Persistent HPV infection after conization of cervical intraepithelial neoplasia—— a systematic review and meta-analysis

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Methods PubMed, EMBASE and Cochrane library were retrieved from January 1, 1998 to September 10, 2021. Random-effects models for meta-analyses was used and pooled relative risks with 95% confidence intervals was reported. Literature screening, data extraction and assessment of the risk of bias in the included studies were conducted independently by two researchers. Data-analysis was performed with Stata software, version 12.0. Results A total of 28 studies were enrolled finally in this study. Meta-analysis revealed that surgical margin and residual disease were correlated positively with the persistent HPV infection after conization. Compared with patients infected with other types of HPV, CIN patients with HPV 16 have higher persistent infection rate (OR = 1.967, 95% CI (1.232–3.140), P < 0.05). Conclusions CIN patients with postmenopausal, surgical margin and residual lesions positive, and HPV 16 are prone to persistent HPV infection after conization. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Human papillomavirus (HPV) is one amongst the foremost common sexually transmitted viruses among young women around the world 1 . Although the most HPV infections are transient and cleared in a couple of years when exposure, 10–20% of HPV infections are latent and persistent 3 . Persistent insecure HPV infection is related powerfully and systematically to high-grade cervical intraepithelial neoplasia (CIN), which is taken into account necessary for the progression of cervical precancerous lesions to cervical cancer (CC) 2 . Cervical conization is a widely used method for the diagnosis and treatment of CIN now 4 . Unfortunately, a relatively high incidence of recurrence after conization, especially in the patients with high-risk human papillomavirus (HR-HPV) 5 – 7 . Surgical margin, CIN grade, surgical method, endocervical gland involvement (EGI), age, parity and immunological dysfunction are the potential factors affecting the persistence and/or recurrence of CIN 8 . Therefore, assessing these factors that contribute to persistent HR HPV infection after cervical conization may help identify women at higher risk of disease recurrence. Here, we tend to performed a systematic review and meta-analysis to explore the implication of personal history (e.g., menopausal, marriage, smoking status) and clinical factors (e.g., surgical margin, endocervical gland involvement, CIN types, etc.) related to persistent HPV infection after conization of CIN. Methods Search Strategy and Selection Criteria PubMed, EMBASE, and Cochrane library were retrieved from January 1, 1998 to September 10, 2021. The domains of the search terms were HPV (human papillomavirus), CIN (cervical intraepithelial neoplasia), conization, loop excision. We combined conization and loop excision with the boolean operator “OR”, and the result was combined with the other terms with “AND”. It was eligible if the study has reported the main results of our interests, which was the persistent HPV infection after conization of CIN. We excluded those studies that did not mention HPV infection before conization or if those articles met any of the subsequent conditions: comments, case reports, reviews, conference records, and communications (Fig. 1 ). Data Extraction All studies were reviewed and evaluated critically by 2 researchers, independently. All information was extracted independently in duplicate manner by 2 researchers. Data extraction included study characteristics (author, year, study period) and information on personal history (e.g., patient age, menopausal status, marriage status, smoking status) and clinical factors (e.g., surgical margin, endocervical gland involvement, CIN types, residual disease, cervical invasive carcinoma, the type of HPV.) related to infection and/or persistent infection of HPV. Statistical Analyses Odds ratio with 95% confidence intervals (CIs) were calculated. The inconsistency index ( I 2 ) and Q statistics were measured. The heterogeneity between studies was assessed by Cochran Q ( P 50%) tests. The random effects model was accustomed calculate the pooled effect, and a bilateral P value < 0.05 was considered statistically significant. Perform a sensitivity analysis by removing one study at a time from the meta-analysis then assessing its impact on the combined results. We have a tendency to use Begg’s and Egger’s tests to spot whether or not there was publication bias. The funnel plot wasn't used for publication bias as a result of quite ten studies were needed for such analysis. All analyses were carried on using Stata, version 12.0. Patient Involvement None, because study was based on published literature. Results Study selection 202 papers were deleted when the initial titles and abstracts screening among the total 432 retrieved papers. Another 144 papers excluded after reviewed fully. A total 28 papers were finally enrolled in systematic review and meta-analysis. The features of the 28 papers were illustrated in Table 1 . The number of patients ranged from 31 to 1734 in this selected 28 papers. The recruitment of patients came from two types of research, 12 prospective studies and 16 retrospective studies. The Personal History Of Patients Associated With Persistent Hpv Infection Yung-TaekOuh et al 9 , Derya Kilic et al 10 , Rosario Lara-Peñaranda et al 11 , Kyeong A So et al 12 , Eralp Baser et al 13 , and Jeong-Yeol Park et al 14 reported the menopausal status in CIN patients after surgery with HPV persistence compared to without HPV persistence. Moderate heterogeneity was found in the six articles ( I 2 = 61.9%). A random-effect model was adopted during this analysis. The comprehensive analysis found that persistent HPV infection when conization was influenced by menopausal status. Postmenopausal status was positively correlative with the persistent HR-HPV infection (OR = 2.098, 95% CI: 1.156 to 3.809, P = 0.015) (Fig. 2 A). Yung-Taek Ouh et al 9 , Kyeong A So et al 12 , and Jeong-Yeol Park et al 14 reported the marriage status in CIN patients after surgery with HPV persistence compared to without HPV persistence. Low heterogeneity was found in the 3 researches ( I 2 = 49%). The comprehensive analysis found that persistent HPV infection after conization or LEEP was not obvious correlation with marriage status (OR = 0.972, 95% CI: 0.566 to 1.670, P = 0.919) (Fig. 2 B). We identified 3 eligible studies 10 , 15 , 16 including 431 CIN patients after surgery to investigate smoking correlate to persistent HPV positive. Our meta-analysis showed that smoking has no effect on persistent HPV positive (OR = 1.268; 95% CI: 0.78 to 2.062, P = 0.339, Fig. 2 C). Low heterogeneity was found in the three researches ( I 2 = 0%). The Clinical Factors Associated With Persistent Hpv Infection We identified 13 eligible studies 9,10,12–14,16−23 reported the type of CIN in patients after surgery with HPV persistence compared to without HPV persistence. According to the literature, we divide CIN types into CIN2 and CIN3 to meta-analysis. Our meta-analysis showed that the type of CIN (CIN2 or CIN3) has no effect on persistent HPV infection (OR = 1.383; 95% CI : 0.972 to 1.967, P = 0.072, Fig. 3 A). Low heterogeneity was found in the 13 researches ( I 2 = 38.9%). We identified 6 eligible studies 9 , 10 , 13 , 15 , 24 , 25 reported surgical margin in patients after