HPV16, Multigravida, and Post-CIN2 Vaccination in Chinese Patients : A Retrospective Cohort Study

HPV16, Multigravida, and Post-CIN2 Vaccination in Chinese Patients : A Retrospective Cohort Study | 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 HPV16, Multigravida, and Post-CIN2 Vaccination in Chinese Patients : A Retrospective Cohort Study Kaiyang Geng, Siyu Bai, Ruizhen Liu, Longyu Jia, Yan Zhai, Zhihua Sun, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6379197/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: This study explores predictive factors influencing clinical outcomes in patients with cervical intraepithelial neoplasia grade 2 (CIN2) managed through simple observation. Methods: Between January 2012 and March 2021, we retrospectively analyzed data from 510 CIN2 patients managed with observation strategies at Beijing Chaoyang Hospital, Capital Medical University. Result:A total of 510 eligible patients were enrolled in this study ,with a mean age of 30.15 ± 5.82 years, and 384 (75.3%) of the cases were nulliparous. During the follow-up period (mean 37.0 ± 1.3 months), 60 (12%) opted for surgical treatment, 363 (71%) patients achieved remission time 9.1 months（range: 5.1-17.3 )months. persistent CIN2 was detected in 55 (11%), disease progression occurred in 32 (6%), and no deaths were reported, with a five-year disease progression rate (DPR) of 9.2%. Independent risk factors for disease progression included more than three pregnancies (OR 4.38, 95% CI 1.63-11.79, P=0.003), HPV16 infection (OR 4.07, 95% CI 1.88-8.81，P<0.001), and post-diagnosis HPV vaccination was an independent protective factor (OR 0.29, 95% CI 0.08-0.98, P=0.046，P=0.046). The 5-year disease progression rate (DPR) was 2.6% for patients with three or fewer HPV16-negative and vaccinated pregnancies and 72% for patients with three or more pregnancies, HPV16-positive, and unvaccinated after CIN2 diagnosis. Conclusion: Simple observation with intensive surveillance is a safe strategy for CIN2 management. Patients with HPV16 and more than three pregnancies should consider conization after childbearing, while unvaccinated patients are advised to receive HPV vaccination. CIN2 Conservative treatment Multiple pregnancies HPV-16 HPV Vaccine Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Cervical cancer remains the fourth most prevalent malignancy among women globally, accounting for approximately 604,000 new cases and 342,000 deaths in 2020 [ 1 ]. The primary etiological factor contributing to the development of cervical cancer is persistent infection with high-risk human papillomavirus (HR-HPV). The transition from HR-HPV infection to invasive cervical cancer typically takes between 8 to 10 years [ 2 ]. Consequently, alongside effective screening techniques, it is imperative to manage HPV-associated CINs appropriately to prevent and treat cervical cancer. CINs are classified into three grades—CIN1, CIN2, and CIN3—according to the 2003 edition of the WHO Classification of Tumors of the Female Reproductive System. This classification outlines a continuum of morphological changes in the squamous epithelium of the cervix, progressing from aberrant hyperplasia to carcinoma [ 3 ]. However, the diagnostic consistency of CIN2 among pathologists is poor, particularly when compared to CIN1 and CIN3, with diagnostic agreement falling below 50% [ 4 ]. Moreover, it has been found that certain CIN2 lesions are reversible and may arise from transient HPV infections. The revised 2014 WHO nomenclature for tumors of the female reproductive system recommended the use of two categories: high-grade squamous intraepithelial lesions (HSIL) and low-grade squamous intraepithelial lesions (LSIL). LSIL encompasses CIN1, flat condyloma, and panniculocytosis, while HSIL includes CIN2, CIN3, severe atypical hyperplasia, and carcinoma in situ. Notably, CIN2 is no longer recognized as an independent histological subtype [ 3 ]HSIL, primarily resulting from persistent HR-HPV infection, carries a significantly elevated risk of progressing to cervical cancer and often necessitates intervention, such as cervical conization. Notably, cervical insufficiency associated with cervical conization may result in miscarriage, preterm labor, and premature rupture of membranes during pregnancy in young women [ 5 ]. Nevertheless, the majority of preneoplastic lesions do not advance to cancer, highlighting the need for more judicious interventions for CINs, particularly CIN2, as a crucial strategy to reduce morbidity and mortality while enhancing the quality of life for patients. In our recent clinical practice, a straightforward observation strategy has been recommended as a treatment option for patients diagnosed with CIN2 under their fully informed consent, over the past decade. This study conducted a retrospective analysis of the clinical and pathological data of patients with CIN2 who were managed through simple follow-up protocols. The aim was to investigate the risk factors associated with disease progression to CIN3 or invasive cervical cancer and to provide valuable insights for the effective management of this patient population. Materials and methods Study Design This study retrospectively collected and analyzed the medical records of patients diagnosed with CIN2 who were treated at Beijing Chaoyang Hospital, Capital Medical University， between January 2012 and March 2021 . The institution serves as one of referral centers for the diagnosis and treatment of precancerous lesions of the female lower genital tract in Beijing, China. The inclusion criteria for the study were as follows: 1) women aged ≥18 years; 2) histological diagnosis of CIN2 without prior treatment; 3) a follow-up period of no less than 6 months; and 4) a request for conservative treatment accompanied by the signing of an informed consent form. The exclusion criteria included: 1) pregnant or lactating women; 2) individuals with immunosuppressive conditions (such as autoimmune diseases or acquired immune deficiency syndrome [AIDS]); 3) women with any type of malignant tumors, either concurrently or sequentially; and 4) those who had previously received treatment for cervical HSIL, adenocarcinoma in situ (AIS), or invasive cervical cancer. Data collection Demographic characteristics of the patients, as well as results from cytology, HPV testing, and colposcopy, were retrospectively collected. HPV testing was performed on samples stored in needle test vials using real-time polymerase chain reaction (PCR) with Liferiver (China), a system designed to identify high-risk HPV (HR-HPV) genotypes. The presence of HPV16, HPV18, and other HR-HPV types (HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV66, and HPV68) was documented. Cytological analysis was conducted using the ThinPrep Pap test (Hologic, USA) on exfoliated cells collected from the cervix surface, with results reported according to the Bethesda system terminology. Colposcopy was performed by experienced colposcopists. The histological diagnosis of CIN was established based on the morphological characteristics identified through hematoxylin and eosin staining, in accordance with WHO criteria. The initial diagnosis of CIN2 was validated by two pathologists with extensive expertise in gynecologic pathology, each of whom independently reviewed the pathological sections. In cases of disagreement, a joint review was conducted. If consensus was not achieved, a third expert was consulted to evaluate the slides until a consensus diagnosis was reached, ensuring that at least two pathologists agreed on the final interpretation. Throughout the follow-up period, patients had the option to discontinue observation and request conization at any time. Follow-up evaluations were conducted every six months, during which patients underwent gynecological examinations, cytological assessments, and colposcopy. Cervical biopsy was performed as necessary. Following two consecutive negative results for both ThinPrep cytology test (TCT) and HR-HPV tests, patients could transition to annual follow-up. Disease regression was defined by the occurrence of one or more of the following criteria: 1) TCT and HR-HPV results were both negative; 2) HR-HPV was negative while TCT results showed abnormalities categorized as atypical squamous cells of undetermined significance (ASCUS) or LSIL, without any abnormal findings on colposcopy or negative cervical biopsy results; 3) cervical biopsy, endocervical curettage (ECC), or loop electrosurgical excision procedure (LEEP) pathological results were classified as ≤CIN1. The maintenance of CIN2 status for one year or longer was classified as persistent CIN2, which necessitated close monitoring. The presence of CIN3, adenocarcinoma in situ (AIS), or invasive cervical cancer was classified as disease progression; in such cases, withdrawal from the study and timely surgical intervention were recommended. Data analysis Data were analyzed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA). Categorical variables were analyzed by the χ2 test or Fisher exact test. Univariate and multivariate logistic regression analyses were performed to identify influential regressors. Additionally, Kaplan-Meier analyses were employed to assess the five-year incidence of disease progression. Based on the multivariate Cox regression model, the hazards ratio (HR) was adjusted for covariates. All statistical tests were conducted at an alpha level of 0.05. Ethics approval and consent to participate Ethical approval for this study was obtained from the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University (CMU).Ethics Batch Number:2025-ke-401 Results During the study period, a total of 588 women were diagnosed with CIN2. Eight patients who received LEEP as initial treatment were excluded from the analysis. Additionally, patients with autoimmune diseases (specifically systemic lupus erythematosus [SLE] and Hashimoto's thyroiditis, totaling two cases) and those with a history of conization surgery (three cases) were also excluded. Furthermore, eight pregnant patients and 57 individuals lacking follow-up information were excluded. Consequently, 510 eligible women were included in this analysis. Table 1 Demographical characteristics and clinical data of the patients Variables All patients Results (n=510) Age (y, Mean ± SD) (y, Range) 30.15±5.82 18-61 Educational level Below bachelor's degree Bachelor degree or above 146/510 (28.6%, 95%CI 24.5-32.7) 364/510 (71.4%, 95%CI 67.3-75.5) Smoking Yes No 248/510 (48.6%, 95%CI 44.1-52.9) 262/510 (51.4%, 95%CI 47.0-55.7) Weekly drug use Yes No 47/510 (9.2%, 95% CI 6.9-11.8) 463/510 (90.8%, 95%CI 88.2-93.1) Contraception (before diagnosis) Condom only Condom or none 232/510 (45.5%, 95%CI 41.2-49.8) 278/510 (54.5%, 95%CI 50.2-58.8) Contraception(after diagnosis) Condom only Condom or none 312/510 (61.2%, 95%CI 57.1-65.3) 198/510 (38.8%, 95%CI 34.7-42.9) Age at first intercourse (y, Mean ±SD) 21.24±2.74 Number of sexual partners (before diagnosis of CIN2) ≤1 >1 121/510 (23.7%, 95%CI 20.0-27.5) 389/510 (76.3%, 95%CI 