other sources. After deduplication using Endnote20 software, 719 studies remained. Titles and abstracts were reviewed, and studies not meeting the inclusion criteria were excluded, leaving 62. After a full-text review, 13 studies 25–37 were included in the meta-analysis (Fig. 1 ). The included studies were retrospective cohort studies, encompassing 3026 patients, with 459 (15.17%) experiencing TI non-closure, subsequently converted to PS after surgery. Study characteristics and quality evaluation The baseline characteristics and quality evaluations are shown in Table 1 . The score for each article included in this study ranged between 7 and 9, indicating sufficient study quality (Fig. 2 ). The meta-analysis results for risk factors are presented in Table 2 . Table 1 Studies characteristics and quality Study Country Study design Period Patients C/NC Sex(male) C-NC Age(years) C-NC NOS grade Abe 2017 Japan Cohort study 2012–2015 25/91 84 NA 8 Barenboim 2022 Germany Cohort study 2000–2018 25/211 12/88 65 (34–83)/62 (33–82) 9 Chiu 2014 Canada Cohort study 2006–2012 24/138 19/100 66 ± 11/61.7 ± 11.11 7 Eray 2019 Turkey Cohort study 2015–2018 12/54 10/40 61.67 ± 12.0/58.1 ± 10.9 7 Kim 2015 Korea Cohort study 2004–2011 23/112 15/76 66 ± 11/61 ± 10 9 Kim 2016 Korea Cohort study 2001–2008 64/609 49/390 58.5 ± 11.2/59.7 ± 10.0 8 Lee 2015 Korea Cohort study 2000–2009 28/203 16/138 more than 65 year (21/139) 7 Li 2014 China Cohort study 2014–2017 58/220 46/147 74.5 ± 5.02/73.79 ± 4.60 7 Liu 2021 China Cohort study 2012–2019 34/232 NA NA 8 Zhu 2022 China Cohort study 2013–2019 52/368 38/250 62.2 ± 7.8/64.6 ± 9.6 8 Pan 2016 China Cohort study 2006–2013 51/245 31/145 59(33–77)/59(22–87) 8 Wang 2016 China Cohort study 2008–2018 51/230 33/152 more than 65 year (33/179) 8 Zeman 2020 Poland Cohort study 2008–2018 38/63 30/37 61.98 ± 10.6/61.61 ± 10.81 9 Zhang 2022 China Cohort study 2011–2019 26/159 20/92 62(32–81)/59(25–81) 8 C: Closure; NC: Non-Closure; NOS: Newcastle-Ottawa Scale; NA: Not Available Table 2 Outcomes of meta analysis Risk factors No. of studies No. of Patients Heterogeneity Statistical model statistical method Effect estimate [95%CI] P I 2 P Patient-related factors Age (years) 9 2131 0% 0.69 Fixed-effects WMD 1.21[0.10, 2.31] 0.03* Age (≥ 65 years old) 6 1256 40% 0.14 Fixed-effects OR 1.40[1.03, 1.91] 0.03* Sex (male) 11 2644 13% 0.32 Fixed-effects OR 1.37[1.08, 1.73] 0.009* BMI (kg/m²) 6 1438 0% 0.87 Fixed-effects WMD -0.11[-0.67, 0.44] 0.69 Smoking 2 954 0% 0.56 Fixed-effects OR 1.21[0.10, 2.31] 0.10 Comorbidity 4 1271 0% 0.64 Fixed-effects OR 1.73[1.24, 2.40] 0.001* ASA score ≥ 3 10 2543 57% 0.01 Random-effects OR 2.13[1.27, 3.55] 0.004* Tumor-related factors Location (≤ 5 cm) 5 1598 0% 0.55 Fixed-effects OR 1.22 [0.90, 1.65] 0.20 Location (cm) 3 1094 0% 0.52 Fixed-effects WMD -0.45[-0.95, 0.67] 0.09 Metastasis 6 1157 50% 0.07 Random-effects OR 5.94[3.10,11.39] < 0.001* Preoperative Hb (g/dL) 2 463 0% 0.99 Fixed-effects WMD -0.61 [-1.56, 0.33] 0.20 Preoperative Alb (g/dL) 2 463 0% 0.47 Fixed-effects WMD -1.21[-5.95, 3.54] 0.62 CEA (ng/ml) 2 251 25% 0.25 Fixed-effects WMD 1.44[-15.17, 18.05] 0.87 Treatment-related factors NRT 9 2477 23% 0.24 Fixed-effects OR 1.07 [0.82, 1.41] 0.21 NCT 5 996 0% 0.60 Fixed-effects OR 0.76 [0.50, 1.16] 0.20 History of abdominal surgery 6 1732 34% 0.18 Fixed-effects OR 1.24 [0.87, 1.76] 0.23 Open surgery 5 1018 66% 0.02 Random-effects OR 2.26[1.09, 4.67] 0.03* Incidence of TI non-closure 13 3026 61% 0.002 Random-effects RD 0.16[0.13, 0.19] < 0.001* CI: Confidence interval; WMD: Weighted mean difference; OR: Odds ratio; BMI: Body mass index; ASA: American Society of Anesthesiologists; Hb: hemoglobin; Alb: albumin; CEA: Carcinoma embryonic antigen; NRT: Neoadjuvant radiotherapy; NCT: Neoadjuvant chemotherapy; TI: Temporary ileostomy. Data analysis Patient-related factors Age: Strong evidence from nine studies 26–30,32,34,36,37 explored the association between age and TI non-closure after rectal cancer surgery. The meta-analysis suggested that older patients were at greater risk for TI non-closure (WMD = 1.21, 95% CI: 0.10 to 2.31, p = 0.03, I²=0%). Moreover, meta-analysis results of six studies 27,32,34–37 revealed that patients > 65 years had a 40% increase in the risk of TI non-closure (OR = 1.40, 95%CI: 1.04 to 1.91, p = 0.03, I²=40%) (Fig. 3 ). Sex: Strong evidence from 11 studies 26–32,34−37 explored the association between sex and TI non-closure after rectal cancer surgery. The meta-analysis indicated that male sex was associated with a greater risk for TI non-closure (OR = 1.37, 95%CI: 1.08 to 1.73, p = 0.009, I²=13%) (Fig. 3 ). BMI: Moderate evidence from six studies 28–30,32,36,37 analyzed the association between BMI and TI non-closure after rectal cancer surgery. The pooled analysis indicated no association between BMI and the risk of TI non-closure (WMD=-0.11, 95%CI: -0.67 to 0.44, p = 0.69, I²=0%) (Fig. 3 ). Smoking: Moderate evidence from two studies 29,35 analyzed the relationship between smoking and TI non-closure after rectal cancer resection. There was no association between smoking and the risk of TI non-closure (OR = 1.40, 95%CI: 0.94 to 2.09, p = 0.10, I²=0%) (Fig. 4 ). Comorbidity: Moderate evidence from four studies 29,30,32,37 explored the association between comorbidities and TI non-closure after rectal cancer surgery. The meta-analysis suggested that having comorbidity was associated with a 73% increase in the risk of TI non-closure (OR = 1.73, 95%CI: 1.24 to 2.40, p = 0.001, I²=0%) (Fig. 4 ). ASA score: Strong evidence from ten studies 26–32,34,35,37 explored the association between ASA scores and TI non-closure after rectal cancer surgery. The meta-analysis found that an ASA score ≥ 3 was associated with more than two-fold increased risk of TI non-closure (OR = 2.13, 95%CI: 1.27 to 3.55, p = 0.004, I²=57%) (Fig. 4 ). After sensitivity analysis, when we excluded the study of Li et al 32 , the heterogeneity was markedly reduced (p = 0.80, I²=0%) (Supplementary Table 2). However, the results of the factor did not change; therefore, it was included in the meta-analysis, and the random-effects model was combined to verify the reliability of the results. Tumor-related factors Location: Moderate evidence from five studies 29–32,35 explored the relationship between tumor location and TI non-closure after rectal cancer surgery. The meta-analysis found no association between tumor location from anus < 5 cm and the risk of TI non-closure (OR = 1.22, 95%CI: 0.90 to 1.65, p = 0.20, I²=0%). Moreover, a pooled analysis of three studies 26,29,37 found that tumor location was not associated with the risk of TI non-closure. (WMD=-0.45, 95%CI: -0.90 to 0.07, p = 0.09, I²=40%) (Fig. 5 ). Metastasis: Strong evidence from six studies 28,30,32,34–36 explored the association between distant metastasis and TI non-closure after rectal cancer surgery. The pooled analysis showed that distant metastasis was associated with a nearly six-fold increased risk of TI non-closure (OR = 5.94, 95%CI: 3.10 to 11.39, p < 0.001, I²=50%) (Fig. 5 ). After sensitivity analysis, when the studies by Kim et al 30 and Li et al 32 were excluded, heterogeneity significantly reduced (p = 0.43, I²=0%) (Supplementary Table 2). However, the results of the factor did not change; therefore, it was included in the meta-analysis, and the random-effects model was combined to verify the reliability of the results. Laboratory test: Moderate evidence from two studies analyzed the association between preoperative levels of Hb 32,37 , Alb 32,37 , and CEA 28,37 and the risk of TI non-closure. No evidence was found to alter the risk of TI non-closure after rectal cancer surgery. (WMD= -0.61, p = 0.20; WMD= -1.21, p = 0.62; WMD = 1.44, p = 0.87) (Supplementary Fig. 1.). Treatment-related factors NCRT: Strong evidence from five 26,28,29,32,35 and nine 26,27,29–32,34,35,37 studies explored the relationship between NCT and NRT and the risk of TI non-closure, respectively. The meta-analysis did not find evidence that NCT or NRT increased the risk of TI non-closure after surgery (OR = 0.76, 95%CI: 0.50 to 1.16, p = 0.20, I²=0%; OR = 1.07, 95%CI: 0.82 to 1.41, p = 0.23, I²=34%) (Fig. 6 ). History of abdominal surgery: Strong evidence from six studies 27,29,30,34,35,37 explored the association between a history of abdominal surgery and TI non-closure after rectal cancer surgery. The pooled analysis indicated no association between a history of abdominal surgery and the risk of TI non-closure (OR = 1.24, 95%CI: 0.87 to 1.76, p = 0.23, I²=34%) (Fig. 6 ). Open surgery: Moderate evidence from five studies 27,28,31,32,35 explored the association between open surgery and TI non-closure after rectal cancer surgery. The meta-analysis found that open surgery was associated with a greater risk for TI non-closure (OR = 2.26, 95%CI: 1.09 to 4.67, p = 0.03, I²=67%). However, after excluding the study by Li et al 32 in sensitivity analysis, the heterogeneity was significantly reduced (p = 0.87, I²=0%) (Supplementary Table 2), and the results changed. This change may be attributed to the fact that their study included more patients who underwent