surgery with HPV persistence compared to without HPV persistence. Our meta-analysis revealed that surgical margin was positively correlated with the persistent HPV infection (OR = 1.309; 95% CI : 1.068 to 1.603, P = 0.009, Fig. 3 B). Moderate heterogeneity was found in the 6 researches ( I 2 = 0%). We identified 5 eligible studies 26 – 30 reported residual disease in patients after surgery with persistent HPV infection compared to without persistent HPV infection. In those researches, they identified the residual lesions through examinations included liquid-based cytology test (LCT), HPV test, and colposcopy. Our meta-analysis revealed that residual disease was positively correlated with the persistent HPV infection (OR = 20.102; 95% CI: 7.485 to 53.987, P = 0.000, Fig. 3 C). Moderate heterogeneity was found in the five researches ( I 2 = 66.7%). We identified 3 eligible studies 9 , 11 , 31 reported endocervical gland involvement (EGI) in patients after surgery with HPV persistence compared to without HPV persistence. EGI mean that cervical biopsy involves glands. Our meta-analysis revealed that EGI has no effect on persistent HPV infection (OR = 1.700; 95% CI: 0.757 to 3.818, P = 0.198, Fig. 3 D). High heterogeneity was found in the three researches ( I 2 = 86.1%). The Type Of Hpv Correlated With Persistent Hpv Infection We identified 7 eligible studies 13,16,17,32−35 including 1790 CIN patients after surgery to investigate the relationship between HPV types and persistent HPV infection and non-persistent HPV infection. Our results revealed that there had positive effect in persistent HPV infection between HPV 16 and other types of HPV. (OR = 1.967; 95% CI: 1.232 to 3.140, P = 0.005, Fig. 4 A). Moderate heterogeneity was found in the 7 researches ( I 2 = 61.5%). We identified 5 eligible studies 13 , 16 , 17 , 34 , 35 including 1516 CIN patients after surgery to investigate the relationship between HPV types and persistent HPV infection and non-persistent HPV infection. Our results revealed that there had no effect in persistent HPV infection between HPV 18 and other types of HPV. (OR = 1.482; 95% CI: 0.826 to 2.661; P = 0.187, Fig. 4 B). Low heterogeneity was found in the 5 researches ( I 2 = 0%). Sensitivity Analysis In our analysis on the menopausal status in patients with persistent HPV infection, heterogeneity was discovered in the researches ( I 2 = 61.9%). Sensitivity analysis was used to eliminate individual studies by sequentially. The results indicated that there was one study (the 13th study) that contributed considerably to heterogeneity (Fig. 5 ). The pooled OR (OR = 2.553, 95% CI: 1.713 to 3.805, P = 0.000) of the remaining studies changed the final trend after withdrawing this study. In our sensitivity analysis, the quantity of patients in the 13th study less than others. In our analysis on the EGI with persistent HPV infection, heterogeneity was observed in the three researches ( I 2 = 86.1%). Sensitivity analysis was performed to eliminate individual studies by sequentially. The results indicated that no studies have made a significant contribution to heterogeneity. Moreover, the pooled OR of remaining studies have not changed the final trend. Publication Bias In the meta-analysis on the type of CIN in patients after surgery with persistent HPV infection have identified 13 eligible studies. No evidence of publication bias was found in our study through funnel plot, Egger’s test ( P > 0.05) and Begg’s test ( P > 0.05). Discussion Our research is the first meta-analysis investigating the factors correlated with the role of HPV status after CIN conization. It indicated that the menopausal status, surgical margin, residual disease and HPV 16 correlated positively with persistent HPV infection after conization, while the marriage, smoking, the type of CIN (CIN2 or CIN3), EGI, and HPV18 had no impact on the persistent HPV infection. Naouel Tifaoui et al 36 reported that follow-up of women with normal cytology and positive HPV showed a higher percentage of HPV persistence among menopausal women. HPV infections in young patients are mostly transient and corresponding symptoms are rarely seen. On the contrary, older people are prone to persistent infection and cervical cancer. The postmenopausal status woman, immunity declines with age, leading to a long time for virus clearance after HPV infection. Here, our study also revealed that menopausal status correlated positively with persistent HPV infection after conization. There is a study show that smoking is an important factor that increase the risk of HR-HPV persistency 37 . Smoking is an immunosuppressant and one of the significant factors leading to the development of cervical cancer 38 . However, our study revealed that smoking did not have any impact on persistent HPV infection after conization. Marriage may be related to sexual contact, contraception, childbirth and other factors that may affect HPV reinfection. However, our study shows that persistent HPV infection after conization or LEEP was not obvious correlation with marriage. We should refine other aspects about marriage, but there was not enough data. Surgical margin and residual disease showed the residual status of the cervix after surgery. The residual rate after surgery varies from studies, mainly thanks to the dearth of standardization of the conization operation and the totally different applied mathematics strategies used for analysis 30 . Nonetheless, our results showed that both surgical margins and residual disease were positively associated with persistent HPV infection. Studies have reported that the resection failure rate defined as persistent or recurrent CIN grade 2 or more severe (CIN2+) was 4–18%, and most cases were diagnosed 2 years after initial treatment 39 – 41 . So, we analysis the influence of CIN2 and CIN3 in patients with HPV persistence after conization. Unexpectedly, the type of CIN (CIN2 or CIN3) in patients after conization did not have any impact on persistent HPV infection. However, the relationship between the severity of cervical precancerous lesions and the ongoing risk was unclear, patients with inferior cervical lesions showed the higher infectious viral loads than that in CIN-3 patients 42 . Yung-Taek Ouh et al 9 found that the HPV persistence rate in CIN-2 patients after treatment was higher than that in CIN-3 patients, which was inconsistent with previous research reports 43 . EGI did not have any impact on persistent HPV infection. The standard treatment of CIN, especially high-grade lesions, was conization or LEEP 44 . Even if the lesion was utterly resected, these patients with high-grade lesions have a higher risk of recurrence compared to the general population 45 . Therefore, when patients had endocervical gland involvement, they usually choose further surgical treatment, such as hysterectomy. Maybe this is one of reason that EGI did not have any impact on persistent HPV infection after conization. HPV 16 or HPV 18 had a negative impact on the survival rate in patients with cervical cancer 46 . Our meta-analysis revealed that HPV 16, not HPV 18 have a positive impact on the persistent HPV infection compared to other types HPV after conization. In our included meta-analysis studies, there were a few patients who diagnosed as HPV18 before conization. Then, it wasn’t value to HPV18 persistence infected after conization for our study because the number of patients studied is too small. We also acknowledge that our meta-analysis has several