72.5-80.0) Number of sexual partners (after diagnosis of CIN2) ≤1 >1 383/510 (75.1%, 95%CI 71.2-78.6) 127/510 (24.9%, 95%CI 21.4-28.8) Number of pregnancies ≤3 >3 482/510 (94.5%, 95%CI 92.5-96.5) 28/510 (5.5%, 95%CI 3.5-7.5) Number of deliveries ≤1 >1 463/510 (90.8%, 95%CI 88.2-93.1) 47/510 (9.2%, 95%CI 6.9-11.8) Symptoms Cervical contact bleeding Others 83/510 (16.3%, 95%CI 13.1-19.6) 427/510 (83.7%, 95%CI 80.4-86.9) Menstruation Regular menstruation Menopause 505/510 (99.0%, 95%CI 98.0-99.8) 5/510 (1.0%, 95%CI 0.2-2.0) Vaccination Yes No 153/510 (30.0%, 95%CI 25.9-33.9) 357/510 (70.0%, 95%CI 66.1-74.1) Vaccination before diagnosis of CIN2 Yes No 28/510 (5.5%, 95%CI 3.5-7.5) 482/510 (94.5%, 95%CI 92.5-96.5) Vaccination after diagnosis of CIN2 Yes No 385/510 (75.5%, 95%CI 71.7-79.2) 125/510 (24.5%, 95%CI 20.8-28.3) Previous cytology ≤ASCUS >ASCUS 360/510 (70.6%, 95%CI 66.6-74.6) 150/510 (29.4%, 95%CI 25.4-33.4) HPV genotypes 16+ Other genotypes 172/510 (33.7%, 95%CI 29.6-37.8) 338/510 (66.3%, 95%CI 62.2-70.4) Number of biopsies =1 >1 276/510 (54.1%, 95%CI 49.8-58.5) 234/510 (45.9%, 95%CI 41.5-50.2) The mean age of the 510 patients enrolled in the study was 30.15 ± 5.82 years (Table1) , with 384 patients (75.3%) being nulliparous. During the mean follow-up period of 37.0 ± 1.3 months, 60 patients opted to discontinue simple observation and chose cervical conization based on their personal choice. At the final visit, persistent CIN2 was identified in 55 patients (11%), of whom 43 underwent LEEP surgery. Disease progression was observed in 32 patients (6%), including 31 cases of CIN3 and one case of cervical carcinoma in situ. Disease regression was noted in 363 patients (71%), comprising 329 cases that were double negative for both TCT and HPV, and 34 cases of CIN1. The median time to remission was 9.1 months (range: 5.1–17.3 months). No patients died as a result of the disease. During the study period, 96 women (25.0%) achieved pregnancy and had full-term deliveries. (Fig.1) In the univariate analysis, the following factors were identified as risk factors for disease progression: age greater than 30 years (P < 0.001), HPV16 infection (P < 0.001), a history of more than three pregnancies (P < 0.001), and having more than one delivery (P = 0.001) (Table 2). Among the study population, 5.49% (28 out of 510) of patients received vaccination before the diagnosis of CIN2, while 24.51% (125 out of 510) were vaccinated following their diagnosis. HPV vaccination whether before or after histologically diagnosed of CIN2 conferred a protective effect (P = 0.042), and vaccination administered only after the diagnosis of CIN2 also served as a protective factor (P = 0.046) (Table2). Table 2 The univariate and multivariate analysis of the distribution of indicators characteristics and risk factors. Variables All patients Results (n=510) Regression+CIN2 Progression to CIN3/AIS (n=478) (n=32) P value Multivariate analysis P value OR (95%CI) Age (y, Mean ± SD) 30.15±5.82 0.186 Age (y) >30 ≤30 187 15 291 17 <0.001 Educational level Below bachelor's degree Bachelor degree or above 135 11 343 21 0.457 Smoking Yes No 229 19 249 13 0.209 Weekly drug use Yes No 42 5 436 27 0.195 Contraception (before diagnosis) Condom only Condom or none 221 11 257 21 0.192 Contraception (after diagnosis) Condom only Condom or none 295 17 183 15 0.334 Age at first intercourse (y, Mean ±SD) 21.24 ±2.74 0.242 Age at first intercourse (y) ≥18 1 112 9 366 23 0.546 Number of sexual partners (after diagnosis of CIN2) ≤1 >1 360 23 118 9 0.663 Number of pregnancies ≤3 >3 457 25 21 7 1 439 24 39 8 0.001 Symptoms Cervical contact bleeding Others 78 5 400 27 0.918 Menstruation Regular menstruation Menopause 474 31 4 1 0.730 Vaccination Yes No 149 4 329 28 0.042 Vaccination before diagnosis of CIN2 Yes No 27 1 451 31 0.837 Vaccination after diagnosis of CIN2 Yes No 122 3 356 29 0.046 0.286 (0.08-0.98) 0.046 1 Previous cytology ≤ASCUS >ASCUS 338 22 140 10 0.814 HPV genotypes 16+ Other genotypes 151 21 327 11 <0.001 4.07 (1.88-8.81) 1 260 16 218 16 0.629 In the multivariate analysis, HPV16 infection (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.88-8.81, P < 0.001) and having more than three pregnancies (OR 4.38, 95% CI 1.63-11.79, P = 0.003) were identified as independent risk factors for disease progression. Notably, HPV vaccination after the diagnosis of CIN2 was recognized as an independent protective factor (OR 0.29, 95% CI 0.08-0.98, P=0.046) (Table 2). According to the multivariate Cox regression analysis, the risk of disease progression was higher for patients who did not receive the vaccine after diagnosis of CIN2 (HR 3.39, 95% CI 1.02-11.20, P=0.046), with pregnancies >3 (HR 3.95, 95% CI 1.69-9.26, P=0.002), and HPV16 positive (HR 3.70, 95% CI 1.77-7.75, P=0.001), as shown in Table3. Table3.Progression-free survival analysis by the Cox model. CI, confidence interval. Factors Hazards ratio (95% CI) p value Pregnancy times ≤3 versus >3 3.95 (1.69-9.26) 0.002 Vaccination after diagnosis of CIN2 Non-recipients versus recipients 3.39 (1.02-11.20) 0.046 HPV genotypes 16+ versus Others 3.70 (1.77-7.75) 0.001 The overall 5-year disease progression rate was 9.2% (Fig. 2). As the survival curve consistently remained above 50%, the median time to disease progression was not reached. The mean time to progression was 56.486 months (±0.607 months). For patients who ultimately progressed to CIN3+, the median time to disease progression was 13.200 months (±0.574 months). The five-year risk of disease progression (DPR) was 72% for patients exhibiting HPV16 infection, having more than three pregnancies, and not receiving HPV vaccination after the diagnosis of CIN2. In contrast, for patients with three or fewer pregnancies, who were HPV16 negative and received vaccination after the diagnosis of CIN2, the five-year DPR was significantly lower at 2.6%. (Fig. 3, 4, 5) Discussion The conservative management of CIN2 remains a controversial topic. Following the release of updated guidelines in 2012, an increasing body of literature has emerged that supports the safety of conservative management strategies for women diagnosed with CIN2 [6]. This study included 510 patients with CIN2 who received simple observation management strategies, representing one of the largest samples of research focusing on such strategies for CIN2 published to date. The mean follow-up period exceeded 36 months. Our data provided a compelling foundation for the clinical management of this patient population. In our study, the majority of patients (71%) experienced remission. Disease progression occurred in only a small proportion of patients (6%), which is lower than the 10–18% reported in previous studies [5, 7]. The lower rate of progression may be attributed to the fact that 30% of the patients had been vaccinated against HPV. Our data indicate that multiple pregnancies are associated with an increased risk of progression of CIN2. A local study in Paraguay demonstrated that women with more than four pregnancies had a threefold increased risk of CIN2+, compared to those with zero to one pregnancy [8]. This association between a high number of pregnancies and CIN2+ has been corroborated by other studies, particularly among younger women [9]. It is hypothesized that the risk may be exacerbated by several full-term pregnancies occurring in a short timeframe [9]. Notably, the mode of delivery—whether vaginal or via cesarean section—does not appear to influence the progression of squamous intraepithelial lesions (SIL) [10]. During pregnancy, the elevated concentrations of estrogen stimulate the eversion of the cervical squamous-column junction. Consequently, the duration of exposure to potential carcinogens, such as HPV infection, is prolonged within the transformation zone [11]. Additionally, as the duration of pregnancy extends, colposcopic assessment becomes more challenging, potentially leading to increased rates of misdiagnosis. Physiological changes during pregnancy, which include heightened squamous metaplasia and increased vascularity of the cervix, along with morphological alterations, may complicate the differentiation between active squamous metaplasia, low-grade CIN, and benign lesions that may present as suspicious abnormalities [12]. Furthermore, other studies have shown that hormonal mechanisms, similar to those associated with oral contraceptive use, may also play a role. Steroid contraceptive hormones are thought to bind to specific DNA sequences within transcriptional regulatory regions on HPV DNA. The integration of HR-HPV DNA into the host genome enhances the expression of the E6 and E7 HPV oncoproteins, which interfere with the function of the p53 tumor suppressor gene, ultimately leading to carcinogenesis [13]. Changes in hormone levels during pregnancy may also diminish the immune response to HPV infection [14]. In the presence of antigens, progesterone and estradiol may skew specific T cells towards a cytokine profile characterized by coexpression of interleukin-10 (IL-10) and interleukin-4 (IL-4), potentially facilitating HPV persistence by preventing the elimination of infected cells by cytotoxic T lymphocytes [15]. In our study, a significant majority of patients (60.4%) were aged 30 years or younger, with a mean age of 30 years and a median age of 29 years, spanning an age range of 18 to 61 years. Previous studies have not sufficiently addressed the importance of patient age. Although multivariate analysis in our study revealed no significant difference in age between those with disease progression and those without (P=0.702), age remains a crucial factor with predictive value for potential CIN2+ cases. A global review indicates that the incidence of high-grade cervical lesions peaks at a relatively younger age, specifically between 25 and 40 years [16]. Conversely, the age-related patterns of low-grade lesions generally decline after peaking in younger cohorts (20-30 years) [16]. In women with precancerous lesions, the risk appears to peak or plateau around 35-55 years of age [17]. One study reported a prevalence of 58.7% for HR-HPV among women younger than 25 years, alongside a notable prevalence of high-grade cervical disease at 9.4%. Among women in this age group with CIN3, all were positive for HPV16/18 [18]. Therefore, we recommend heightened attention to the prevalence of HR-HPV infections, particularly among young women, alongside the necessity of regular monitoring of cervical lesion status. Despite the high-risk status associated with HPV16/18 in younger women, our study found that over 90% of young women with CIN2 experienced either regression or persistence, consistent with previous research [10]. Existing literature supports the justification for active surveillance in histologically confirmed CIN2 cases among untreated young women, rather than immediate intervention [7]. The findings from our study suggest that HPV16 infection, accounting for 33.7% of all positive infections, represents one of the risk factors for disease progression, aligning with data from