emergency surgery for obstruction or perforation, which tended to be open surgeries and resulted in serious infection-related complications. The probability of PS also tended to increase. Therefore, the study by Li et al 32 was excluded from this meta-analysis, and the final result showed that open surgery did not significantly increase the risk of TI non-closure after rectal cancer surgery (OR = 1.56, 95%CI; 0.96 to 2.52, p = 0.07, I²=0%) (Fig. 6 ). Incidence of ileostomy non-closure Strong evidence from thirteen studies 25–37 has reported the occurrence of TI non-closure after rectal cancer surgery. The results of the meta-analysis showed that the incidence of TI non-closure was 16% (95%CI: 13–19%, I²=61%) (Fig. 7 ). Publication bias A funnel plot of male sex was used to identify any evidence of publication bias. The two sides of the funnel plot were approximately symmetrical, suggesting that there was no evidence of publication bias in this study (Fig. 8 ). The funnel plots of the other factors are presented in Supplementary Figs. 2–12. Sensitivity analysis The meta-analysis indicated obvious heterogeneity in several risk factors, including ASA score (I²=57%, p = 0.01), distant metastasis (I²=50%, p = 0.07), and open surgery (I²=66%, p = 0.02). Sensitivity analysis excluded the study by Li et al. on open surgery, which markedly reduced the heterogeneity among studies and changed the results of the meta-analysis. Therefore, we excluded the studies by Li et al. from the final results for open surgery. Sensitivity analysis results for other factors did not show obvious changes in heterogeneity or the results of meta-analysis; therefore, the corresponding studies were not excluded. DISCUSSION Currently, protective ileostomy is the most widely used procedure for reducing AL after rectal cancer surgery. The decision to perform protective ileostomy is influenced by factors such as tumor location, neoadjuvant therapy, and the general condition of the patient. 38 However, approximately 6–23% of patients with TI never experience closure, significantly impacting their quality of life. Early identification of high-risk groups for TI non-closure is important to guide preoperative decision-making. We conducted a meta-analysis of 13 studies with available data to identify risk factors for TI non-closure and conversion to PS after rectal cancer surgery. Five risk factors for TI non-closure were identified, namely, older age (> 65 years old), male sex, ASA score ≥ 3, comorbidity, and distant metastasis. BMI, preoperative Hb level, preoperative Alb level, preoperative CEA level, tumor location, NCRT, smoking, history of abdominal surgery, and open surgery did not significantly alter the risk. In addition, the incidence of TI non-closure after rectal cancer surgery was 16% (95%CI: 13–19%). Patient-related factors These results indicate that the risk of TI non-closure increases with age. In particular, patients aged > 65 years had a 40% increased risk of TI non-closure, which is consistent with past research. 14,16 On one hand, this may be due to elderly patients having more underlying diseases and being weakened after primary surgery, leading to reluctance to undergo ileostomy closure surgery again. On the other hand, elderly patients are more prone to developing AL, anastomotic stenosis (AS), fecal incontinence, pelvic septicemia, and other complications after rectal cancer surgery 39,40 . It is foreseeable that these complications significantly increase the risk of TI non-closure. In addition, elderly patients have lower QoL requirements, and some are accustomed to the lifestyle of a stoma and unwilling to pay for ileostomy closure surgery. In terms of sex, we found that male patients were at a greater risk for TI non-closure. Several studies 41,42 have shown that male patients are at a higher risk of developing rectal AL and AS after rectal cancer surgery. Since AL is a primary risk factor for TI non-closure, this may explain the higher risk observed in male patients. In addition, we found that patients with comorbidities and ASA scores ≥ 3 showed a significantly increased risk of TI non-closure. Comorbidities influenced anesthesia risk, post-operative complications, and post-operative weakness in patients undergoing surgery. 43 Severe post-operative complications can lead to malnutrition, hypoproteinemia, anemia, and other diseases, reducing the possibility of a second surgery. Moreover, serious complications such as pelvic septicemia, chronic infection of the pelvic cavity, and prolonged wounds can lead to cachexia in patients. These complications have long-term and far-reaching impact on patients and increase their fear of reoperation, 44,45 which is the main reason for patients avoiding ileostomy closure surgery. Tumor-related factors Our results showed that the distance of the tumor from the anus was not a risk factor for TI non-closure after surgery. However, most studies included in this meta-analysis distinguished between low rectal cancer ( 5 cm). Whether sphincter-preserving surgery for ultra-low rectal cancer (< 3 cm) increases the risk of TI non-closure requires further exploration. However, in patients with preoperative distant metastasis, the risk of TI non-closure was nearly six times greater than that in patients without metastasis, which is similar to the findings of most past studies. 46–48 Clinically, patients with distant metastatic rectal cancer have a worse prognosis, higher risk of post-operative recurrence, and shorter life expectancy, and some patients are more likely to develop mechanical ileus due to secondary abdominal malignancies, all of which are risks affecting TI closure. In addition, patients with distant metastasis tend to have longer chemotherapy cycles; TI closure surgery delays chemotherapy and may lead to ileostomy-related renal impairment and water and electrolyte balance disturbances, reducing chemotherapy tolerance. Therefore, we strongly recommend protective colostomy or Hartmann's surgery for patients with distant metastasis. Other reported risk factors for TI non-closure include preoperative nutritional status, preoperative fibrinogen concentration, and socioeconomic status. However, owing to the lack of relevant studies and data, this meta-analysis could not be further analyzed. Zeman et al. 36 suggested that a high plasma fibrinogen concentration before surgery may be an independent risk factor for TI non-closure. They found that plasma fibrinogen accelerated tumor progression and increased the risk of post-operative infection, AL, and other inflammatory reactions, which were the reasons for its influence on TI closure. Zafar et al. 49 showed that stoma closure was correlated with race, insurance type, and income status. They found that white patients had higher rates of closure than black patients, privately insured patients had higher rates of reversal than uninsured patients, and household income among those in the top quartile had higher rates of reversal than those in the bottom quartile. Future studies should provide a more comprehensive preoperative assessment of these risk factors. Incidence of TI non-closure The meta-analysis results revealed that the incidence of TI non-closure after sphincter-preserving surgery for rectal cancer is approximately 16%; that is, approximately 1 out of 6 people experience TI non-closure and convert to PS. The main reason for the difference in the rate of TI non-closure in the existing studies is the different definitions of ileostomy non-closure. However, most TIs are performed within 6 months of the operation, and if TI closure is not achieved after 1 year, it is defined as TI non-closure. Therefore, preoperative imaging staging should be strengthened in patients with rectal cancer to determine the presence of distant metastases, and a careful anesthesia risk assessment should be carried out. For high-risk groups with TI non-closure, early identification of high-risk factors can lead to better treatment decisions, making it more beneficial for patients to undergo protective colostomy or Hartman surgery after sphincter-preserving surgery. This approach is more suitable for PS than ileostomy. However, it is important to consider that this choice preserves the patient's expectations of restoring a stoma. In summary, patients benefit most from assessing the risk of PS before surgery and developing a personalized surgical strategy for each patient. Limitations This study had few limitations. First, all 13 studies included in the meta-analysis were retrospective; however, they were of medium to high quality based on the quality evaluation. Second, the studies included a wide range of populations, ethnicities, and study methods, reflecting high heterogeneity, especially in the definition of TI non-closure. Nevertheless, the observed heterogenicity may be attributed to the evaluated population or study design rather than actual differences. For risk factors with high heterogeneity, we used a random-effects model to verify the reliability of the results. In addition, owing to the strict inclusion criteria, fewer articles were included in the