limitations. Firstly, all the relevant factors analyzed were single factors, and there may be interactions between different factors. Therefore, in the future, it is expected that a larger sample size test will be used for further verification and correction. Secondly, the enclosed articles weren't randomized clinical trials (RCTs). Additionally, attributable to the inherent limitations of retrospective studies, more largescale irregular clinical trials are required to check and verify our results. Last but not least, these researches recruited a wide range of patients, from CIN I to CIN III and even carcinoma in situ, which may increase the heterogeneity of the meta-analysis. Nevertheless, our study lays the foundation for further understanding of the factors influencing persistent HPV infection after conization. Conclusion CIN patients with postmenopausal status, positive surgical margin and residual lesions, and HPV 16 are easier presence persistent HPV infection after conization. Declarations Ethics approval and consent to participate The study was approved by the institutional ethical committee of the Public Health Clinical Center of Chengdu, with informed consent waived due to the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials All data generated or analysed during this study are included in these published articles [and their supplementary information files]. Role of human papillomavirus status after conization for high‐grade cervical intraepithelial neoplasia Risk factors for type-specific persistence of high-risk human papillomavirus and residual/recurrent cervical intraepithelial neoplasia after surgical treatment Long‐term predictors of residual or recurrent cervical intraepithelial neoplasia 2–3 after treatment with a large loop excision of the transformation zone: a retrospective study Factors affecting residual/recurrent cervical intraepithelial neoplasia after cervical conization with negative margins Predictors of Human papillomavirus (HPV) persistence after treatment of high grade cervical lesions; does cervical cytology have any prognostic value in primary HPV screening? Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia Does the trend toward less deep excisions in LLETZ to minimize obstetric risk lead to less favorable oncological outcomes? Persistent HPV-16 infection leads to recurrence of high-grade cervical intraepithelial neoplasia The Value of Partial HPV Genotyping After Conization of Cervical Dysplasias Clearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia Age-related changes in pre- and post-conization HPV genotype distribution among women with high-grade cervical intraepithelial neoplasia A randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients Pre- and post-conization high-risk HPV testing predicts residual/recurrent disease in patients treated for CIN 2–3 Risk factors of persistent HPV infection after treatment for high ‑ grade squamous intraepithelial lesion Human papillomavirus genotyping predicts residual/recurrent disease after local treatment for cervical intraepithelial neoplasia better than viral DNA testing Human Papillomavirus Test After Conization in Predicting Residual Disease in Subsequent Hysterectomy Specimens Residual lesions in uterine specimens after loop electrosurgical excision procedure in patients with CIN Recurrent high-grade cervical lesion after primary conization is associated with persistent human papillomavirus infection in Norway Persistence of human papillomavirus DNA in cervical lesions after treatment with diathermic large loop excision Human papillomavirus infection in patients with residual or recurrent cervical intraepithelial neoplasia Does LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing? Risk factors for human papillomavirus persistence among women undergoing cold-knife conization for treatment of high-grade cervical intraepithelial neoplasia Progression of cervical intraepithelial neoplasia grade 2 lesions among Japanese women harboring different genotype categories of high-risk human papillomaviruses The association of pre-conization high-risk HPV load and the persistence of HPV infection and persistence/recurrence of cervical intraepithelial neoplasia after conization Factors associated with HPV persistence after treatment for high-grade cervical intra-epithelial neoplasia with large loop excision of the transformation zone (LLETZ) Human papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia Age, margin status, high-risk human papillomavirus and cytology independently predict recurrent high-grade cervical intraepithelial neoplasia up to 6 years after treatment Clinical Significance of the Interaction between Human Papillomavirus (HPV) Type 16 and Other High-Risk Human Papillomaviruses in Women with Cervical Intraepithelial Neoplasia (CIN) and Invasive Cervical Cancer Competing interests No conflict of interest. Funding Not applicable Authors' contributions Qingsong Liu and Yueyang Zhang designed the topic. Yueyang Zhang and Zhiwen Ni collected the data. Yueyang Zhang and Ting Wei analysed the data. Yueyang Zhang and Ting Wei prepared figures. Qingsong Liu , Yueyang Zhang and Zhiwen Ni wrote the main manuscript text. All authors reviewed the manuscript. Acknowledgements Not applicable. References Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. The Lancet . 2013;382(9895):889-899. doi: 10.1016/S0140-6736(13)60022-7 Koshiol J, Lindsay L, Pimenta JM, Poole C, Jenkins D, Smith JS. Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol . 2008;168(2):123-137. doi: 10.1093/aje/kwn036 Shanmugasundaram S, You J. Targeting persistent human papillomavirus infection. Viruses . 2017;9(8):229. doi: 10.3390/v9080229 Melnikow J, Mcgahan C, Sawaya GF, Ehlen T, Coldman A. 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Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. Br J Cancer . 2000;82(7):1332-1338. doi: 10.1054/bjoc.1999.1100 Arbyn M, Ronco G, Anttila A, et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine . 2012;30 Suppl 5: F88-F99. doi: 10.1016/j.vaccine.2012.06.095 Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol . 2011;12(5):441-450. doi: 10.1016/S1470-2045(11)70078-X Ren H, Jia M, Zhao S, Li H, Fan S. Factors correlated with the accuracy of colposcopy-directed biopsy: a systematic review and meta-analysis. J Invest Surg . 2020: 1-9. doi: 10.1080/08941939.2020.1850944 Sherman ME, Wang SS, Wheeler CM, et al. Determinants of human papillomavirus load among women with histological cervical intraepithelial neoplasia 3: dominant impact of surrounding low-grade lesions. Cancer Epidemiol Biomarkers Prev . 2003;12(10):1038-1044. Costa S, De Simone P, Venturoli S, et al. Factors predicting human papillomavirus clearance in cervical intraepithelial neoplasia lesions treated by conization. Gynecol Oncol . 2003;90(2):358-365. doi: 10.1016/s0090-8258(03)00268-3 Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol . 2013;121(4):829-846. doi: 10.1097/AOG.0b013e3182883a34 Melnikow J, Mcgahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the british columbia cohort study. J Natl Cancer Inst . 2009;101(10):721-728. doi: 10.1093/jnci/djp089 Pilch H, Gunzel S, Schaffer U, et al. The presence of hpv dna in cervical cancer: correlation with clinico-pathologic parameters and prognostic significance: 10 years experience at the department of obstetrics and gynecology of the mainz university. Int J Gynecol Cancer . 2001;11(1):39-48. doi: 10.1046/j.1525-1438.2001. 