other contemporary studies [19]. Different HR-HPV genotypes exhibit varying carcinogenic potentials, with HPV16 recognized as a significant viral factor in disease persistence and progression. HPV genotyping could enhance risk-based management strategies for women diagnosed with CIN2. Our results indicate that the presence of HPV16 substantially increases the risk of progression to CIN2 compared to other HPV genotypes, a finding that has been consistently validated across studies, as well as its prevalence in CIN3 and cervical cancer cases [20]. Current research emphasizes that the E6 and E7 oncoproteins of HPV16 play a critical role in carcinogenesis [13]. E6 and E7 oncoproteins play a crucial role in promoting viral replication by modulating various cellular processes, including cell cycle control, cell survival, cell differentiation, immune evasion, and the DNA damage response [21, 22]. The extent of HPV integration into the host genome varies by HPV type. Studies indicate that approximately 76% of cancers associated with HPV16 exhibit gene integration, while nearly all cancers linked to HPV18 also demonstrate this integration. Furthermore, different variant lineages may possess varying integration potentials due to differences in E6 and E7 activity [23, 24]. A significant target of the HR-HPV oncoproteins E6 and E7 is the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like protein 3 (APOBEC3). Research has shown that mutations in APOBEC, triggered by the host's immune response to HPV infection, may constitute the primary source of mutations found in HPV-positive tumors [23, 25]. Consequently, we emphasize the need for close monitoring of patients infected with HPV16. In our study, a significant majority of patients (71%) experienced remission, aligning with findings from several other studies in the literature [7, 20]. Disease progression occurred in only a small proportion of patients (6%), which is lower than the 10-18% range reported in previous research [5, 7]. This reduced rate of progression may be partially attributed to the fact that 30% of the patients had received prophylactic HPV vaccinations before or after their CIN2 diagnosis. HPV vaccination has been widely recognized as an effective measure for the prevention of cervical cancer. Evidence suggests that HPV vaccines provide protection against cervical precancerous lesions in both adolescent girls and young women, with greater efficacy observed in those with lesions associated with HPV16/18 and those testing negative for HR-HPV at enrollment [26]. Additionally, HPV vaccines offer a degree of cross-protective effects, with even bivalent HPV vaccinations exhibiting cross-protection against various HPV types, including types 35, 52, and 58 [27, 28]. Our findings indicate that HPV vaccination functions as an independent protective factor against the progression of CIN2. The protective effect of the HPV vaccine is evident regardless of whether it was administered prior to or following the diagnosis of CIN2. Previous reports have noted a reduction in the risk of CIN2+ occurrences associated with the implementation of catch-up HPV vaccination for younger populations [26]. Despite the capacity of prophylactic vaccines to prevent new HPV infections and reinfections, the incidence of CINs remains prevalent. This persistence can be attributed primarily to the inability of prophylactic HPV vaccines to eliminate pre-existing infections and related conditions. The currently licensed prophylactic vaccines are developed based on virus-like particles (VLPs) derived from the papillomavirus L1 capsid protein. These VLPs closely mimic the natural spatial structure of the target antigen, effectively inducing a high titer of serum neutralizing antibodies post-vaccination [29]. However, the integration of HPV viral DNA into the host genome results in the deletion of late genes L1 and L2, which compromises the L1-specific immune response initiated by prophylactic vaccines, thereby rendering them ineffective in clearing existing HPV infections [30]. Therapeutic vaccines are currently undergoing clinical trials, utilizing mechanisms that deliver target antigens to antigen-presenting cells (APCs), which subsequently activate the immune response of HPV-specific CD8+ cytotoxic T lymphocytes and CD4+ helper T lymphocytes [31]. These therapeutic vaccines aim to induce a cell-mediated immune response against specific HPV antigens, particularly the E6 and E7 oncoproteins, which are critical for the survival and progression of HPV-infected cancer cells [32]. Given that HPV E6 and E7 are constitutively expressed in both premalignant and invasive lesions but are absent in healthy tissues [33], they represent ideal targets for the immunotherapy of HPV-induced malignancies. Consequently, most therapeutic HPV vaccines currently in development utilize E6 and E7 proteins as target antigens. Notably, there are synthetic DNA therapeutic vaccines targeting HPV16/18 E6 and E7 proteins designed for CIN2/3, which have demonstrated the potential for viral clearance, histopathological regression, and the prevention of low-risk lesions from progressing to high-risk lesions and cancer [34]. In addition, therapeutic vaccines have been investigated as standalone treatments for patients with premalignant diseases caused by HPV, and they may also serve as adjunctive therapies alongside chemotherapy and immunotherapy for cancers [35]. Presently, therapeutic HPV vaccines encompass a variety of platforms, including recombinant vector vaccines, nucleic acid vaccines, and subunit vaccines. Innovative delivery methods, such as needle-free biojectors and oral administration, are also being explored, exhibiting promising translational potential for the treatment of HPV16/18 infection and disease [36, 37]. HPV vaccination may enhance treatment efficacy and mitigate tumor recurrence, particularly in cases associated with HPV. A retrospective study conducted by Kang et al. in 2015 analyzed HPV vaccination data from 737 patients who underwent cervical conization. Following this procedure, 360 patients received the HPV vaccine postoperatively to prevent cervical exposure to the virus. The findings indicated that the absence of vaccination after surgery constituted an independent risk factor for disease recurrence [38]. Recent literature supports that combining surgical resection with postoperative vaccination significantly reduces the risk of recurrence of CIN2+ [38-41]. The SPERANZA project posits that through immune mechanisms activated by surgery, postoperative vaccination can elevate local antibody concentrations, which are crucial during the regeneration of resected tissues. Additionally, vaccination following LEEP has been identified as beneficial in preventing recurrence after conization [41]. Collectively, these studies suggest that HPV vaccination may offer both preventative and therapeutic benefits for HPV-related cervical lesions. The strengths of this study include several key factors. Firstly, the study population was substantial, and the extended follow-up period provided ample time to observe the various factors influencing conservative management of CIN2 as well as the natural progression of the disease. Secondly, we employed a standardized colposcopy referral process instead of alternative methods, which contributed to the accuracy of our findings. Additionally, the demographic data collected was detailed and comprehensive, thereby enhancing the credibility of the results. To our knowledge, this was the first study to evaluate the impact of HPV vaccination following a histological diagnosis of CIN2. Our results indicated a protective effect of HPV vaccination on disease progression during conservative observation of CIN2. However, this study also had certain limitations. Firstly, it was a retrospective cohort study, which introduced the potential for recall bias during follow-up assessments. Secondly, the research was conducted at a single center, which may have limited the generalizability of the findings. Thirdly, for patients who were lost to follow-up after their initial visit, we were unable to obtain test results from other healthcare facilities they may have visited. Future research should focus on prospective, multicenter studies to identify specific and accurate predictors of outcomes in this patient population. Conclusion In conclusion, conservative management strategies for patients with CIN2 have been demonstrated to be a safe approach. The low rate of progression associated with CIN2 supports the viability of conservative treatment for patients who choose this option. However, for patients who are infected with HPV-16 and have had multiple pregnancies, clinical management should consider conization or the completion of childbearing followed by conization, due to their elevated risk of disease progression. Furthermore, for unvaccinated patients diagnosed with CIN2, HPV vaccination is strongly recommended to mitigate potential progression of the disease. Abbreviations CIN2: cervical intraepithelial neoplasia grade 2 OR: odds ratio CI: confidence interval HPV: human papillomavirs HR-HPV: high-risk HPV HSIL: high-grade squamous intraepithelial lesions LSIL: low-grade squamous intraepithelial lesions AIS: adenocarcinoma in situ PCR: polymerase chain reaction TCT: ThinPrep cytology test ASCUS: atypical squamous cells of undetermined significance ECC: endocervical curettage LEEP: loop electrosurgical excision procedure HR: hazard ratio CMU: Capital Medical University SLE: specifically systemic lupus erythematosus APOBEC3: apolipoprotein B mRNA editing enzyme catalytic polypeptide-like protein 3 APC: antigen-presenting cells SPERANZA: SPERimentazione ANti HPV Zona Apuana Declarations Acknowledgements We sincerely thank the Chinese patients who participated in this study for their understanding and cooperation during the follow-up process. We also extend our gratitude to all staff members involved in this research for their contributions to study design, data analysis, and manuscript preparation. Authors' contributions HM B, J L, KY G and SY B: conception and design of the study, assembly, analysis and interpretation of the data, and manuscript writing. RZ L, LY J, Y Z, ZH S, RL J and X L: provision of study materials, analysis and interpretation of the data. Funding This study was supported by the Science and Technology Program of Chaoyang District, Beijing, China, Project No. CYSF2214 Data availability The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate The study adhered to ethical standards outlined in the Declaration of Helsinki，with ethical approval obtained from the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University （Approval Number: 2025-ke-401）.Written informed consent was obtained from all participants prior to their inclusion in the study. Consent for publication Not applicable. Competing interests The authors declare no competing interests. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Cancer J Clin. 2021;71(3):209–49. de Sanjosé S, Brotons M, Pavón MA. The natural history of human papillomavirus infection. Best Pract Res Clin Obstet Gynecol. 