meta-analysis, and some risk factors could not be pooled due to differences in reporting forms. This may have impacted the comprehensiveness of the study results in assessing the risk factors for TI non-closure. However, the existing meta-analysis results still hold guiding significance for developing a personalized surgical strategy for each patient with rectal cancer. CONCLUSION We conducted a meta-analysis of 13 studies worldwide, revealing that older age, male sex, ASA score ≥ 3, comorbidity, and distant metastasis were preoperative risk factors for TI non-closure after rectal cancer surgery. The current incidence of TI non-closure and conversion to PS was 16% (95%CI, 13–19%). These findings enable surgeons to better identify high-risk individuals before surgery, inform patients about the possibility of PS, and develop personalized surgical strategies to minimize the incidence of permanent ileostomy by selecting protective colostomy or Hartmann surgery. In the future, large and rigorously designed randomized controlled trials are warranted to further explore more comprehensive preoperative risk factors, including ultra-low rectal cancer and surgical methods, as well as further verify the reliability of the results of this study. Declarations Ethical approval Not applicable Sources of funding Not available Authors’ contributions F.H.: Study design and idea; drafting the manuscript and figure; processing the date. C.T.: date acquisition and analysis, reviewing the manuscript. F.Y.: Drafting the figure. D.C.: Reviewing the manuscript. J.X.: Date acquisition and analysis. Y.Z.: Reviewing the manuscript. D.Z.: Reviewing the manuscript. K.Q.: Study conception and design, reviewing the manuscript. All authors conduce to the manuscript revision and approved the submitted version. Conflict of interest disclosure The authors declare that they have no conflict of interest. Research registration unique identifying number The name of the registry: RROSPERO; Research Registration Unique Identifying Number. (UIN): CRD42023476511. Data statement All data generated or analyzed during this study are included in this published article. No additional unpublished data are available. References Borstlap WAA, Westerduin E, Aukema TS, Bemelman WA, Tanis PJ. Anastomotic Leakage and Chronic Presacral Sinus Formation After Low Anterior Resection: Results From a Large Cross-sectional Study. Ann Surg. Nov 2017;266(5):870–877. Du CZ, Fan ZH, Yang YF, Yuan P, Gu J. 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Nov 2020;25(11):1960–1968. Zeman M, Czarnecki M, Chmielarz A, Idasiak A, Grajek M, Czarniecka A. Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients. World J Surg Oncol. Aug 14 2020;18(1):207. Zhang B, Zhuo GZ, Zhao K, et al. Cumulative Incidence and Risk Factors of Permanent Stoma After Intersphincteric Resection for Ultralow Rectal Cancer. Dis Colon Rectum. Jan 1 2022;65(1):66–75. Balla A, Saraceno F, Rullo M, et al. Protective ileostomy creation after anterior resection of the rectum: Shared decision-making or still subjective? Colorectal Dis. Apr 2023;25(4):647–659. Manceau G, Karoui M, Werner A, Mortensen NJ, Hannoun L. Comparative outcomes of rectal cancer surgery between elderly and non-elderly patients: a systematic review. Lancet Oncol. Dec 2012;13(12):e525-536. Paun BC, Cassie S, MacLean AR, Dixon E, Buie WD. Postoperative complications following surgery for rectal cancer. Ann Surg. May 2010;251(5):807–818. Lipska MA, Bissett IP, Parry BR, Merrie AE. Anastomotic leakage after lower gastrointestinal anastomosis: men are at a higher risk. ANZ J Surg. Jul 2006;76(7):579–585. He F, Yang F, Chen D, et al. Risk factors for anastomotic stenosis after radical resection of rectal cancer: A systematic review and meta-analysis. Asian J Surg. Sep 11 2023. Loogman L, de Nes LCF, Heil TC, et al. The Association Between Modifiable Lifestyle Factors and Postoperative Complications of Elective Surgery in Patients With Colorectal Cancer. Dis Colon Rectum. Nov 1 2021;64(11):1342–1353. Brown SR, Mathew R, Keding A, Marshall HC, Brown JM, Jayne DG. The impact of postoperative complications on long-term quality of life after curative colorectal cancer surgery. Ann Surg. May 2014;259(5):916–923. González N, Loroño A, Aguirre U, et al. Risk scores to predict mortality 2 and 5 years after surgery for colorectal cancer in elderly patients. World J Surg Oncol. Aug 26 2021;19(1):252. Zhou X, Wang B, Li F, Wang J, Fu W. Risk Factors Associated With Nonclosure of Defunctioning Stomas After Sphincter-Preserving Low Anterior Resection of Rectal Cancer: A Meta-Analysis. Dis Colon Rectum. May 2017;60(5):544–554. Holmgren K, Kverneng Hultberg D, Haapamäki MM, Matthiessen P, Rutegård J, Rutegård M. High stoma prevalence and stoma reversal complications following anterior resection for rectal cancer: a population-based multicentre study. Colorectal Dis. Dec 2017;19(12):1067–1075. Lindgren R, Hallböök O, Rutegård J, Sjödahl R, Matthiessen P. What is the risk for a permanent stoma after low anterior resection of the rectum for cancer? A six-year follow-up of a multicenter trial. Dis Colon Rectum. Jan 2011;54(1):41–47. Zafar SN, Changoor NR, Williams K, et al. Race and socioeconomic disparities in national stoma reversal rates. Am J Surg. Apr 2016;211(4):710–715. Additional Declarations No competing interests reported. Supplementary Files Supplementalmaterials.docx SuppmentaryDigitalcontent1..docx Cite Share Download PDF Status: Published Journal Publication published 12 Apr, 2024 Read the published version in World Journal of Surgical Oncology → Version 1 posted Editorial decision: Revision requested 27 Feb, 2024 Reviews received at journal 27 Feb, 2024 Reviews received at journal 19 Feb, 2024 Reviewers agreed at journal 13 Feb, 2024 Reviewers agreed at journal 31 Jan, 2024 Reviewers agreed at journal 31 Jan, 2024 Reviewers invited by journal 31 Jan, 2024 Editor assigned by journal 30 Jan, 2024 Submission checks completed at journal 23 Jan, 2024 First submitted to journal 22 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3888064","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":268908281,"identity":"046ffedc-58d9-4ae3-995b-a4ff4cae5415","order_by":0,"name":"Fan He","email":"","orcid":"","institution":"First Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"He","suffix":""},{"id":268908282,"identity":"d6f22978-b558-4555-83df-e6aadfca95e2","order_by":1,"name":"Chenglin tang","email":"","orcid":"","institution":"First Affiliated Hospital of Chongqing Medical 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2","display":"","copyAsset":false,"role":"figure","size":283227,"visible":true,"origin":"","legend":"\u003cp\u003eRisk or bias graph.\u003c/p\u003e","description":"","filename":"Figure200.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/4511e2316478a8ed05682a98.png"},{"id":50227701,"identity":"f8d5c93e-f91d-4ed1-bffc-015dcf83bcc3","added_by":"auto","created_at":"2024-01-26 18:33:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":584117,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot detailing the association of patient- related factors with ileostomy non-closure after rectal cancer resection. (A) age\u0026gt; 65 years old; (B) age; (C)sex (male); (D) BMI.\u003c/p\u003e","description":"","filename":"Figure300.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/8135138a448a631d32bc3680.png"},{"id":50227403,"identity":"30b08c7d-bbda-4c0e-a50b-24976f102e08","added_by":"auto","created_at":"2024-01-26 18:25:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":361385,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot detailing the association of patient- related factors with ileostomy non-closure after rectal cancer rescetion. (A) smoking; (B) comorbidity; (C)ASA score≥3.\u003c/p\u003e","description":"","filename":"Figure400.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/2e460ab38180270de19e204c.png"},{"id":50227700,"identity":"5c781c3c-6aef-4b57-8e14-62f85a30f9d6","added_by":"auto","created_at":"2024-01-26 18:33:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":337760,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot detailing the association of tumor- related factors with ileostomy non-closure after rectal cancer rescetion. (A) tumor location distance \u0026lt;5cm from anus; (B) tumor location distance from anus; (C)metastasis.\u003c/p\u003e","description":"","filename":"Figure500.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/0473543b0a1889d1ecaf682c.png"},{"id":50227702,"identity":"1187b6c8-8847-4474-83ca-19e46cf775dd","added_by":"auto","created_at":"2024-01-26 18:33:39","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":519561,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot detailing the association of treatment- related factors with ileostomy non-closure after rectal cancer rescetion. (A) preoperative Hb; (B) preoperative Alb; (C) preoperative CEA.\u003c/p\u003e","description":"","filename":"Figure600.