011001039. x Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table.1.xlsx Table 1. The basic characteristics description of included studies supplementary.doc Cite Share Download PDF Status: Published Journal Publication published 03 May, 2023 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Major revision 15 Feb, 2023 Reviews received at journal 02 Feb, 2023 Reviewers agreed at journal 31 Jan, 2023 Reviewers invited by journal 31 Jan, 2023 Editor assigned by journal 30 Jan, 2023 Editor invited by journal 23 Jan, 2023 Submission checks completed at journal 23 Jan, 2023 First submitted to journal 11 Nov, 2022 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-2265069","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":169993912,"identity":"6933b389-b128-4fa1-b482-35f9c59c4944","order_by":0,"name":"Yueyang Zhang","email":"","orcid":"","institution":"Public Health Clinical Center of Chengdu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yueyang","middleName":"","lastName":"Zhang","suffix":""},{"id":169993914,"identity":"3ea26f75-d874-40a9-9d2b-d60dc836c05f","order_by":1,"name":"Zhiwen Ni","email":"","orcid":"","institution":"Chengdu first people's hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhiwen","middleName":"","lastName":"Ni","suffix":""},{"id":169993916,"identity":"52d83a3c-89d7-4f0f-8da7-e1236000cefe","order_by":2,"name":"Ting Wei","email":"","orcid":"","institution":"Nanchong Central Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Wei","suffix":""},{"id":169993919,"identity":"3c349e2a-5121-4e0c-9f10-67f289ebf1bf","order_by":3,"name":"Qingsong Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBACefnzDx8k/vnHw0+0FsMZPMwGHxsOyEg2EK3nBg+b5MyGAzYGB4jVwTi795g07447PMbHkzcw/KjYRlgLu8y5ZGveM894zM48K2DsOXObCFsaEgxv87Ax85jdyDFgZmwjQgvDgQQDaZAW4xlEa7mRYyQ5s+0wj4EEsVoMe44lG3w4k8YjAfTLQaL8Is/efPBBQoWNPX978sYHPyqIcRgCJBAfNQgtpOoYBaNgFIyCEQIAyWdACojuHJIAAAAASUVORK5CYII=","orcid":"","institution":"Chengdu Women's and Children's Central Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Qingsong","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2022-11-12 04:29:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2265069/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2265069/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-023-02360-w","type":"published","date":"2023-05-03T20:42:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":32063413,"identity":"9ac9c1dc-bc5a-4af4-9b16-f6b6e445d3ef","added_by":"auto","created_at":"2023-01-25 22:57:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":62971,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of computerized search and the eligible studies included in this systematic review and meta-analysis\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/58879cb3bf91fa3f1389500a.jpg"},{"id":32064629,"identity":"fbc6ca68-6d1d-4c65-a385-e12eeccfbbd0","added_by":"auto","created_at":"2023-01-25 23:05:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":305888,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeta analysis of the personal history of patients associated with persistent HPV infection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: Menopausal status correlated with persistent HPV infection. B: Marriage status correlated with persistent HPV infection. C: Smoking correlated with persistent HPV infection.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/3743f81c5fef0284bbe33fb7.jpg"},{"id":32063414,"identity":"9b836112-b2d8-4ba5-8ecb-8e0a40f03495","added_by":"auto","created_at":"2023-01-25 22:57:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":382563,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeta analysis of the clinical factors associated with persistent HPV infection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: The type of CIN correlated with persistent HPV infection. B: Surgical margin correlated with persistent HPV infection. C: Residual disease correlated with persistent HPV infection. D: EGI correlated with persistent HPV infection.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/c217e8ca233440088540bead.jpg"},{"id":32063416,"identity":"da153766-2c27-4af2-aa7f-ad5a646dc491","added_by":"auto","created_at":"2023-01-25 22:57:30","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":251622,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeta analysis of the type of HPV correlated with persistent HPV infection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA: HPV16 correlated with persistent HPV infection. B: HPV18 correlated withpersistent HPV infection\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/146f010b16d6a177a15ccf5d.jpg"},{"id":32064630,"identity":"1fbaed73-1d3a-4c7b-bea0-96dcd097f8a9","added_by":"auto","created_at":"2023-01-25 23:05:30","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":43511,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSensitivity analysis for testing OR for the menopausal status.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/740cf409ab93d5015fbc05ed.jpg"},{"id":44728259,"identity":"e9aeb5ac-0d42-4c59-a229-370dee42d0bf","added_by":"auto","created_at":"2023-10-16 21:02:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":661601,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/6df48142-56e5-4fd6-ac1f-130ebcd4259d.pdf"},{"id":32063415,"identity":"fd50517d-aa26-47e9-80df-80ff235c2fbe","added_by":"auto","created_at":"2023-01-25 22:57:30","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12782,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. The basic characteristics description of included studies\u003c/p\u003e","description":"","filename":"table.1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/e12d3daed6bbdd4005f88d90.xlsx"},{"id":32063419,"identity":"728fcb2a-aebd-4955-88cd-9ce1ae4dbf59","added_by":"auto","created_at":"2023-01-25 22:57:31","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":5757486,"visible":true,"origin":"","legend":"","description":"","filename":"supplementary.doc","url":"https://assets-eu.researchsquare.com/files/rs-2265069/v1/46ad47915f1e249c75372d34.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Persistent HPV infection after conization of cervical intraepithelial neoplasia—— a systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eHuman papillomavirus (HPV) is one amongst the foremost common sexually transmitted viruses among young women around the world \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although the most HPV infections are transient and cleared in a couple of years when exposure, 10\u0026ndash;20% of HPV infections are latent and persistent \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Persistent insecure HPV infection is related powerfully and systematically to high-grade cervical intraepithelial neoplasia (CIN), which is taken into account necessary for the progression of cervical precancerous lesions to cervical cancer (CC) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCervical conization is a widely used method for the diagnosis and treatment of CIN now \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Unfortunately, a relatively high incidence of recurrence after conization, especially in the patients with high-risk human papillomavirus (HR-HPV) \u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Surgical margin, CIN grade, surgical method, endocervical gland involvement (EGI), age, parity and immunological dysfunction are the potential factors affecting the persistence and/or recurrence of CIN \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Therefore, assessing these factors that contribute to persistent HR HPV infection after cervical conization may help identify women at higher risk of disease recurrence. Here, we tend to performed a systematic review and meta-analysis to explore the implication of personal history (e.g., menopausal, marriage, smoking status) and clinical factors (e.g., surgical margin, endocervical gland involvement, CIN types, etc.) related to persistent HPV infection after conization of CIN.