2018;47:2–13. Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, et al. 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Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res. 2002;70(2):238–48. Ting J, Kruzikas DT, Smith JS. A global review of age-specific and overall prevalence of cervical lesions. Int J Gynecol cancer: official J Int Gynecol Cancer Soc. 2010;20(7):1244–9. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet (London England). 2007;370(9590):890–907. Stoler MH, Wright TC Jr., Sharma A, Zhang G, Apple R, Wright TL, Behrens CM. The interplay of age stratification and HPV testing on the predictive value of ASC-US cytology. Results from the ATHENA HPV study. Am J Clin Pathol. 2012;137(2):295–303. Zeng Z, Yang H, Li Z, He X, Griffith CC, Chen X, Guo X, Zheng B, Wu S, Zhao C. Prevalence and Genotype Distribution of HPV Infection in China: Analysis of 51,345 HPV Genotyping Results from China's Largest CAP Certified Laboratory. J Cancer. 2016;7(9):1037–43. Salvadó A, Miralpeix E, Solé-Sedeno JM, Kanjou N, Lloveras B, Duran X, Mancebo G. Predictor factors for conservative management of cervical intraepithelial neoplasia grade 2: Cytology and HPV genotyping. Gynecol Oncol. 2021;162(3):569–74. Hong S, Laimins LA. Manipulation of the innate immune response by human papillomaviruses. Virus Res. 2017;231:34–40. Moody CA, Laimins LA. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10(8):550–60. Integrated genomic and. molecular characterization of cervical cancer. Nature. 2017;543(7645):378–84. Li T, Yang Z, Zhang C, Wang S, Mei B. Genetic variation of E6 and E7 genes of human papillomavirus type 16 from central China. Virol J. 2023;20(1):217. Yeo-Teh NSL, Ito Y, Jha S. High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis. Int J Mol Sci 2018, 19(6). Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018;5(5):Cd009069. Hoes J, Woestenberg PJ, Bogaards JA, King AJ, de Melker HE, Berkhof J, Hoebe C, van der Sande MAB, van Benthem BHB. Population Impact of Girls-Only Human Papillomavirus 16/18 Vaccination in The Netherlands: Cross-Protective and Second-Order Herd Effects. Clin Infect diseases: official publication Infect Dis Soc Am. 2021;72(5):e103–11. Malagón T, Drolet M, Boily MC, Franco EL, Jit M, Brisson J, Brisson M. Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(10):781–9. Buck CB, Day PM, Trus BL. The papillomavirus major capsid protein L1. Virology. 2013;445(1–2):169–74. Yang A, Farmer E, Wu TC, Hung CF. Perspectives for therapeutic HPV vaccine development. J Biomed Sci. 2016;23(1):75. Smalley Rumfield C, Roller N, Pellom ST, Schlom J, Jochems C. Therapeutic Vaccines for HPV-Associated Malignancies. ImmunoTargets therapy. 2020;9:167–200. Lin MJ, Svensson-Arvelund J, Lubitz GS, Marabelle A, Melero I, Brown BD, Brody JD. Cancer vaccines: the next immunotherapy frontier. Nat cancer. 2022;3(8):911–26. Hancock G, Hellner K, Dorrell L. Therapeutic HPV vaccines. Best Pract Res Clin Obstet Gynecol. 2018;47:59–72. Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, Edwards L, Parker RL, Denny L, Giffear M, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet (London England). 2015;386(10008):2078–88. Melief CJM, van der Gracht E, Wiekmeijer AS. Combination immunotherapy with synthetic long peptides and chemotherapy or PD-1 blocker for cancers caused by human papilloma virus type 16. Semin Immunopathol. 2023;45(2):273–7. Ikeda Y, Adachi K, Tomio K, Eguchi-Kojima S, Tsuruga T, Uchino-Mori M, Taguchi A, Komatsu A, Nagamatsu T, Oda K et al. A Placebo-Controlled, Double-Blind Randomized (Phase IIB) Trial of Oral Administration with HPV16 E7-Expressing Lactobacillus, GLBL101c, for the Treatment of Cervical Intraepithelial Neoplasia Grade 2 (CIN2). Vaccines 2021, 9(4). Peng S, Tu HF, Cheng M, Hu MH, Tsai HL, Tsai YC, Koenig C, Brayton C, Wang H, Chang YN, et al. Immune responses, therapeutic anti-tumor effects, and tolerability upon therapeutic HPV16/18 E6/E7 DNA vaccination via needle-free biojector. mBio. 2023;14(5):e0212123. Kang WD, Choi HS, Kim SM. Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2-3)? Gynecol Oncol. 2013;130(2):264–8. Kechagias KS, Kalliala I, Bowden SJ, Athanasiou A, Paraskevaidi M, Paraskevaidis E, Dillner J, Nieminen P, Strander B, Sasieni P, et al. Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis. BMJ (Clinical Res ed). 2022;378:e070135. Bogani G, Raspagliesi F, Sopracordevole F, Ciavattini A, Ghelardi A, Simoncini T, Petrillo M, Plotti F, Lopez S, Casarin J et al. Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison. Vaccines 2020, 8(4). Ghelardi A, Parazzini F, Martella F, Pieralli A, Bay P, Tonetti A, Svelato A, Bertacca G, Lombardi S, Joura EA. SPERANZA project: HPV vaccination after treatment for CIN2. Gynecol Oncol. 2018;151(2):229–34. Additional Declarations No competing interests reported. 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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-6379197","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":452121962,"identity":"36160d61-311b-4d1b-9fdc-bb79c3e148f6","order_by":0,"name":"Kaiyang Geng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYNCCAwwM7O2NjQ8+kKSF58zhZsMZpGm5kd4mzUGMYv4ZOWaSX84ctueRfNggzcBgJ6fbQECLxI0cM2mZG4eZeaQTG4wLGJKNzQ4Q0GIgAdQi8eEwmz1QS/IMhgOJ24jVwsMjebDhMA+xWiQ/3DgswSPB2NhMlBaJM8+KrRnOpBvw8CQ2M84wIMIv/O3JG2/+OGZtz8N+/PmPDxV2cgS1MAhkmEjzMDTD3ElIOdia448//mCoI0bpKBgFo2AUjFQAAEnURaUC5UK0AAAAAElFTkSuQmCC","orcid":"","institution":"Beijing Chao-yang Hospital, Capital Medical University, Beijing","correspondingAuthor":true,"prefix":"","firstName":"Kaiyang","middleName":"","lastName":"Geng","suffix":""},{"id":452121963,"identity":"aa0d513b-4735-425d-aa40-7d9ec2851a5f","order_by":1,"name":"Siyu Bai","email":"","orcid":"","institution":"Fuxing Hospital, Capital Medical University, 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01:08:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6379197/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6379197/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82355725,"identity":"4623aea6-7fd1-44ad-841f-aefd4074ba85","added_by":"auto","created_at":"2025-05-09 11:15:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95295,"visible":true,"origin":"","legend":"\u003cp\u003ePatient outcomes.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/659759b6cca2b848ec43365b.png"},{"id":82355723,"identity":"14bbfd75-89c8-4dab-83a2-b32387c75319","added_by":"auto","created_at":"2025-05-09 11:15:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":13972,"visible":true,"origin":"","legend":"\u003cp\u003eRate of disease progression to CIN3+ in 5 years for all patients\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/6d0b99e614e7eca09a6bcbec.png"},{"id":82355733,"identity":"3ba0dc62-5c4b-4118-8b73-3acbe3920937","added_by":"auto","created_at":"2025-05-09 11:15:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":18775,"visible":true,"origin":"","legend":"\u003cp\u003eRate of disease progression to CIN3+ in 5 years for HPV16\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/a17228b66e0967a69d86c84f.png"},{"id":82355724,"identity":"b2a8ccec-1e4a-495f-8a08-7a13282d90c7","added_by":"auto","created_at":"2025-05-09 11:15:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":15689,"visible":true,"origin":"","legend":"\u003cp\u003eRate of disease progression to CIN3+ in 5 years for pregnancy times\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/179c2912a6b6ab39d7b8a21a.png"},{"id":82355726,"identity":"dedfee88-1357-4951-ae1b-3d5436ae1d89","added_by":"auto","created_at":"2025-05-09 11:15:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":18453,"visible":true,"origin":"","legend":"\u003cp\u003eRate of disease progression to CIN3+ in 5 years for vaccination after the diagnosis of CIN2\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/4acb550a119972107dd03be4.png"},{"id":103909434,"identity":"6542c93c-85a7-4c59-b61c-4776fcc793e9","added_by":"auto","created_at":"2026-03-04 11:43:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":808599,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6379197/v1/30cd82ec-3298-4cb5-afdf-16d24f830134.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"HPV16, Multigravida, and Post-CIN2 Vaccination in Chinese Patients : A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCervical cancer remains the fourth most prevalent malignancy among women globally, accounting for approximately 604,000 new cases and 342,000 deaths in 2020 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The primary etiological factor contributing to the development of cervical cancer is persistent infection with high-risk human papillomavirus (HR-HPV). The transition from HR-HPV infection to invasive cervical cancer typically takes between 8 to 10 years [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Consequently, alongside effective screening techniques, it is imperative to manage HPV-associated CINs appropriately to prevent and treat cervical cancer.\u003c/p\u003e \u003cp\u003eCINs are classified into three grades\u0026mdash;CIN1, CIN2, and CIN3\u0026mdash;according to the 2003 edition of the WHO Classification of Tumors of the Female Reproductive System. This classification outlines a continuum of morphological changes in the squamous epithelium of the cervix, progressing from aberrant hyperplasia to carcinoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, the diagnostic consistency of CIN2 among pathologists is poor, particularly when compared to CIN1 and CIN3, with diagnostic agreement falling below 50% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Moreover, it has been found that certain CIN2 lesions are reversible and may arise from transient HPV infections. The revised 2014 WHO nomenclature for tumors of the female reproductive system recommended the use of two categories: high-grade squamous intraepithelial lesions (HSIL) and low-grade squamous intraepithelial lesions (LSIL). LSIL encompasses CIN1, flat condyloma, and panniculocytosis, while HSIL includes CIN2, CIN3, severe atypical hyperplasia, and carcinoma in situ. Notably, CIN2 is no longer recognized as an independent histological subtype [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]HSIL, primarily resulting from persistent HR-HPV infection, carries a significantly elevated risk of progressing to cervical cancer and often necessitates intervention, such as cervical conization. Notably, cervical insufficiency associated with cervical conization may result in miscarriage, preterm labor, and premature rupture of membranes during pregnancy in young women [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nevertheless, the majority of preneoplastic lesions do not advance to cancer, highlighting the need for more judicious interventions for CINs, particularly CIN2, as a crucial strategy to reduce morbidity and mortality while enhancing the quality of life for patients.