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/4c1751aaa8535bf14345aa67.png"},{"id":50227703,"identity":"673e5d67-6ede-4c95-ab97-6b54666340bd","added_by":"auto","created_at":"2024-01-26 18:33:39","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":205365,"visible":true,"origin":"","legend":"\u003cp\u003eMeta-analysis of pooled data on the incidence of AS.\u003c/p\u003e","description":"","filename":"Figure700.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/14971237f1f04f41add15c39.png"},{"id":50227406,"identity":"42afd69e-68e6-482a-b344-1442e378904d","added_by":"auto","created_at":"2024-01-26 18:25:38","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":64237,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot of the male sex.\u003c/p\u003e","description":"","filename":"Figure800.png","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/31845b20330cec1ab3d0845c.png"},{"id":54712823,"identity":"d11b5c5e-3d70-49b9-b78b-1eed1adbe175","added_by":"auto","created_at":"2024-04-15 15:13:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2348424,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/d48c1a08-45b5-4c83-964a-efdddfd53463.pdf"},{"id":50227408,"identity":"f59f0dd0-a787-42a5-ad24-236f70f29b4e","added_by":"auto","created_at":"2024-01-26 18:25:39","extension":"docx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":847219,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalmaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/818fc2177c0d1444a046552a.docx"},{"id":50227410,"identity":"2e93ba2e-f9fe-420a-88dc-db99385793e5","added_by":"auto","created_at":"2024-01-26 18:25:39","extension":"docx","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":26802,"visible":true,"origin":"","legend":"","description":"","filename":"SuppmentaryDigitalcontent1..docx","url":"https://assets-eu.researchsquare.com/files/rs-3888064/v1/b87ea821f9308081107beb8c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eAnastomotic leak (AL) is the most serious complication following rectal cancer surgery, with an incidence of 3%-20%.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e Among these cases, 10%-35% require reoperation,\u003csup\u003e4\u003c/sup\u003e and approximately 2% of patients die after AL.\u003csup\u003e5\u003c/sup\u003e Moreover, AL may increase the risk of local tumor recurrence after rectal cancer surgery.\u003csup\u003e6,7\u003c/sup\u003e Protective temporary ileostomy (TI) is the simplest and most effective treatment to reduce the severity of AL.\u003csup\u003e8,9\u003c/sup\u003e Fecal diversion can significantly reduce the incidence of AL, shorten hospital stay, and reduce the rate of emergency reoperation. Simultaneously, should AL occur, the associated peritonitis symptoms and systemic inflammatory response are markedly reduced.\u003csup\u003e9,10\u003c/sup\u003e Therefore, many surgeons routinely incorporate TI into sphincter-preserving surgery for rectal cancer.\u003c/p\u003e \u003cp\u003eHowever, an ileostomy is associated with specific complications such as parastomal hernia, intestinal obstrcutions, periostomy dermatitis, high-output dehydration, acute renal impairment, and electrolyte balance disturbance.\u003csup\u003e11,12\u003c/sup\u003e In addition, several studies\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e have shown that 6\u0026ndash;23% of TI will not be reversed due to tumor recurrence, anastomosis-related complications, and poor anal function recovery, resulting in the formation of a permanent stoma (PS). This outcome is closely related to preoperative clinical decision-making. In contrast, studies\u003csup\u003e17\u003c/sup\u003e have shown that ileostomy should be the procedure of choice for short-term temporary stoma, but colostomy is more suitable for patients who need long-term or permanent stoma. In patients with ileostomy, electrolyte disturbance and chronic renal impairment due to high output dehydration and peristomy dermatitis are significantly higher than colostomy, which significantly affects quality of life (QoL) in patients with persistent stoma status.\u003csup\u003e18\u0026ndash;20\u003c/sup\u003e Therefore, early identification of high-risk patients unable to reverse TI is crucial for preoperative consultation and surgical planning, with colostomy or Hartmann surgery offering potential benefits for long-term prognosis. While several studies have explored the causes of TI non-closure, systematic and comprehensive assessments of preoperative risk factors and cumulative incidence of TI non-closure following rectal cancer surgery are still lacking.\u003c/p\u003e \u003cp\u003eThe objective of this study was to explore the preoperative risk factors and cumulative incidence of TI non-closure and conversion to PS after sphincter-preserving surgery for rectal cancer, utilizing a systematic review and meta-analysis.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis systematic review and meta-analysis adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA, Supplementary Digital Content 1.)\u003csup\u003e21\u003c/sup\u003e and Assessing the Methodological Quality of Systematic Reviews (AMSTAR).\u003csup\u003e22\u003c/sup\u003e Additionally, it was registered with the International Center for Prospective Systems Review (PROSPERO: CRD42023476511).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy and selection criteria\u003c/h2\u003e \u003cp\u003eComprehensive searches were conducted on Web of Science, Embase, PubMed, and MEDLINE databases for articles published in English while simultaneously viewing the references of papers. The search strategy included the following keywords: \"ileostomy,\" \"permanent stoma,\" \"non-closure\", \"nonreversal,\" \"no closure,\" and \"rectal cancer\" (Supplementary Table\u0026nbsp;1). The search covered the period from the inception of the database to November 2023, as well as the language was limited to English. All identified literature was imported into Endnote 20 software for screening.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSelection criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) study design: prospective or retrospective cohort study; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) study participants: patients with rectal cancer who underwent sphincter-preserving surgery for rectal cancer and TI; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) study content: exploration of preoperative risk factors for TI non-closure after rectal cancer surgery.\u003c/p\u003e \u003cp\u003eExclusion criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) letters, meetings, comments, trial protocols, and articles that were not available in full text; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) studies that did not provide raw data; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) studies with higher quality and more detailed data selected for studies with repeated cases.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and data extraction\u003c/h2\u003e \u003cp\u003eThe pulled studies were imported into Endnote20 software for initial screening by reviewing the title and abstract. The remaining study underwent a second screening by reviewing the full text to determine the studies that were included in the meta-analysis. All steps were conducted by two authors, and in cases of disagreement, a third author was consulted. The following elements were extracted, (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) study characteristics: author, publication year, study area, study period, and study type, number of cases, sex ratio, grouping method, and age. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) risk factors: sex, age, body mass index (BMI), comorbidities, American Society of Anesthesiologists (ASA) score, smoking, tumor location, metastasis, surgical method, history of abdominal surgery, neoadjuvant chemotherapy (NCT) and neoadjuvant radiotherapy (NRT), preoperative hemoglobin (Hb), preoperative albumin (Alb), and preoperative carcinoma embryonic antigen (CEA). In cases of a lack of information, we made efforts to contact the author by email or phone.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eThe Newcastle-Ottawa Scale (NOS) was used to evaluate retrospective cohort studies and assess the risk of bias of each study in the following three areas: patient representation, exposure and outcome determination, and adequacy of follow up. The total NOS score ranges from 0 to 9, and studies with scores\u0026thinsp;\u0026ge;\u0026thinsp;7 are considered high-quality studies, those with scores 4\u0026ndash;6 are considered moderate-quality studies, and those with scores\u0026thinsp;\u0026le;\u0026thinsp;3 are considered low-quality studies. Quality evaluation was carried out by two authors, and differences were resolved through discussion.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eRevMan 5.3 statistical software provided by the Cochrane Collaboration was used to perform the meta-analysis. Data are reported as the combined weighted mean difference (WMD) for continuous variables and odds ratio (OR) for categorical variables. If the data in the original study were not represented as mean and standard deviation (SD), conversion to mean or SD was performed before meta-analysis.