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eSearch Strategy and Selection Criteria\u003c/h2\u003e\u003cp\u003ePubMed, EMBASE, and Cochrane library were retrieved from January 1, 1998 to September 10, 2021. The domains of the search terms were HPV (human papillomavirus), CIN (cervical intraepithelial neoplasia), conization, loop excision. We combined conization and loop excision with the boolean operator \u0026ldquo;OR\u0026rdquo;, and the result was combined with the other terms with \u0026ldquo;AND\u0026rdquo;.\u003c/p\u003e \u003cp\u003eIt was eligible if the study has reported the main results of our interests, which was the persistent HPV infection after conization of CIN. We excluded those studies that did not mention HPV infection before conization or if those articles met any of the subsequent conditions: comments, case reports, reviews, conference records, and communications (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003eAll studies were reviewed and evaluated critically by 2 researchers, independently. All information was extracted independently in duplicate manner by 2 researchers. Data extraction included study characteristics (author, year, study period) and information on personal history (e.g., patient age, menopausal status, marriage status, smoking status) and clinical factors (e.g., surgical margin, endocervical gland involvement, CIN types, residual disease, cervical invasive carcinoma, the type of HPV.) related to infection and/or persistent infection of HPV.\u003c/p\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eOdds ratio with 95% confidence intervals (CIs) were calculated. The inconsistency index (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e) and Q statistics were measured. The heterogeneity between studies was assessed by Cochran Q (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1) and I\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e (\u0026gt;\u0026thinsp;50%) tests. The random effects model was accustomed calculate the pooled effect, and a bilateral \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Perform a sensitivity analysis by removing one study at a time from the meta-analysis then assessing its impact on the combined results. We have a tendency to use Begg\u0026rsquo;s and Egger\u0026rsquo;s tests to spot whether or not there was publication bias. The funnel plot wasn't used for publication bias as a result of quite ten studies were needed for such analysis. All analyses were carried on using Stata, version 12.0.\u003c/p\u003e\n\u003ch3\u003ePatient Involvement\u003c/h3\u003e\n\u003cp\u003eNone, because study was based on published literature.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003e202 papers were deleted when the initial titles and abstracts screening among the total 432 retrieved papers. Another 144 papers excluded after reviewed fully. A total 28 papers were finally enrolled in systematic review and meta-analysis.\u003c/p\u003e \u003cp\u003eThe features of the 28 papers were illustrated in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The number of patients ranged from 31 to 1734 in this selected 28 papers. The recruitment of patients came from two types of research, 12 prospective studies and 16 retrospective studies.\u003c/p\u003e \n\u003ch3\u003eThe Personal History Of Patients Associated With Persistent Hpv Infection\u003c/h3\u003e\n\u003cp\u003eYung-TaekOuh et al \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, Derya Kilic et al \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, Rosario Lara-Pe\u0026ntilde;aranda et al \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, Kyeong A So et al \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, Eralp Baser et al \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, and Jeong-Yeol Park et al \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e reported the menopausal status in CIN patients after surgery with HPV persistence compared to without HPV persistence. Moderate heterogeneity was found in the six articles (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61.9%). A random-effect model was adopted during this analysis. The comprehensive analysis found that persistent HPV infection when conization was influenced by menopausal status. Postmenopausal status was positively correlative with the persistent HR-HPV infection (OR\u0026thinsp;=\u0026thinsp;2.098, 95% CI: 1.156 to 3.809, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003eYung-Taek Ouh et al \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, Kyeong A So et al \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, and Jeong-Yeol Park et al \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e reported the marriage status in CIN patients after surgery with HPV persistence compared to without HPV persistence. Low heterogeneity was found in the 3 researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;49%). The comprehensive analysis found that persistent HPV infection after conization or LEEP was not obvious correlation with marriage status (OR\u0026thinsp;=\u0026thinsp;0.972, 95% CI: 0.566 to 1.670, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.919) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eWe identified 3 eligible studies \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e including 431 CIN patients after surgery to investigate smoking correlate to persistent HPV positive. Our meta-analysis showed that smoking has no effect on persistent HPV positive (OR\u0026thinsp;=\u0026thinsp;1.268; 95% CI: 0.78 to 2.062, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.339, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Low heterogeneity was found in the three researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \n\u003ch3\u003eThe Clinical Factors Associated With Persistent Hpv Infection\u003c/h3\u003e\n\u003cp\u003eWe identified 13 eligible studies \u003csup\u003e9,10,12\u0026ndash;14,16\u0026minus;23\u003c/sup\u003e reported the type of CIN in patients after surgery with HPV persistence compared to without HPV persistence. According to the literature, we divide CIN types into CIN2 and CIN3 to meta-analysis. Our meta-analysis showed that the type of CIN (CIN2 or CIN3) has no effect on persistent HPV infection (OR\u0026thinsp;=\u0026thinsp;1.383; 95% CI : 0.972 to 1.967, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.072, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Low heterogeneity was found in the 13 researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;38.9%).