\u003c/p\u003e \u003cp\u003eIn our recent clinical practice, a straightforward observation strategy has been recommended as a treatment option for patients diagnosed with CIN2 under their fully informed consent, over the past decade.\u003c/p\u003e \u003cp\u003eThis study conducted a retrospective analysis of the clinical and pathological data of patients with CIN2 who were managed through simple follow-up protocols. The aim was to investigate the risk factors associated with disease progression to CIN3 or invasive cervical cancer and to provide valuable insights for the effective management of this patient population.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study retrospectively collected and analyzed the medical records of patients diagnosed with CIN2 who were treated at Beijing Chaoyang Hospital, Capital Medical University，\u003cstrong\u003ebetween January 2012 and March 2021\u003c/strong\u003e.\u0026nbsp;The institution serves as one of referral centers for the diagnosis and treatment of precancerous lesions of the female lower genital tract in Beijing, China. The inclusion criteria for the study were as follows: 1) women aged ≥18 years; 2) histological diagnosis of CIN2 without prior treatment; 3) a follow-up period of no less than 6 months; and 4) a request for conservative treatment accompanied by the signing of an informed consent form. The exclusion criteria included: 1) pregnant or lactating women; 2) individuals with immunosuppressive conditions (such as autoimmune diseases or acquired immune deficiency syndrome [AIDS]); 3) women with any type of malignant tumors, either concurrently or sequentially; and 4) those who had previously received treatment for cervical HSIL, adenocarcinoma in situ (AIS), or invasive cervical cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDemographic characteristics of the patients, as well as results from cytology, HPV testing, and colposcopy, were retrospectively collected. HPV testing was performed on samples stored in needle test vials using real-time polymerase chain reaction (PCR) with Liferiver (China), a system designed to identify high-risk HPV (HR-HPV) genotypes. The presence of HPV16, HPV18, and other HR-HPV types (HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59, HPV66, and HPV68) was documented. Cytological analysis was conducted using the ThinPrep Pap test (Hologic, USA) on exfoliated cells collected from the cervix surface, with results reported according to the Bethesda system terminology. Colposcopy was performed by experienced colposcopists. The histological diagnosis of CIN was established based on the morphological characteristics identified through hematoxylin and eosin staining, in accordance with WHO criteria. The initial diagnosis of CIN2 was validated by two pathologists with extensive expertise in gynecologic pathology, each of whom independently reviewed the pathological sections. In cases of disagreement, a joint review was conducted. If consensus was not achieved, a third expert was consulted to evaluate the slides until a consensus diagnosis was reached, ensuring that at least two pathologists agreed on the final interpretation.\u003c/p\u003e\n\u003cp\u003eThroughout the follow-up period, patients had the option to discontinue observation and request conization at any time. Follow-up evaluations were conducted every six months, during which patients underwent gynecological examinations, cytological assessments, and colposcopy. Cervical biopsy was performed as necessary. Following two consecutive negative results for both ThinPrep cytology test (TCT) and HR-HPV tests, patients could transition to annual follow-up. Disease regression was defined by the occurrence of one or more of the following criteria: 1) TCT and HR-HPV results were both negative; 2) HR-HPV was negative while TCT results showed abnormalities categorized as atypical squamous cells of undetermined significance (ASCUS) or LSIL, without any abnormal findings on colposcopy or negative cervical biopsy results; 3) cervical biopsy, endocervical curettage (ECC), or loop electrosurgical excision procedure (LEEP) pathological results were classified as ≤CIN1. The maintenance of CIN2 status for one year or longer was classified as persistent CIN2, which necessitated close monitoring. The presence of CIN3, adenocarcinoma in situ (AIS), or invasive cervical cancer was classified as disease progression; in such cases, withdrawal from the study and timely surgical intervention were recommended.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were analyzed using IBM SPSS Statistics version 26.0 (IBM Corp., Armonk, NY, USA). Categorical variables were analyzed by the χ2 test or Fisher exact test. Univariate and multivariate logistic regression analyses were performed to identify influential regressors. Additionally, Kaplan-Meier analyses were employed to assess the five-year incidence of disease progression. Based on the multivariate Cox regression model, the hazards ratio (HR) was adjusted for covariates. All statistical tests were conducted at an alpha level of 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University (CMU).Ethics Batch Number:2025-ke-401\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, a total of 588 women were diagnosed with CIN2. Eight patients who received LEEP as initial treatment were excluded from the analysis. Additionally, patients with autoimmune diseases (specifically systemic lupus erythematosus [SLE] and Hashimoto\u0026apos;s thyroiditis, totaling two cases) and those with a history of conization surgery (three cases) were also excluded. Furthermore, eight pregnant patients and 57 individuals lacking follow-up information were excluded. Consequently, 510 eligible women were included in this analysis.\u003c/p\u003e\n\u003cp\u003eTable 1 Demographical characteristics and clinical data of the patients\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"574\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003eAll patients Results (n=510)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(y, Mean \u0026plusmn; SD)\u003c/p\u003e\n \u003cp\u003e(y, Range)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30.15\u0026plusmn;5.82\u003c/p\u003e\n \u003cp\u003e18-61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eEducational level\u003c/p\u003e\n \u003cp\u003eBelow bachelor\u0026apos;s degree\u003c/p\u003e\n \u003cp\u003eBachelor degree or above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e146/510 (28.6%, \u0026nbsp; \u0026nbsp;95%CI 24.5-32.7)\u003c/p\u003e\n \u003cp\u003e364/510 (71.4%, \u0026nbsp; \u0026nbsp;95%CI 67.3-75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e248/510 (48.6%, \u0026nbsp; \u0026nbsp;95%CI 44.1-52.9)\u003c/p\u003e\n \u003cp\u003e262/510 (51.4%, \u0026nbsp; \u0026nbsp;95%CI 47.0-55.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eWeekly drug use\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47/510 (9.2%, \u0026nbsp; \u0026nbsp; \u0026nbsp;95% CI 6.9-11.8)\u003c/p\u003e\n \u003cp\u003e463/510 (90.8%, \u0026nbsp; \u0026nbsp;95%CI 88.2-93.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eContraception (before diagnosis)\u003c/p\u003e\n \u003cp\u003eCondom only\u003c/p\u003e\n \u003cp\u003eCondom or none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e232/510 (45.5%, \u0026nbsp; \u0026nbsp;95%CI 41.2-49.8)\u003c/p\u003e\n \u003cp\u003e278/510 (54.5%, \u0026nbsp; \u0026nbsp;95%CI 50.2-58.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eContraception(after diagnosis)\u003c/p\u003e\n \u003cp\u003eCondom only\u003c/p\u003e\n \u003cp\u003eCondom or none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e312/510 (61.2%, \u0026nbsp; \u0026nbsp;95%CI 57.1-65.3)\u003c/p\u003e\n \u003cp\u003e198/510 (38.8%, \u0026nbsp; \u0026nbsp;95%CI 34.7-42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eAge at first intercourse (y, Mean \u0026plusmn;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e21.24\u0026plusmn;2.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eNumber of sexual partners\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(before diagnosis of CIN2)\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e121/510 (23.7%, \u0026nbsp; \u0026nbsp;95%CI 20.0-27.5)\u003c/p\u003e\n \u003cp\u003e389/510 (76.3%, \u0026nbsp; \u0026nbsp;95%CI 72.5-80.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eNumber of sexual partners\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(after diagnosis of CIN2)\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e383/510 (75.1%, \u0026nbsp; \u0026nbsp;95%CI 71.2-78.6)\u003c/p\u003e\n \u003cp\u003e127/510 (24.9%, \u0026nbsp; \u0026nbsp;95%CI 21.4-28.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eNumber of pregnancies\u003c/p\u003e\n \u003cp\u003e\u0026le;3\u003c/p\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e482/510 (94.5%, \u0026nbsp; \u0026nbsp;95%CI 92.5-96.5)\u003c/p\u003e\n \u003cp\u003e28/510 (5.5%, \u0026nbsp; \u0026nbsp; \u0026nbsp;95%CI 3.5-7.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eNumber of deliveries\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e463/510 (90.8%, \u0026nbsp; \u0026nbsp;95%CI 88.2-93.1) \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47/510 (9.2%, \u0026nbsp; \u0026nbsp; \u0026nbsp;95%CI 6.9-11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003cp\u003eCervical contact bleeding\u003c/p\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e83/510 (16.3%, \u0026nbsp; \u0026nbsp; 95%CI 13.1-19.6)\u003c/p\u003e\n \u003cp\u003e427/510 (83.7%, \u0026nbsp; \u0026nbsp;95%CI 80.4-86.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eMenstruation\u003c/p\u003e\n \u003cp\u003eRegular\u0026nbsp;menstruation\u003c/p\u003e\n \u003cp\u003eMenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e505/510 (99.0%, \u0026nbsp; \u0026nbsp;95%CI 98.0-99.8)\u003c/p\u003e\n \u003cp\u003e5/510 (1.0%, \u0026nbsp; \u0026nbsp; \u0026nbsp; 95%CI 0.2-2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eVaccination\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e153/510 (30.0%, \u0026nbsp; \u0026nbsp;95%CI 25.9-33.9)\u003c/p\u003e\n \u003cp\u003e357/510 (70.0%, \u0026nbsp; \u0026nbsp;95%CI 66.1-74.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eVaccination before diagnosis of CIN2\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e28/510 (5.5%, 95%CI 3.5-7.5)\u003c/p\u003e\n \u003cp\u003e482/510 (94.5%, 95%CI 92.5-96.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eVaccination after diagnosis of CIN2\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e385/510 (75.5%, 95%CI 71.7-79.2)\u003c/p\u003e\n \u003cp\u003e125/510 (24.5%, 95%CI 20.8-28.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003ePrevious cytology\u003c/p\u003e\n \u003cp\u003e\u0026le;ASCUS\u003c/p\u003e\n \u003cp\u003e\u0026gt;ASCUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e360/510 (70.6%, \u0026nbsp; \u0026nbsp;95%CI 66.6-74.6)\u003c/p\u003e\n \u003cp\u003e150/510 (29.4%, \u0026nbsp; \u0026nbsp;95%CI 25.4-33.