\u003csup\u003e23,24\u003c/sup\u003e All effect sizes were expressed as 95% confidence interval (CI). I\u0026sup2; was used to analyze the heterogeneity of the studies. A funnel plot was used to determine whether bias existed in the results. If there was publication bias or other biases, a sensitivity analysis of the results was performed to determine whether the results were stable and reliable.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSelection of the included studies\u003c/h2\u003e \u003cp\u003eA total of 1605 studies in English were initially retrieved, and five additional studies were supplemented from other sources. After deduplication using Endnote20 software, 719 studies remained. Titles and abstracts were reviewed, and studies not meeting the inclusion criteria were excluded, leaving 62. After a full-text review, 13 studies\u003csup\u003e25\u0026ndash;37\u003c/sup\u003e were included in the meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The included studies were retrospective cohort studies, encompassing 3026 patients, with 459 (15.17%) experiencing TI non-closure, subsequently converted to PS after surgery.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStudy characteristics and quality evaluation\u003c/h2\u003e \u003cp\u003eThe baseline characteristics and quality evaluations are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The score for each article included in this study ranged between 7 and 9, indicating sufficient study quality (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The meta-analysis results for risk factors are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudies characteristics and quality\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePeriod\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003cp\u003eC/NC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSex(male)\u003c/p\u003e \u003cp\u003eC-NC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003cp\u003eC-NC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNOS grade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbe 2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2012\u0026ndash;2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25/91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarenboim 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2000\u0026ndash;2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25/211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12/88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e65 (34\u0026ndash;83)/62 (33\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChiu 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2006\u0026ndash;2012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24/138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19/100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;11/61.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEray 2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2015\u0026ndash;2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12/54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10/40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61.67\u0026thinsp;\u0026plusmn;\u0026thinsp;12.0/58.1\u0026thinsp;\u0026plusmn;\u0026thinsp;10.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKim 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2004\u0026ndash;2011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23/112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15/76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;11/61\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKim 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2001\u0026ndash;2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e64/609\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e49/390\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e58.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2/59.7\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLee 2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKorea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2000\u0026ndash;2009\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28/203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16/138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003emore than 65\u0026nbsp;year (21/139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2014\u0026ndash;2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58/220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46/147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e74.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.02/73.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiu 2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2012\u0026ndash;2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34/232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhu 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2013\u0026ndash;2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e52/368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e38/250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8/64.6\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePan 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2006\u0026ndash;2013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51/245\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31/145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59(33\u0026ndash;77)/59(22\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWang 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2008\u0026ndash;2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e51/230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33/152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003emore than 65\u0026nbsp;year (33/179)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZeman 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2008\u0026ndash;2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38/63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30/37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61.98\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6/61.61\u0026thinsp;\u0026plusmn;\u0026thinsp;10.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhang 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2011\u0026ndash;2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26/159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20/92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62(32\u0026ndash;81)/59(25\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eC: Closure; NC: Non-Closure; NOS: Newcastle-Ottawa Scale; NA: Not Available\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOutcomes of meta analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRisk factors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo. of studies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo. of Patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eStatistical model\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003estatistical method\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEffect estimate\u003c/p\u003e \u003cp\u003e[95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient-related factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.21[0.10, 2.31]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.03*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026ge;\u0026thinsp;65 years old)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.40[1.03, 1.91]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.03*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.37[1.08, 1.73]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.009*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u0026sup2;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1438\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.11[-0.67, 0.44]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e954\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.21[0.10, 2.31]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.73[1.24, 2.40]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASA score\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRandom-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.13[1.27, 3.55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.004*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor-related factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation (\u0026le;\u0026thinsp;5 cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1598\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.22 [0.90, 1.65]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocation (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1094\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.45[-0.95, 0.67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRandom-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.94[3.10,11.39]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative Hb (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.61 [-1.56, 0.33]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreoperative Alb (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e463\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-1.21[-5.95, 3.54]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCEA (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eWMD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.44[-15.17, 18.