\u003c/p\u003e \u003cp\u003eWe identified 6 eligible studies \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e reported surgical margin in patients after surgery with HPV persistence compared to without HPV persistence. Our meta-analysis revealed that surgical margin was positively correlated with the persistent HPV infection (OR\u0026thinsp;=\u0026thinsp;1.309; 95% CI : 1.068 to 1.603, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Moderate heterogeneity was found in the 6 researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e \u003cp\u003eWe identified 5 eligible studies \u003csup\u003e\u003cspan additionalcitationids=\"CR27 CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e reported residual disease in patients after surgery with persistent HPV infection compared to without persistent HPV infection. In those researches, they identified the residual lesions through examinations included liquid-based cytology test (LCT), HPV test, and colposcopy. Our meta-analysis revealed that residual disease was positively correlated with the persistent HPV infection (OR\u0026thinsp;=\u0026thinsp;20.102; 95% CI: 7.485 to 53.987, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Moderate heterogeneity was found in the five researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;66.7%).\u003c/p\u003e \u003cp\u003eWe identified 3 eligible studies \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e reported endocervical gland involvement (EGI) in patients after surgery with HPV persistence compared to without HPV persistence. EGI mean that cervical biopsy involves glands. Our meta-analysis revealed that EGI has no effect on persistent HPV infection (OR\u0026thinsp;=\u0026thinsp;1.700; 95% CI: 0.757 to 3.818, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.198, Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003eD). High heterogeneity was found in the three researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;86.1%).\u003c/p\u003e\n\u003ch3\u003eThe Type Of Hpv Correlated With Persistent Hpv Infection\u003c/h3\u003e\n\u003cp\u003eWe identified 7 eligible studies \u003csup\u003e13,16,17,32\u0026minus;35\u003c/sup\u003e including 1790 CIN patients after surgery to investigate the relationship between HPV types and persistent HPV infection and non-persistent HPV infection. Our results revealed that there had positive effect in persistent HPV infection between HPV 16 and other types of HPV. (OR\u0026thinsp;=\u0026thinsp;1.967; 95% CI: 1.232 to 3.140, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005, Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Moderate heterogeneity was found in the 7 researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61.5%).\u003c/p\u003e \u003cp\u003eWe identified 5 eligible studies \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e including 1516 CIN patients after surgery to investigate the relationship between HPV types and persistent HPV infection and non-persistent HPV infection. Our results revealed that there had no effect in persistent HPV infection between HPV 18 and other types of HPV. (OR\u0026thinsp;=\u0026thinsp;1.482; 95% CI: 0.826 to 2.661; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.187, Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). Low heterogeneity was found in the 5 researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%).\u003c/p\u003e\n\u003ch3\u003eSensitivity Analysis\u003c/h3\u003e\n\u003cp\u003eIn our analysis on the menopausal status in patients with persistent HPV infection, heterogeneity was discovered in the researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61.9%). Sensitivity analysis was used to eliminate individual studies by sequentially. The results indicated that there was one study (the 13th study) that contributed considerably to heterogeneity (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The pooled OR (OR\u0026thinsp;=\u0026thinsp;2.553, 95% CI: 1.713 to 3.805, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.000) of the remaining studies changed the final trend after withdrawing this study. In our sensitivity analysis, the quantity of patients in the 13th study less than others.\u003c/p\u003e \u003cp\u003eIn our analysis on the EGI with persistent HPV infection, heterogeneity was observed in the three researches (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;86.1%). Sensitivity analysis was performed to eliminate individual studies by sequentially. The results indicated that no studies have made a significant contribution to heterogeneity. Moreover, the pooled OR of remaining studies have not changed the final trend.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePublication Bias\u003c/h3\u003e\n\u003cp\u003eIn the meta-analysis on the type of CIN in patients after surgery with persistent HPV infection have identified 13 eligible studies. No evidence of publication bias was found in our study through funnel plot, Egger\u0026rsquo;s test (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and Begg\u0026rsquo;s test (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur research is the first meta-analysis investigating the factors correlated with the role of HPV status after CIN conization. It indicated that the menopausal status, surgical margin, residual disease and HPV 16 correlated positively with persistent HPV infection after conization, while the marriage, smoking, the type of CIN (CIN2 or CIN3), EGI, and HPV18 had no impact on the persistent HPV infection.\u003c/p\u003e \u003cp\u003eNaouel Tifaoui et al \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e reported that follow-up of women with normal cytology and positive HPV showed a higher percentage of HPV persistence among menopausal women. HPV infections in young patients are mostly transient and corresponding symptoms are rarely seen. On the contrary, older people are prone to persistent infection and cervical cancer. The postmenopausal status woman, immunity declines with age, leading to a long time for virus clearance after HPV infection. Here, our study also revealed that menopausal status correlated positively with persistent HPV infection after conization. There is a study show that smoking is an important factor that increase the risk of HR-HPV persistency \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Smoking is an immunosuppressant and one of the significant factors leading to the development of cervical cancer \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. However, our study revealed that smoking did not have any impact on persistent HPV infection after conization. Marriage may be related to sexual contact, contraception, childbirth and other factors that may affect HPV reinfection. However, our study shows that persistent HPV infection after conization or LEEP was not obvious correlation with marriage. We should refine other aspects about marriage, but there was not enough data.