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eHPV genotypes\u003c/p\u003e\n \u003cp\u003e16+\u003c/p\u003e\n \u003cp\u003eOther genotypes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e172/510 (33.7%, \u0026nbsp; \u0026nbsp;95%CI 29.6-37.8)\u003c/p\u003e\n \u003cp\u003e338/510 (66.3%, \u0026nbsp; \u0026nbsp; \u0026nbsp; 95%CI 62.2-70.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 238px;\"\u003e\n \u003cp\u003eNumber of biopsies\u003c/p\u003e\n \u003cp\u003e=1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 336px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e276/510 (54.1%, \u0026nbsp; \u0026nbsp;95%CI 49.8-58.5)\u003c/p\u003e\n \u003cp\u003e234/510 (45.9%, \u0026nbsp; \u0026nbsp;95%CI 41.5-50.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe mean age of the 510 patients enrolled in the study was 30.15 \u0026plusmn; 5.82 years (Table1) , with 384 patients (75.3%) being nulliparous. During the mean follow-up period of 37.0 \u0026plusmn; 1.3 months, 60 patients opted to discontinue simple observation and chose cervical conization based on their personal choice. At the final visit, persistent CIN2 was identified in 55 patients (11%), of whom 43 underwent LEEP surgery. Disease progression was observed in 32 patients (6%), including 31 cases of CIN3 and one case of cervical carcinoma in situ. Disease regression was noted in 363 patients (71%), comprising 329 cases that were double negative for both TCT and HPV, and 34 cases of CIN1. The median time to remission was 9.1 months (range: 5.1\u0026ndash;17.3 months). No patients died as a result of the disease. During the study period, 96 women (25.0%) achieved pregnancy and had full-term deliveries. (Fig.1)\u003c/p\u003e\n\u003cp\u003eIn the univariate analysis, the following factors were identified as risk factors for disease progression: age greater than 30 years (P \u0026lt; 0.001), HPV16 infection (P \u0026lt; 0.001), a history of more than three pregnancies (P \u0026lt; 0.001), and having more than one delivery (P = 0.001) (Table 2). Among the study population, 5.49% (28 out of 510) of patients received vaccination before the diagnosis of CIN2, while 24.51% (125 out of 510) were vaccinated following their diagnosis. HPV vaccination whether before or after histologically diagnosed of CIN2 conferred a protective effect (P = 0.042), and vaccination administered only after the diagnosis of CIN2 also served as a protective factor (P = 0.046) (Table2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003eTable 2 The univariate and multivariate analysis of the distribution of indicators characteristics and risk factors.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"588\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eVariables \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003eAll patients Results\u003c/p\u003e\n \u003cp\u003e(n=510)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eRegression+CIN2 \u0026nbsp; Progression to CIN3/AIS \u0026nbsp; \u0026nbsp; (n=478) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; (n=32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eMultivariate analysis \u0026nbsp; P value\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOR (95%CI) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(y, Mean \u0026plusmn; SD)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30.15\u0026plusmn;5.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eAge (y) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026gt;30\u003c/p\u003e\n \u003cp\u003e\u0026le;30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e187 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;15\u003c/p\u003e\n \u003cp\u003e291 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eEducational level\u003c/p\u003e\n \u003cp\u003eBelow bachelor\u0026apos;s degree\u003c/p\u003e\n \u003cp\u003eBachelor degree or above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e135 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;11\u003c/p\u003e\n \u003cp\u003e343 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e0.457\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e229 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;19\u003c/p\u003e\n \u003cp\u003e249 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eWeekly drug use\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 5\u003c/p\u003e\n \u003cp\u003e436 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eContraception (before diagnosis)\u003c/p\u003e\n \u003cp\u003eCondom only\u003c/p\u003e\n \u003cp\u003eCondom or none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e221 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;11\u003c/p\u003e\n \u003cp\u003e257 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eContraception (after diagnosis)\u003c/p\u003e\n \u003cp\u003eCondom only\u003c/p\u003e\n \u003cp\u003eCondom or none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e295 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;17\u003c/p\u003e\n \u003cp\u003e183 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;15\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.334\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eAge at first intercourse (y, Mean \u0026plusmn;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e21.24 \u0026plusmn;2.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eAge at first intercourse (y)\u003c/p\u003e\n \u003cp\u003e\u0026ge;18\u003c/p\u003e\n \u003cp\u003e\u0026lt;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e451 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;30\u003c/p\u003e\n \u003cp\u003e27 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eNumber of sexual partners\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(before diagnosis of CIN2)\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e112 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;9\u003c/p\u003e\n \u003cp\u003e366 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.546\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eNumber of sexual partners\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(after diagnosis of CIN2)\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e360 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;23\u003c/p\u003e\n \u003cp\u003e118 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eNumber of pregnancies\u003c/p\u003e\n \u003cp\u003e\u0026le;3\u003c/p\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e457 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;25\u003c/p\u003e\n \u003cp\u003e21 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e4.38 (1.63-11.79) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eNumber of deliveries\u003c/p\u003e\n \u003cp\u003e\u0026le;1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e439 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;24\u003c/p\u003e\n \u003cp\u003e39 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003cp\u003eCervical contact bleeding\u003c/p\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e78 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 5\u003c/p\u003e\n \u003cp\u003e400 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eMenstruation\u003c/p\u003e\n \u003cp\u003eRegular\u0026nbsp;menstruation\u003c/p\u003e\n \u003cp\u003eMenopause\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e474 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;31\u003c/p\u003e\n \u003cp\u003e4 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.730\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eVaccination\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e149 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;4\u003c/p\u003e\n \u003cp\u003e329 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;28\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eVaccination before diagnosis of CIN2\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003cp\u003e451 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;31\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.837\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eVaccination after diagnosis of CIN2\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e122 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3\u003c/p\u003e\n \u003cp\u003e356 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.046\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.286 (0.08-0.98) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.046\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003ePrevious cytology\u003c/p\u003e\n \u003cp\u003e\u0026le;ASCUS\u003c/p\u003e\n \u003cp\u003e\u0026gt;ASCUS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e338 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;22\u003c/p\u003e\n \u003cp\u003e140 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.814\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eHPV genotypes\u003c/p\u003e\n \u003cp\u003e16+\u003c/p\u003e\n \u003cp\u003eOther genotypes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e151 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;21\u003c/p\u003e\n \u003cp\u003e327 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;11\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.07 (1.88-8.81) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.0204%;\"\u003e\n \u003cp\u003eNumber of biopsies\u003c/p\u003e\n \u003cp\u003e=1\u003c/p\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 31.9728%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e260 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;16\u003c/p\u003e\n \u003cp\u003e218 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.629\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eIn the multivariate analysis, HPV16 infection (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.88-8.81, P \u0026lt; 0.001) and having more than three pregnancies (OR 4.38, 95% CI 1.63-11.79, P = 0.003) were identified as independent risk factors for disease progression. Notably, HPV vaccination after the diagnosis of CIN2 was recognized as an independent protective factor (OR 0.29, 95% CI 0.08-0.98, P=0.046) (Table 2). According to the multivariate Cox regression analysis, the risk of disease progression was higher for patients who did not receive the vaccine after diagnosis of CIN2 (HR 3.39, 95% CI 1.02-11.20, P=0.046), with pregnancies \u0026gt;3 (HR 3.95, 95% CI 1.69-9.26, P=0.002), and HPV16 positive (HR 3.70, 95% CI 1.77-7.75, P=0.001), as shown in Table3.\u003c/p\u003e\n\u003cp\u003eTable3.Progression-free survival analysis by the Cox model. CI, confidence interval.