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-related factors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.07 [0.82, 1.41]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.76 [0.50, 1.16]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of abdominal surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1732\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFixed-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.24 [0.87, 1.76]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpen surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRandom-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.26[1.09, 4.67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.03*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncidence of TI non-closure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3026\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRandom-effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.16[0.13, 0.19]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eCI: Confidence interval; WMD: Weighted mean difference; OR: Odds ratio; BMI: Body mass index; ASA: American Society of Anesthesiologists; Hb: hemoglobin; Alb: albumin; CEA: Carcinoma embryonic antigen; NRT: Neoadjuvant radiotherapy; NCT: Neoadjuvant chemotherapy; TI: Temporary ileostomy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003ePatient-related factors\u003c/h2\u003e \u003cp\u003eAge: Strong evidence from nine studies\u003csup\u003e26\u0026ndash;30,32,34,36,37\u003c/sup\u003e explored the association between age and TI non-closure after rectal cancer surgery. The meta-analysis suggested that older patients were at greater risk for TI non-closure (WMD\u0026thinsp;=\u0026thinsp;1.21, 95% CI: 0.10 to 2.31, p\u0026thinsp;=\u0026thinsp;0.03, I\u0026sup2;=0%). Moreover, meta-analysis results of six studies\u003csup\u003e27,32,34\u0026ndash;37\u003c/sup\u003e revealed that patients\u0026thinsp;\u0026gt;\u0026thinsp;65 years had a 40% increase in the risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.40, 95%CI: 1.04 to 1.91, p\u0026thinsp;=\u0026thinsp;0.03, I\u0026sup2;=40%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSex: Strong evidence from 11 studies\u003csup\u003e26\u0026ndash;32,34\u0026minus;37\u003c/sup\u003e explored the association between sex and TI non-closure after rectal cancer surgery. The meta-analysis indicated that male sex was associated with a greater risk for TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.37, 95%CI: 1.08 to 1.73, p\u0026thinsp;=\u0026thinsp;0.009, I\u0026sup2;=13%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBMI: Moderate evidence from six studies\u003csup\u003e28\u0026ndash;30,32,36,37\u003c/sup\u003e analyzed the association between BMI and TI non-closure after rectal cancer surgery. The pooled analysis indicated no association between BMI and the risk of TI non-closure (WMD=-0.11, 95%CI: -0.67 to 0.44, p\u0026thinsp;=\u0026thinsp;0.69, I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSmoking: Moderate evidence from two studies\u003csup\u003e29,35\u003c/sup\u003e analyzed the relationship between smoking and TI non-closure after rectal cancer resection. There was no association between smoking and the risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.40, 95%CI: 0.94 to 2.09, p\u0026thinsp;=\u0026thinsp;0.10, I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eComorbidity: Moderate evidence from four studies\u003csup\u003e29,30,32,37\u003c/sup\u003e explored the association between comorbidities and TI non-closure after rectal cancer surgery. The meta-analysis suggested that having comorbidity was associated with a 73% increase in the risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.73, 95%CI: 1.24 to 2.40, p\u0026thinsp;=\u0026thinsp;0.001, I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eASA score: Strong evidence from ten studies\u003csup\u003e26\u0026ndash;32,34,35,37\u003c/sup\u003e explored the association between ASA scores and TI non-closure after rectal cancer surgery. The meta-analysis found that an ASA score\u0026thinsp;\u0026ge;\u0026thinsp;3 was associated with more than two-fold increased risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;2.13, 95%CI: 1.27 to 3.55, p\u0026thinsp;=\u0026thinsp;0.004, I\u0026sup2;=57%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). After sensitivity analysis, when we excluded the study of Li et al\u003csup\u003e32\u003c/sup\u003e, the heterogeneity was markedly reduced (p\u0026thinsp;=\u0026thinsp;0.80, I\u0026sup2;=0%) (Supplementary Table\u0026nbsp;2). However, the results of the factor did not change; therefore, it was included in the meta-analysis, and the random-effects model was combined to verify the reliability of the results.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTumor-related factors\u003c/h2\u003e \u003cp\u003eLocation: Moderate evidence from five studies\u003csup\u003e29\u0026ndash;32,35\u003c/sup\u003e explored the relationship between tumor location and TI non-closure after rectal cancer surgery. The meta-analysis found no association between tumor location from anus\u0026thinsp;\u0026lt;\u0026thinsp;5 cm and the risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.22, 95%CI: 0.90 to 1.65, p\u0026thinsp;=\u0026thinsp;0.20, I\u0026sup2;=0%). Moreover, a pooled analysis of three studies\u003csup\u003e26,29,37\u003c/sup\u003e found that tumor location was not associated with the risk of TI non-closure. (WMD=-0.45, 95%CI: -0.90 to 0.07, p\u0026thinsp;=\u0026thinsp;0.09, I\u0026sup2;=40%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMetastasis: Strong evidence from six studies\u003csup\u003e28,30,32,34\u0026ndash;36\u003c/sup\u003e explored the association between distant metastasis and TI non-closure after rectal cancer surgery. The pooled analysis showed that distant metastasis was associated with a nearly six-fold increased risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;5.94, 95%CI: 3.10 to 11.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I\u0026sup2;=50%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). After sensitivity analysis, when the studies by Kim et al\u003csup\u003e30\u003c/sup\u003e and Li et al\u003csup\u003e32\u003c/sup\u003e were excluded, heterogeneity significantly reduced (p\u0026thinsp;=\u0026thinsp;0.43, I\u0026sup2;=0%) (Supplementary Table\u0026nbsp;2). However, the results of the factor did not change; therefore, it was included in the meta-analysis, and the random-effects model was combined to verify the reliability of the results.\u003c/p\u003e \u003cp\u003eLaboratory test: Moderate evidence from two studies analyzed the association between preoperative levels of Hb\u003csup\u003e32,37\u003c/sup\u003e, Alb\u003csup\u003e32,37\u003c/sup\u003e, and CEA\u003csup\u003e28,37\u003c/sup\u003e and the risk of TI non-closure. No evidence was found to alter the risk of TI non-closure after rectal cancer surgery. (WMD= -0.61, p\u0026thinsp;=\u0026thinsp;0.20; WMD= -1.21, p\u0026thinsp;=\u0026thinsp;0.62; WMD\u0026thinsp;=\u0026thinsp;1.44, p\u0026thinsp;=\u0026thinsp;0.87) (Supplementary Fig.\u0026nbsp;1.).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTreatment-related factors\u003c/h2\u003e \u003cp\u003eNCRT: Strong evidence from five\u003csup\u003e26,28,29,32,35\u003c/sup\u003e and nine\u003csup\u003e26,27,29\u0026ndash;32,34,35,37\u003c/sup\u003e studies explored the relationship between NCT and NRT and the risk of TI non-closure, respectively. The meta-analysis did not find evidence that NCT or NRT increased the risk of TI non-closure after surgery (OR\u0026thinsp;=\u0026thinsp;0.76, 95%CI: 0.50 to 1.16, p\u0026thinsp;=\u0026thinsp;0.20, I\u0026sup2;=0%; OR\u0026thinsp;=\u0026thinsp;1.07, 95%CI: 0.82 to 1.41, p\u0026thinsp;=\u0026thinsp;0.23, I\u0026sup2;=34%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHistory of abdominal surgery: Strong evidence from six studies\u003csup\u003e27,29,30,34,35,37\u003c/sup\u003e explored the association between a history of abdominal surgery and TI non-closure after rectal cancer surgery. The pooled analysis indicated no association between a history of abdominal surgery and the risk of TI non-closure (OR\u0026thinsp;=\u0026thinsp;1.24, 95%CI: 0.87 to 1.76, p\u0026thinsp;=\u0026thinsp;0.23, I\u0026sup2;=34%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOpen surgery: Moderate evidence from five studies\u003csup\u003e27,28,31,32,35\u003c/sup\u003e explored the association between open surgery and TI non-closure after rectal cancer surgery. The meta-analysis found that open surgery was associated with a greater risk for TI non-closure (OR\u0026thinsp;=\u0026thinsp;2.26, 95%CI: 1.09 to 4.67, p\u0026thinsp;=\u0026thinsp;0.03, I\u0026sup2;=67%). However, after excluding the study by Li et al\u003csup\u003e32\u003c/sup\u003e in sensitivity analysis, the heterogeneity was significantly reduced (p\u0026thinsp;=\u0026thinsp;0.87, I\u0026sup2;=0%) (Supplementary Table\u0026nbsp;2), and the results changed. This change may be attributed to the fact that their study included more patients who underwent emergency surgery for obstruction or perforation, which tended to be open surgeries and resulted in serious infection-related complications. The probability of PS also tended to increase. Therefore, the study by Li et al\u003csup\u003e32\u003c/sup\u003e was excluded from this meta-analysis, and the final result showed that open surgery did not significantly increase the risk of TI non-closure after rectal cancer surgery (OR\u0026thinsp;=\u0026thinsp;1.56, 95%CI; 0.96 to 2.52, p\u0026thinsp;=\u0026thinsp;0.07, I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eIncidence of ileostomy non-closure\u003c/h2\u003e \u003cp\u003eStrong evidence from thirteen studies\u003csup\u003e25\u0026ndash;37\u003c/sup\u003e has reported the occurrence of TI non-closure after rectal cancer surgery. The results of the meta-analysis showed that the incidence of TI non-closure was 16% (95%CI: 13\u0026ndash;19%, I\u0026sup2;=61%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003ePublication bias\u003c/h2\u003e \u003cp\u003eA funnel plot of male sex was used to identify any evidence of publication bias. The two sides of the funnel plot were approximately symmetrical, suggesting that there was no evidence of publication bias in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e). The funnel plots of the other factors are presented in Supplementary Figs.\u0026nbsp;2\u0026ndash;12.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eThe meta-analysis indicated obvious heterogeneity in several risk factors, including ASA score (I\u0026sup2;=57%, p\u0026thinsp;=\u0026thinsp;0.01), distant metastasis (I\u0026sup2;=50%, p\u0026thinsp;=\u0026thinsp;0.07), and open surgery (I\u0026sup2;=66%, p\u0026thinsp;=\u0026thinsp;0.02). Sensitivity analysis excluded the study by Li et al. on open surgery, which markedly reduced the heterogeneity among studies and changed the results of the meta-analysis. Therefore, we excluded the studies by Li et al. from the final results for open surgery. Sensitivity analysis results for other factors did not show obvious changes in heterogeneity or the results of meta-analysis; therefore, the corresponding studies were not excluded.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCurrently, protective ileostomy is the most widely used procedure for reducing AL after rectal cancer surgery. The decision to perform protective ileostomy is influenced by factors such as tumor location, neoadjuvant therapy, and the general condition of the patient.\u003csup\u003e38\u003c/sup\u003e However, approximately 6\u0026ndash;23% of patients with TI never experience closure, significantly impacting their quality of life. Early identification of high-risk groups for TI non-closure is important to guide preoperative decision-making. We conducted a meta-analysis of 13 studies with available data to identify risk factors for TI non-closure and conversion to PS after rectal cancer surgery. Five risk factors for TI non-closure were identified, namely, older age (\u0026gt;\u0026thinsp;65 years old), male sex, ASA score\u0026thinsp;\u0026ge;\u0026thinsp;3, comorbidity, and distant metastasis. BMI, preoperative Hb level, preoperative Alb level, preoperative CEA level, tumor location, NCRT, smoking, history of abdominal surgery, and open surgery did not significantly alter the risk. In addition, the incidence of TI non-closure after rectal cancer surgery was 16% (95%CI: 13\u0026ndash;19%).\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003ePatient-related factors\u003c/h2\u003e \u003cp\u003eThese results indicate that the risk of TI non-closure increases with age. In particular, patients aged\u0026thinsp;\u0026gt;\u0026thinsp;65 years had a 40% increased risk of TI non-closure, which is consistent with past research.\u003csup\u003e14,16\u003c/sup\u003e On one hand, this may be due to elderly patients having more underlying diseases and being weakened after primary surgery, leading to reluctance to undergo ileostomy closure surgery again. On the other hand, elderly patients are more prone to developing AL, anastomotic stenosis (AS), fecal incontinence, pelvic septicemia, and other complications after rectal cancer surgery\u003csup\u003e39,40\u003c/sup\u003e. It is foreseeable that these complications significantly increase the risk of TI non-closure. In addition, elderly patients have lower QoL requirements, and some are accustomed to the lifestyle of a stoma and unwilling to pay for ileostomy closure surgery. In terms of sex, we found that male patients were at a greater risk for TI non-closure. Several studies\u003csup\u003e41,42\u003c/sup\u003e have shown that male patients are at a higher risk of developing rectal AL and AS after rectal cancer surgery. Since AL is a primary risk factor for TI non-closure, this may explain the higher risk observed in male patients.\u003c/p\u003e \u003cp\u003eIn addition, we found that patients with comorbidities and ASA scores\u0026thinsp;\u0026ge;\u0026thinsp;3 showed a significantly increased risk of TI non-closure. Comorbidities influenced anesthesia risk, post-operative complications, and post-operative weakness in patients undergoing surgery.\u003csup\u003e43\u003c/sup\u003e Severe post-operative complications can lead to malnutrition, hypoproteinemia, anemia, and other diseases, reducing the possibility of a second surgery. Moreover, serious complications such as pelvic septicemia, chronic infection of the pelvic cavity, and prolonged wounds can lead to cachexia in patients. These complications have long-term and far-reaching impact on patients and increase their fear of reoperation,\u003csup\u003e44,45\u003c/sup\u003e which is the main reason for patients avoiding ileostomy closure surgery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eTumor-related factors\u003c/h2\u003e \u003cp\u003eOur results showed that the distance of the tumor from the anus was not a risk factor for TI non-closure after surgery. However, most studies included in this meta-analysis distinguished between low rectal cancer (\u0026lt;\u0026thinsp;5 cm) and middle and high rectal cancers (\u0026gt;\u0026thinsp;5 cm). Whether sphincter-preserving surgery for ultra-low rectal cancer (\u0026lt;\u0026thinsp;3 cm) increases the risk of TI non-closure requires further exploration. However, in patients with preoperative distant metastasis, the risk of TI non-closure was nearly six times greater than that in patients without metastasis, which is similar to the findings of most past studies.\u003csup\u003e46\u0026ndash;48\u003c/sup\u003e Clinically, patients with distant metastatic rectal cancer have a worse prognosis, higher risk of post-operative recurrence, and shorter life expectancy, and some patients are more likely to develop mechanical ileus due to secondary abdominal malignancies, all of which are risks affecting TI closure. In addition, patients with distant metastasis tend to have longer chemotherapy cycles; TI closure surgery delays chemotherapy and may lead to ileostomy-related renal impairment and water and electrolyte balance disturbances, reducing chemotherapy tolerance. Therefore, we strongly recommend protective colostomy or Hartmann's surgery for patients with distant metastasis.\u003c/p\u003e \u003cp\u003eOther reported risk factors for TI non-closure include preoperative nutritional status, preoperative fibrinogen concentration, and socioeconomic status. However, owing to the lack of relevant studies and data, this meta-analysis could not be further analyzed. Zeman et al.\u003csup\u003e36\u003c/sup\u003e suggested that a high plasma fibrinogen concentration before surgery may be an independent risk factor for TI non-closure. They found that plasma fibrinogen accelerated tumor progression and increased the risk of post-operative infection, AL, and other inflammatory reactions, which were the reasons for its influence on TI closure. Zafar et al.\u003csup\u003e49\u003c/sup\u003e showed that stoma closure was correlated with race, insurance type, and income status. They found that white patients had higher rates of closure than black patients, privately insured patients had higher rates of reversal than uninsured patients, and household income among those in the top quartile had higher rates of reversal than those in the bottom quartile. Future studies should provide a more comprehensive preoperative assessment of these risk factors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eIncidence of TI non-closure\u003c/h2\u003e \u003cp\u003eThe meta-analysis results revealed that the incidence of TI non-closure after sphincter-preserving surgery for rectal cancer is approximately 16%; that is, approximately 1 out of 6 people experience TI non-closure and convert to PS. The main reason for the difference in the rate of TI non-closure in the existing studies is the different definitions of ileostomy non-closure. However, most TIs are performed within 6 months of the operation, and if TI closure is not achieved after 1 year, it is defined as TI non-closure.