\u003c/p\u003e \u003cp\u003eSurgical margin and residual disease showed the residual status of the cervix after surgery. The residual rate after surgery varies from studies, mainly thanks to the dearth of standardization of the conization operation and the totally different applied mathematics strategies used for analysis \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Nonetheless, our results showed that both surgical margins and residual disease were positively associated with persistent HPV infection. Studies have reported that the resection failure rate defined as persistent or recurrent CIN grade 2 or more severe (CIN2+) was 4\u0026ndash;18%, and most cases were diagnosed 2 years after initial treatment \u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. So, we analysis the influence of CIN2 and CIN3 in patients with HPV persistence after conization. Unexpectedly, the type of CIN (CIN2 or CIN3) in patients after conization did not have any impact on persistent HPV infection. However, the relationship between the severity of cervical precancerous lesions and the ongoing risk was unclear, patients with inferior cervical lesions showed the higher infectious viral loads than that in CIN-3 patients \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Yung-Taek Ouh et al \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e found that the HPV persistence rate in CIN-2 patients after treatment was higher than that in CIN-3 patients, which was inconsistent with previous research reports\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. EGI did not have any impact on persistent HPV infection. The standard treatment of CIN, especially high-grade lesions, was conization or LEEP \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Even if the lesion was utterly resected, these patients with high-grade lesions have a higher risk of recurrence compared to the general population \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Therefore, when patients had endocervical gland involvement, they usually choose further surgical treatment, such as hysterectomy. Maybe this is one of reason that EGI did not have any impact on persistent HPV infection after conization.\u003c/p\u003e \u003cp\u003eHPV 16 or HPV 18 had a negative impact on the survival rate in patients with cervical cancer \u003csup\u003e46\u003c/sup\u003e. Our meta-analysis revealed that HPV 16, not HPV 18 have a positive impact on the persistent HPV infection compared to other types HPV after conization. In our included meta-analysis studies, there were a few patients who diagnosed as HPV18 before conization. Then, it wasn\u0026rsquo;t value to HPV18 persistence infected after conization for our study because the number of patients studied is too small.\u003c/p\u003e \u003cp\u003eWe also acknowledge that our meta-analysis has several limitations. Firstly, all the relevant factors analyzed were single factors, and there may be interactions between different factors. Therefore, in the future, it is expected that a larger sample size test will be used for further verification and correction. Secondly, the enclosed articles weren't randomized clinical trials (RCTs). Additionally, attributable to the inherent limitations of retrospective studies, more largescale irregular clinical trials are required to check and verify our results. Last but not least, these researches recruited a wide range of patients, from CIN I to CIN III and even carcinoma in situ, which may increase the heterogeneity of the meta-analysis. Nevertheless, our study lays the foundation for further understanding of the factors influencing persistent HPV infection after conization.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCIN patients with postmenopausal status, positive surgical margin and residual lesions, and HPV 16 are easier presence persistent HPV infection after conization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional ethical committee of the Public Health Clinical Center of Chengdu, with informed consent waived due to the retrospective nature of the study.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in these published articles [and their supplementary information files].\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eRole of human papillomavirus status after conization for high‐grade cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eRisk factors for type-specific persistence of high-risk human papillomavirus and residual/recurrent cervical intraepithelial neoplasia after surgical treatment\u003c/li\u003e\n\u003cli\u003eLong‐term predictors of residual or recurrent cervical intraepithelial neoplasia 2\u0026ndash;3 after treatment with a large loop excision of the transformation zone: a retrospective study\u003c/li\u003e\n\u003cli\u003eFactors affecting residual/recurrent cervical intraepithelial neoplasia after cervical conization with negative margins\u003c/li\u003e\n\u003cli\u003ePredictors of Human papillomavirus (HPV) persistence after treatment of high grade cervical lesions; does cervical cytology have any prognostic value in primary HPV screening?\u003c/li\u003e\n\u003cli\u003eHuman papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia\u003c/li\u003e\n\u003cli\u003eDoes the trend toward less deep excisions in LLETZ to minimize obstetric risk lead to less favorable oncological outcomes?\u003c/li\u003e\n\u003cli\u003ePersistent HPV-16 infection leads to recurrence of high-grade cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eThe Value of Partial HPV Genotyping After Conization of Cervical Dysplasias\u003c/li\u003e\n\u003cli\u003eClearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eAge-related changes in pre- and post-conization HPV genotype distribution among women with high-grade cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eA randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients\u003c/li\u003e\n\u003cli\u003ePre- and post-conization high-risk HPV testing predicts residual/recurrent disease in patients treated for CIN 2\u0026ndash;3\u003c/li\u003e\n\u003cli\u003eRisk factors of persistent HPV infection after treatment for high ‑ grade squamous intraepithelial lesion\u003c/li\u003e\n\u003cli\u003eHuman papillomavirus genotyping predicts residual/recurrent disease after local treatment for cervical intraepithelial neoplasia better than viral DNA testing\u003c/li\u003e\n\u003cli\u003eHuman Papillomavirus Test After Conization in Predicting Residual Disease in Subsequent Hysterectomy Specimens\u003c/li\u003e\n\u003cli\u003eResidual lesions in uterine specimens after loop electrosurgical excision procedure in patients with CIN\u003c/li\u003e\n\u003cli\u003eRecurrent high-grade cervical lesion after primary conization is associated with persistent human papillomavirus infection in Norway\u003c/li\u003e\n\u003cli\u003ePersistence of human papillomavirus DNA in cervical lesions after treatment with diathermic large loop excision\u003c/li\u003e\n\u003cli\u003eHuman papillomavirus infection in patients with residual or recurrent cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eDoes LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing?\u003c/li\u003e\n\u003cli\u003eRisk factors for human papillomavirus persistence among women undergoing cold-knife conization for treatment of high-grade cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eProgression of cervical intraepithelial neoplasia grade 2 lesions among Japanese women harboring different genotype categories of high-risk human papillomaviruses\u003c/li\u003e\n\u003cli\u003eThe association of pre-conization high-risk HPV load and the persistence of HPV infection and persistence/recurrence of cervical intraepithelial neoplasia after conization\u003c/li\u003e\n\u003cli\u003eFactors associated with HPV persistence after treatment for high-grade cervical intra-epithelial neoplasia with large loop excision of the transformation zone (LLETZ)\u003c/li\u003e\n\u003cli\u003eHuman papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia\u003c/li\u003e\n\u003cli\u003eAge, margin status, high-risk human papillomavirus and cytology independently predict recurrent high-grade cervical intraepithelial neoplasia up to 6 years after treatment\u003c/li\u003e\n\u003cli\u003eClinical Significance of the Interaction between Human Papillomavirus (HPV) Type 16 and Other High-Risk Human Papillomaviruses in Women with Cervical Intraepithelial Neoplasia (CIN) and Invasive Cervical Cancer\u003c/li\u003e\n\u003c/ol\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQingsong Liu and Yueyang Zhang designed the topic. Yueyang Zhang and Zhiwen Ni collected the data. Yueyang Zhang and Ting Wei analysed the data. Yueyang Zhang and Ting Wei prepared figures. Qingsong Liu , Yueyang Zhang and Zhiwen Ni wrote the main manuscript text. All authors reviewed the manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCrosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. \u003cem\u003eThe Lancet\u003c/em\u003e. 2013;382(9895):889-899. doi: 10.1016/S0140-6736(13)60022-7\u003c/li\u003e\n\u003cli\u003eKoshiol J, Lindsay L, Pimenta JM, Poole C, Jenkins D, Smith JS. 