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"482\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 229px;\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 253px;\"\u003e\n \u003cp\u003eHazards ratio (95% CI) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;p value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 229px;\"\u003e\n \u003cp\u003ePregnancy times\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;3 versus \u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 253px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.95 (1.69-9.26) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 229px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eVaccination after diagnosis of CIN2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNon-recipients versus recipients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 253px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.39 (1.02-11.20) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 229px;\"\u003e\n \u003cp\u003eHPV genotypes\u003c/p\u003e\n \u003cp\u003e16+ versus Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 253px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.70 (1.77-7.75) \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe overall 5-year disease progression rate was 9.2% (Fig. 2). As the survival curve consistently remained above 50%, the median time to disease progression was not reached. The mean time to progression was 56.486 months (\u0026plusmn;0.607 months). For patients who ultimately progressed to CIN3+, the median time to disease progression was 13.200 months (\u0026plusmn;0.574 months). \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe five-year risk of disease progression (DPR) was 72% for patients exhibiting HPV16 infection, having more than three pregnancies, and not receiving HPV vaccination after the diagnosis of CIN2. In contrast, for patients with three or fewer pregnancies, who were HPV16 negative and received vaccination after the diagnosis of CIN2, the five-year DPR was significantly lower at 2.6%. (Fig. 3, 4, 5)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe conservative management of CIN2 remains a controversial topic. Following the release of updated guidelines in 2012, an increasing body of literature has emerged that supports the safety of conservative management strategies for women diagnosed with CIN2 [6]. This study included 510 patients with CIN2 who received simple observation management strategies, representing one of the largest samples of research focusing on such strategies for CIN2 published to date. The mean follow-up period exceeded 36 months. Our data provided a compelling foundation for the clinical management of this patient population. In our study, the majority of patients (71%) experienced remission. Disease progression occurred in only a small proportion of patients (6%), which is lower than the 10–18% reported in previous studies [5, 7]. The lower rate of progression may be attributed to the fact that 30% of the patients had been vaccinated against HPV.\u003c/p\u003e\n\u003cp\u003eOur data indicate that multiple pregnancies are associated with an increased risk of progression of CIN2. A local study in Paraguay demonstrated that women with more than four pregnancies had a threefold increased risk of CIN2+, compared to those with zero to one pregnancy [8]. This association between a high number of pregnancies and CIN2+ has been corroborated by other studies, particularly among younger women [9]. It is hypothesized that the risk may be exacerbated by several full-term pregnancies occurring in a short timeframe [9]. Notably, the mode of delivery—whether vaginal or via cesarean section—does not appear to influence the progression of squamous intraepithelial lesions (SIL) [10].\u003c/p\u003e\n\u003cp\u003eDuring pregnancy, the elevated concentrations of estrogen stimulate the eversion of the cervical squamous-column junction. Consequently, the duration of exposure to potential carcinogens, such as HPV infection, is prolonged within the transformation zone [11]. Additionally, as the duration of pregnancy extends, colposcopic assessment becomes more challenging, potentially leading to increased rates of misdiagnosis. Physiological changes during pregnancy, which include heightened squamous metaplasia and increased vascularity of the cervix, along with morphological alterations, may complicate the differentiation between active squamous metaplasia, low-grade CIN, and benign lesions that may present as suspicious abnormalities [12]. Furthermore, other studies have shown that hormonal mechanisms, similar to those associated with oral contraceptive use, may also play a role. Steroid contraceptive hormones are thought to bind to specific DNA sequences within transcriptional regulatory regions on HPV DNA. The integration of HR-HPV DNA into the host genome enhances the expression of the E6 and E7 HPV oncoproteins, which interfere with the function of the p53 tumor suppressor gene, ultimately leading to carcinogenesis [13]. Changes in hormone levels during pregnancy may also diminish the immune response to HPV infection [14]. In the presence of antigens, progesterone and estradiol may skew specific T cells towards a cytokine profile characterized by coexpression of interleukin-10 (IL-10) and interleukin-4 (IL-4), potentially facilitating HPV persistence by preventing the elimination of infected cells by cytotoxic T lymphocytes [15].\u003c/p\u003e\n\u003cp\u003eIn our study, a significant majority of patients (60.4%) were aged 30 years or younger, with a mean age of 30 years and a median age of 29 years, spanning an age range of 18 to 61 years. Previous studies have not sufficiently addressed the importance of patient age. Although multivariate analysis in our study revealed no significant difference in age between those with disease progression and those without (P=0.702), age remains a crucial factor with predictive value for potential CIN2+ cases. A global review indicates that the incidence of high-grade cervical lesions peaks at a relatively younger age, specifically between 25 and 40 years\u0026nbsp;[16]. Conversely, the age-related patterns of low-grade lesions generally decline after peaking in younger cohorts (20-30 years) [16].\u0026nbsp;In women with precancerous lesions, the risk appears to peak or plateau around 35-55 years of age\u0026nbsp;[17]. One study reported a prevalence of 58.7% for HR-HPV among women younger than 25 years, alongside a notable prevalence of high-grade cervical disease at 9.4%. Among women in this age group with CIN3, all were positive for HPV16/18\u0026nbsp;[18]. Therefore, we recommend heightened attention to the prevalence of HR-HPV infections, particularly among young women, alongside the necessity of regular monitoring of cervical lesion status. Despite the high-risk status associated with HPV16/18 in younger women, our study found that over 90% of young women with CIN2 experienced either regression or persistence, consistent with previous research\u0026nbsp;[10]. Existing literature supports the justification for active surveillance in histologically confirmed CIN2 cases among untreated young women, rather than immediate intervention\u0026nbsp;[7].\u003c/p\u003e\n\u003cp\u003eThe findings from our study suggest that HPV16 infection, accounting for 33.7% of all positive infections, represents one of the risk factors for disease progression, aligning with data from other contemporary studies [19]. Different HR-HPV genotypes exhibit varying carcinogenic potentials, with HPV16 recognized as a significant viral factor in disease persistence and progression. HPV genotyping could enhance risk-based management strategies for women diagnosed with CIN2. Our results indicate that the presence of HPV16 substantially increases the risk of progression to CIN2 compared to other HPV genotypes, a finding that has been consistently validated across studies, as well as its prevalence in CIN3 and cervical cancer cases [20]. Current research emphasizes that the E6 and E7 oncoproteins of HPV16 play a critical role in carcinogenesis [13]. E6 and E7 oncoproteins play a crucial role in promoting viral replication by modulating various cellular processes, including cell cycle control, cell survival, cell differentiation, immune evasion, and the DNA damage response [21, 22]. The extent of HPV integration into the host genome varies by HPV type. Studies indicate that approximately 76% of cancers associated with HPV16 exhibit gene integration, while nearly all cancers linked to HPV18 also demonstrate this integration. Furthermore, different variant lineages may possess varying integration potentials due to differences in E6 and E7 activity [23, 24]. A significant target of the HR-HPV oncoproteins E6 and E7 is the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like protein 3 (APOBEC3). Research has shown that mutations in APOBEC, triggered by the host's immune response to HPV infection, may constitute the primary source of mutations found in HPV-positive tumors [23, 25]. Consequently, we emphasize the need for close monitoring of patients infected with HPV16.\u003c/p\u003e\n\u003cp\u003eIn our study, a significant majority of patients (71%) experienced remission, aligning with findings from several other studies in the literature [7, 20]. Disease progression occurred in only a small proportion of patients (6%), which is lower than the 10-18% range reported in previous research [5, 7]. This reduced rate of progression may be partially attributed to the fact that 30% of the patients had received prophylactic HPV vaccinations before or after their CIN2 diagnosis. HPV vaccination has been widely recognized as an effective measure for the prevention of cervical cancer. Evidence suggests that HPV vaccines provide protection against cervical precancerous lesions in both adolescent girls and young women, with greater efficacy observed in those with lesions associated with HPV16/18 and those testing negative for HR-HPV at enrollment [26]. Additionally, HPV vaccines offer a degree of cross-protective effects, with even bivalent HPV vaccinations exhibiting cross-protection against various HPV types, including types 35, 52, and 58 [27, 28].