\u003c/p\u003e \u003cp\u003eTherefore, preoperative imaging staging should be strengthened in patients with rectal cancer to determine the presence of distant metastases, and a careful anesthesia risk assessment should be carried out. For high-risk groups with TI non-closure, early identification of high-risk factors can lead to better treatment decisions, making it more beneficial for patients to undergo protective colostomy or Hartman surgery after sphincter-preserving surgery. This approach is more suitable for PS than ileostomy. However, it is important to consider that this choice preserves the patient's expectations of restoring a stoma. In summary, patients benefit most from assessing the risk of PS before surgery and developing a personalized surgical strategy for each patient.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study had few limitations. First, all 13 studies included in the meta-analysis were retrospective; however, they were of medium to high quality based on the quality evaluation. Second, the studies included a wide range of populations, ethnicities, and study methods, reflecting high heterogeneity, especially in the definition of TI non-closure. Nevertheless, the observed heterogenicity may be attributed to the evaluated population or study design rather than actual differences. For risk factors with high heterogeneity, we used a random-effects model to verify the reliability of the results. In addition, owing to the strict inclusion criteria, fewer articles were included in the meta-analysis, and some risk factors could not be pooled due to differences in reporting forms. This may have impacted the comprehensiveness of the study results in assessing the risk factors for TI non-closure. However, the existing meta-analysis results still hold guiding significance for developing a personalized surgical strategy for each patient with rectal cancer.\u003c/p\u003e \u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eWe conducted a meta-analysis of 13 studies worldwide, revealing that older age, male sex, ASA score\u0026thinsp;\u0026ge;\u0026thinsp;3, comorbidity, and distant metastasis were preoperative risk factors for TI non-closure after rectal cancer surgery. The current incidence of TI non-closure and conversion to PS was 16% (95%CI, 13\u0026ndash;19%). These findings enable surgeons to better identify high-risk individuals before surgery, inform patients about the possibility of PS, and develop personalized surgical strategies to minimize the incidence of permanent ileostomy by selecting protective colostomy or Hartmann surgery. In the future, large and rigorously designed randomized controlled trials are warranted to further explore more comprehensive preoperative risk factors, including ultra-low rectal cancer and surgical methods, as well as further verify the reliability of the results of this study.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSources of funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF.H.: Study design and idea; drafting the manuscript and figure; processing the date. C.T.: date acquisition and analysis, reviewing the manuscript. F.Y.: Drafting the figure. D.C.: Reviewing the manuscript. J.X.: Date acquisition and analysis. Y.Z.: Reviewing the manuscript. D.Z.: Reviewing the manuscript. K.Q.: Study conception and design, reviewing the manuscript. All authors conduce to the manuscript revision and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch registration unique identifying number\u0026nbsp;\u003c/strong\u003eThe name of the registry: RROSPERO; Research Registration Unique Identifying Number. (UIN): CRD42023476511.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. No additional unpublished data are available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBorstlap WAA, Westerduin E, Aukema TS, Bemelman WA, Tanis PJ. 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Risk Factors Associated With Nonclosure of Defunctioning Stomas After Sphincter-Preserving Low Anterior Resection of Rectal Cancer: A Meta-Analysis. Dis Colon Rectum. May 2017;60(5):544\u0026ndash;554.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmgren K, Kverneng Hultberg D, Haapam\u0026auml;ki MM, Matthiessen P, Ruteg\u0026aring;rd J, Ruteg\u0026aring;rd M. High stoma prevalence and stoma reversal complications following anterior resection for rectal cancer: a population-based multicentre study. Colorectal Dis. Dec 2017;19(12):1067\u0026ndash;1075.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLindgren R, Hallb\u0026ouml;\u0026ouml;k O, Ruteg\u0026aring;rd J, Sj\u0026ouml;dahl R, Matthiessen P. What is the risk for a permanent stoma after low anterior resection of the rectum for cancer? A six-year follow-up of a multicenter trial. Dis Colon Rectum. 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Apr 2016;211(4):710\u0026ndash;715.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Temporary ileostomy, Risk factors, Rectal cancer, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-3888064/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3888064/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTemporary ileostomy (TI) has proven effective in reducing the severity of anastomotic leakage after rectal cancer surgery; however, some ileostomies fail to reverse over time, leading to conversion into a permanent stoma (PS). In this study, we aimed to investigate the preoperative risk factors and cumulative incidence of TI non-closure after sphincter-preserving surgery for rectal cancer.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eWe conducted a meta-analysis after searching the Embase, Web of Science, PubMed, and MEDLINE databases from their inception until November 2023. We collected all published studies on the risk factors related to TI non-closure after sphincter-preserving surgery for rectal cancer.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 1610 studies were retrieved, and 13 studies were included for meta-analysis, comprising 3026 patients. The results of the meta-analysis showed that the identified risk factors included older age (p\u0026thinsp;=\u0026thinsp;0.03), especially\u0026thinsp;\u0026gt;\u0026thinsp;65 years of age (p\u0026thinsp;=\u0026thinsp;0.03), male sex (p\u0026thinsp;=\u0026thinsp;0.009), American Society of Anesthesiologists score\u0026thinsp;\u0026ge;\u0026thinsp;3 (p\u0026thinsp;=\u0026thinsp;0.004), comorbidity (p\u0026thinsp;=\u0026thinsp;0.001), and distant metastasis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Body mass index, preoperative hemoglobin, preoperative albumin, preoperative carcinoma embryonic antigen, tumor location, neoadjuvant chemoradiotherapy, smoking, history of abdominal surgery, and open surgery did not significantly change the risk of TI non-closure\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe identified five preoperative risk factors for TI non-closure after sphincter-preserving surgery for rectal cancer. This information enables surgeons to identify high-risk groups before surgery, inform patients about the possibility of PS in advance, and consider performing protective colostomy or Hartmann surgery.\u003c/p\u003e","manuscriptTitle":"Preoperative risk factors and cumulative incidence of temporary ileostomy non-closure after sphincter-preserving surgery for rectal cancer: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-26 18:25:34","doi":"10.21203/rs.3.rs-3888064/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-02-28T04:00:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-28T03:25:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-20T02:09:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c5790b0e-3cf5-4768-8e23-7560e597551e","date":"2024-02-13T16:17:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9014dd7e-ae0c-4ad1-b662-ff493edb1d15","date":"2024-02-01T00:22:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5181cad5-3f53-4ae8-915d-f68b38808f11","date":"2024-01-31T18:11:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-31T17:45:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-30T15:55:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-24T00:35:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2024-01-22T13:33:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ff1f04d3-23bf-4650-83d1-8e7d7e693244","owner":[],"postedDate":"January 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-15T15:07:32+00:00","versionOfRecord":{"articleIdentity":"rs-3888064","link":"https://doi.org/10.1186/s12957-024-03363-z","journal":{"identity":"world-journal-of-surgical-oncology","isVorOnly":false,"title":"World Journal of Surgical Oncology"},"publishedOn":"2024-04-12 15:02:20","publishedOnDateReadable":"April 12th, 2024"},"versionCreatedAt":"2024-01-26 18:25:34","video":"","vorDoi":"10.1186/s12957-024-03363-z","vorDoiUrl":"https://doi.org/10.1186/s12957-024-03363-z","workflowStages":[]},"version":"v1","identity":"rs-3888064","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3888064","identity":"rs-3888064","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}