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Predictors of human papillomavirus (hpv) persistence after treatment of high grade cervical lesions; Does cervical cytology have any prognostic value in primary hpv screening? \u003cem\u003eAnn Diagn Pathol\u003c/em\u003e. 2020;49:151626. doi: 10.1016/j.anndiagpath.2020.151626\u003c/li\u003e\n\u003cli\u003eLara Pe\u0026ntilde;aranda R, Rodr\u0026iacute;guez L\u0026oacute;pez PM, Plitt Stevens J, Ortiz Gonz\u0026aacute;lez A, Remezal Solano M, Mart\u0026iacute;nez Cend\u0026aacute;n JP. Does the trend toward less deep excisions in lletz to minimize obstetric risk lead to less favorable oncological outcomes? \u003cem\u003eInt J Gynecol Obstet\u003c/em\u003e. 2020;148(3):316-324. doi: 10.1002/ijgo.13080\u003c/li\u003e\n\u003cli\u003eSo KA, A P. 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Human papillomavirus type-specific persistence and reappearance after successful conization in patients with cervical intraepithelial neoplasia. \u003cem\u003eInt J Clin Oncol\u003c/em\u003e. 2016;21(3):580-587. doi: 10.1007/s10147-015-0929-x\u003c/li\u003e\n\u003cli\u003eHuang HJ, Tung HJ, Yang LY, et al. Role of human papillomavirus status after conization for high‐grade cervical intraepithelial neoplasia. \u003cem\u003eInt J Cancer\u003c/em\u003e. 2021;148(3):665-672. doi: 10.1002/ijc.33251\u003c/li\u003e\n\u003cli\u003eS\u0026ouml;derlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. \u003cem\u003eJ Med Virol\u003c/em\u003e. 2014;86(4):634-641. doi: 10.1002/jmv.23806\u003c/li\u003e\n\u003cli\u003eByun JM, Jeong DH, Kim YN, et al. 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High-risk hpv detection and associated cervical lesions in a population of french menopausal women. \u003cem\u003eJ Clin Virol\u003c/em\u003e. 2018; 108:12-18. doi: 10.1016/j.jcv.2018.08.010\u003c/li\u003e\n\u003cli\u003eSchmeink CE, Melchers WJ, Siebers AG, Quint WG, Massuger LF, Bekkers RL. Human papillomavirus persistence in young unscreened women, a prospective cohort study. \u003cem\u003ePlos One\u003c/em\u003e. 2011;6(11):e27937. doi: 10.1371/journal.pone.0027937\u003c/li\u003e\n\u003cli\u003eKjellberg L, Hallmans G, Ahren AM, et al. Smoking, diet, pregnancy and oral contraceptive use as risk factors for cervical intra-epithelial neoplasia in relation to human papillomavirus infection. \u003cem\u003eBr J Cancer\u003c/em\u003e. 2000;82(7):1332-1338. doi: 10.1054/bjoc.1999.1100\u003c/li\u003e\n\u003cli\u003eArbyn M, Ronco G, Anttila A, et al. 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Determinants of human papillomavirus load among women with histological cervical intraepithelial neoplasia 3: dominant impact of surrounding low-grade lesions. \u003cem\u003eCancer Epidemiol Biomarkers Prev\u003c/em\u003e. 2003;12(10):1038-1044.\u003c/li\u003e\n\u003cli\u003eCosta S, De Simone P, Venturoli S, et al. Factors predicting human papillomavirus clearance in cervical intraepithelial neoplasia lesions treated by conization. \u003cem\u003eGynecol Oncol\u003c/em\u003e. 2003;90(2):358-365. doi: 10.1016/s0090-8258(03)00268-3\u003c/li\u003e\n\u003cli\u003eMassad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. \u003cem\u003eObstet Gynecol\u003c/em\u003e. 2013;121(4):829-846. doi: 10.1097/AOG.0b013e3182883a34\u003c/li\u003e\n\u003cli\u003eMelnikow J, Mcgahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the british columbia cohort study. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e. 2009;101(10):721-728. doi: 10.1093/jnci/djp089\u003c/li\u003e\n\u003cli\u003ePilch H, Gunzel S, Schaffer U, et al. The presence of hpv dna in cervical cancer: correlation with clinico-pathologic parameters and prognostic significance: 10 years experience at the department of obstetrics and gynecology of the mainz university. \u003cem\u003eInt J Gynecol Cancer\u003c/em\u003e. 2001;11(1):39-48. doi: 10.1046/j.1525-1438.2001. 011001039. x\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2265069/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2265069/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo systematically evaluate several factors of human papillomavirus (HPV) persistent infection following conization in patients with cervical intraepithelial neoplasia (CIN).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePubMed, EMBASE and Cochrane library were retrieved from January 1, 1998 to September 10, 2021. Random-effects models for meta-analyses was used and pooled relative risks with 95% confidence intervals was reported. Literature screening, data extraction and assessment of the risk of bias in the included studies were conducted independently by two researchers. Data-analysis was performed with Stata software, version 12.0.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 28 studies were enrolled finally in this study. Meta-analysis revealed that surgical margin and residual disease were correlated positively with the persistent HPV infection after conization. Compared with patients infected with other types of HPV, CIN patients with HPV 16 have higher persistent infection rate (OR\u0026thinsp;=\u0026thinsp;1.967, 95% CI (1.232\u0026ndash;3.140), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCIN patients with postmenopausal, surgical margin and residual lesions positive, and HPV 16 are prone to persistent HPV infection after conization.\u003c/p\u003e","manuscriptTitle":"Persistent HPV infection after conization of cervical intraepithelial neoplasia—— a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-25 22:57:25","doi":"10.21203/rs.3.rs-2265069/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-02-15T07:09:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-02-02T20:02:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47289f3b-77c4-4e30-9992-6af85fd30f93","date":"2023-01-31T07:19:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-01-31T07:12:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-01-30T15:41:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-01-23T12:09:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-01-23T12:00:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2022-11-12T04:27:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"152d0bcc-da38-4629-bb5b-671d5c956c4d","owner":[],"postedDate":"January 25th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T20:52:10+00:00","versionOfRecord":{"articleIdentity":"rs-2265069","link":"https://doi.org/10.1186/s12905-023-02360-w","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2023-05-03 20:42:15","publishedOnDateReadable":"May 3rd, 2023"},"versionCreatedAt":"2023-01-25 22:57:25","video":"","vorDoi":"10.1186/s12905-023-02360-w","vorDoiUrl":"https://doi.org/10.1186/s12905-023-02360-w","workflowStages":[]},"version":"v1","identity":"rs-2265069","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2265069","identity":"rs-2265069","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}