\u003c/p\u003e\n\u003cp\u003eOur findings indicate that HPV vaccination functions as an independent protective factor against the progression of CIN2. The protective effect of the HPV vaccine is evident regardless of whether it was administered prior to or following the diagnosis of CIN2. Previous reports have noted a reduction in the risk of CIN2+ occurrences associated with the implementation of catch-up HPV vaccination for younger populations [26]. Despite the capacity of prophylactic vaccines to prevent new HPV infections and reinfections, the incidence of CINs remains prevalent. This persistence can be attributed primarily to the inability of prophylactic HPV vaccines to eliminate pre-existing infections and related conditions. The currently licensed prophylactic vaccines are developed based on virus-like particles (VLPs) derived from the papillomavirus L1 capsid protein. These VLPs closely mimic the natural spatial structure of the target antigen, effectively inducing a high titer of serum neutralizing antibodies post-vaccination [29]. However, the integration of HPV viral DNA into the host genome results in the deletion of late genes L1 and L2, which compromises the L1-specific immune response initiated by prophylactic vaccines, thereby rendering them ineffective in clearing existing HPV infections [30]. Therapeutic vaccines are currently undergoing clinical trials, utilizing mechanisms that deliver target antigens to antigen-presenting cells (APCs), which subsequently activate the immune response of HPV-specific CD8+ cytotoxic T lymphocytes and CD4+ helper T lymphocytes [31]. These therapeutic vaccines aim to induce a cell-mediated immune response against specific HPV antigens, particularly the E6 and E7 oncoproteins, which are critical for the survival and progression of HPV-infected cancer cells [32]. Given that HPV E6 and E7 are constitutively expressed in both premalignant and invasive lesions but are absent in healthy tissues [33], they represent ideal targets for the immunotherapy of HPV-induced malignancies. Consequently, most therapeutic HPV vaccines currently in development utilize E6 and E7 proteins as target antigens. Notably, there are synthetic DNA therapeutic vaccines targeting HPV16/18 E6 and E7 proteins designed for CIN2/3, which have demonstrated the potential for viral clearance, histopathological regression, and the prevention of low-risk lesions from progressing to high-risk lesions and cancer [34]. In addition, therapeutic vaccines have been investigated as standalone treatments for patients with premalignant diseases caused by HPV, and they may also serve as adjunctive therapies alongside chemotherapy and immunotherapy for cancers [35]. Presently, therapeutic HPV vaccines encompass a variety of platforms, including recombinant vector vaccines, nucleic acid vaccines, and subunit vaccines. Innovative delivery methods, such as needle-free biojectors and oral administration, are also being explored, exhibiting promising translational potential for the treatment of HPV16/18 infection and disease [36, 37].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHPV vaccination may enhance treatment efficacy and mitigate tumor recurrence, particularly in cases associated with HPV. A retrospective study conducted by Kang et al. in 2015 analyzed HPV vaccination data from 737 patients who underwent cervical conization. Following this procedure, 360 patients received the HPV vaccine postoperatively to prevent cervical exposure to the virus. The findings indicated that the absence of vaccination after surgery constituted an independent risk factor for disease recurrence [38]. Recent literature supports that combining surgical resection with postoperative vaccination significantly reduces the risk of recurrence of CIN2+ [38-41]. The SPERANZA project posits that through immune mechanisms activated by surgery, postoperative vaccination can elevate local antibody concentrations, which are crucial during the regeneration of resected tissues. Additionally, vaccination following LEEP has been identified as beneficial in preventing recurrence after conization [41]. Collectively, these studies suggest that HPV vaccination may offer both preventative and therapeutic benefits for HPV-related cervical lesions.\u003c/p\u003e\n\u003cp\u003eThe strengths of this study include several key factors. Firstly, the study population was substantial, and the extended follow-up period provided ample time to observe the various factors influencing conservative management of CIN2 as well as the natural progression of the disease. Secondly, we employed a standardized colposcopy referral process instead of alternative methods, which contributed to the accuracy of our findings. Additionally, the demographic data collected was detailed and comprehensive, thereby enhancing the credibility of the results. To our knowledge, this was the first study to evaluate the impact of HPV vaccination following a histological diagnosis of CIN2. Our results indicated a protective effect of HPV vaccination on disease progression during conservative observation of CIN2. However, this study also had certain limitations. Firstly, it was a retrospective cohort study, which introduced the potential for recall bias during follow-up assessments. Secondly, the research was conducted at a single center, which may have limited the generalizability of the findings. Thirdly, for patients who were lost to follow-up after their initial visit, we were unable to obtain test results from other healthcare facilities they may have visited. Future research should focus on prospective, multicenter studies to identify specific and accurate predictors of outcomes in this patient population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, conservative management strategies for patients with CIN2 have been demonstrated to be a safe approach. The low rate of progression associated with CIN2 supports the viability of conservative treatment for patients who choose this option. However, for patients who are infected with HPV-16 and have had multiple pregnancies, clinical management should consider conization or the completion of childbearing followed by conization, due to their elevated risk of disease progression. Furthermore, for unvaccinated patients diagnosed with CIN2, HPV vaccination is strongly recommended to mitigate potential progression of the disease.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCIN2: cervical intraepithelial neoplasia grade 2\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOR: odds\u0026nbsp;ratio\u003c/p\u003e\n\u003cp\u003eCI: confidence interval\u003c/p\u003e\n\u003cp\u003eHPV: human\u0026nbsp;papillomavirs\u003c/p\u003e\n\u003cp\u003eHR-HPV: high-risk HPV\u003c/p\u003e\n\u003cp\u003eHSIL: high-grade squamous intraepithelial lesions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLSIL: low-grade squamous intraepithelial lesions AIS: adenocarcinoma in\u0026nbsp;situ\u003c/p\u003e\n\u003cp\u003ePCR: polymerase chain reaction TCT: ThinPrep cytology test\u003c/p\u003e\n\u003cp\u003eASCUS: atypical squamous cells of undetermined significance\u0026nbsp;ECC: endocervical\u0026nbsp;curettage\u003c/p\u003e\n\u003cp\u003eLEEP: loop electrosurgical excision procedure HR: hazard ratio\u003c/p\u003e\n\u003cp\u003eCMU: Capital Medical University\u003c/p\u003e\n\u003cp\u003eSLE: specifically systemic lupus erythematosus\u003c/p\u003e\n\u003cp\u003eAPOBEC3: apolipoprotein B mRNA editing enzyme catalytic polypeptide-like protein 3\u003c/p\u003e\n\u003cp\u003eAPC: antigen-presenting cells\u003c/p\u003e\n\u003cp\u003eSPERANZA: SPERimentazione ANti HPV Zona Apuana\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the Chinese patients who participated in this study for their understanding and cooperation during the follow-up process. We also extend our gratitude to all staff members involved in this research for their contributions to study design, data analysis, and manuscript preparation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHM B, J L, KY G and SY B: conception and design of the study, assembly, analysis and interpretation of the data, and manuscript writing. RZ L, LY J, Y Z, ZH S, RL J and X L: provision of study materials, analysis and interpretation of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Science and Technology Program of Chaoyang District, Beijing, China, Project No. CYSF2214\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to ethical standards outlined in the Declaration of Helsinki，with ethical approval obtained from the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University （Approval Number: 2025-ke-401）.Written informed consent was obtained from all participants prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2-3)? Gynecol Oncol. 2013;130(2):264\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKechagias KS, Kalliala I, Bowden SJ, Athanasiou A, Paraskevaidi M, Paraskevaidis E, Dillner J, Nieminen P, Strander B, Sasieni P, et al. Role of human papillomavirus (HPV) vaccination on HPV infection and recurrence of HPV related disease after local surgical treatment: systematic review and meta-analysis. BMJ (Clinical Res ed). 2022;378:e070135.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogani G, Raspagliesi F, Sopracordevole F, Ciavattini A, Ghelardi A, Simoncini T, Petrillo M, Plotti F, Lopez S, Casarin J et al. Assessing the Long-Term Role of Vaccination against HPV after Loop Electrosurgical Excision Procedure (LEEP): A Propensity-Score Matched Comparison. Vaccines 2020, 8(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhelardi A, Parazzini F, Martella F, Pieralli A, Bay P, Tonetti A, Svelato A, Bertacca G, Lombardi S, Joura EA. SPERANZA project: HPV vaccination after treatment for CIN2. Gynecol Oncol. 2018;151(2):229\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"CIN2, Conservative treatment, Multiple pregnancies, HPV-16, HPV Vaccine","lastPublishedDoi":"10.21203/rs.3.rs-6379197/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6379197/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: This study explores predictive factors influencing clinical outcomes in patients with cervical intraepithelial neoplasia grade 2 (CIN2) managed through simple observation.\u003c/p\u003e\n\u003cp\u003eMethods: \u003cem\u003eBetween January 2012 and March 2021, we retrospectively analyzed data from 510 CIN2 patients managed with observation strategies at Beijing Chaoyang Hospital, Capital Medical University.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eResult:A total of 510 eligible patients were enrolled in this study ,with a mean age of 30.15 ± 5.82 years, and 384 (75.3%) of the cases were nulliparous. During the follow-up period (mean 37.0 ± 1.3 months), 60 (12%) opted for surgical treatment, 363 (71%) patients achieved remission time 9.1 months（range: 5.1-17.3 )months. persistent CIN2 was detected in 55 (11%), disease progression occurred in 32 (6%), and no deaths were reported, with a five-year disease progression rate (DPR) of 9.2%. Independent risk factors for disease progression included more than three pregnancies (OR 4.38, 95% CI 1.63-11.79, P=0.003), HPV16 infection (OR 4.07, 95% CI 1.88-8.81，P\u0026lt;0.001), and post-diagnosis HPV vaccination was an independent protective factor (OR 0.29, 95% CI 0.08-0.98, P=0.046，P=0.046). The 5-year disease progression rate (DPR) was 2.6% for patients with three or fewer HPV16-negative and vaccinated pregnancies and 72% for patients with three or more pregnancies, HPV16-positive, and unvaccinated after CIN2 diagnosis.\u003c/p\u003e\n\u003cp\u003eConclusion: Simple observation with intensive surveillance is a safe strategy for CIN2 management. Patients with HPV16 and more than three pregnancies should consider conization after childbearing, while unvaccinated patients are advised to receive HPV vaccination.\u003c/p\u003e","manuscriptTitle":"HPV16, Multigravida, and Post-CIN2 Vaccination in Chinese Patients : A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 11:15:27","doi":"10.21203/rs.3.rs-6379197/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"659e6dc3-ecbb-4d45-ab9e-81d5178d6009","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-04T11:42:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 11:15:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6379197","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6379197","identity":"rs-6379197","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}