Association of Pelvic Inflammatory Disease (PID) with Ovarian Cancer: A Nationwide Population-Based Retrospective Cohort Study from Taiwan

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Infection and inflammation play an important role in carcinogenesis and PID has been reported to be associated with ovarian cancer, although the evidence is controversial. Aim: We sought to determine whether PID is associated with an elevated risk of ovarian cancer in Asian women. Methods: Using data from Taiwan’s National Health Insurance Research Database (NHIRD), our retrospective cohort study included women diagnosed with PID (cases) between the years of 2000 till 2013. Each case was matched with two women without PID (controls) by age and the year of first entry into the database. Both study cohorts were followed-up until the first event of ovarian cancer, withdrawal from the NHI program, death, or the end of the study period (December 31, 2013). Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios (HRs and aHRs) with their corresponding 95% confidence intervals (95% CIs) for the association of PID and ovarian cancer risk, with and without adjusting for potential confounders. Results: During an approximate 10 years of follow-up, cases were significantly more likely than controls to develop ovarian cancer (incidence rates of 0.27 and 0.16 per 1,000 person-years, respectively; P < 0.001). Women with a history of PID had a 1.49-fold elevated risk for ovarian cancer (aHR, 1.49; 95% CI, 1.21–1.84; P < 0.001). Conclusion: Our study evidence supports the contention that PID increases the risk of developing ovarian cancer amongst Taiwanese women. Gynecologists should undertake careful assessments and closely follow patients with PID, who are at long-term risk of developing ovarian cancer. Our findings need further verification in other international cohorts. Internal Medicine Preventive Medicine PID NHIRD Database patients Figures Figure 1 Figure 1 Figure 1 Figure 2 Figure 2 Figure 2 Introduction Pelvic inflammatory disease (PID) is caused by sexually transmitted infections at various sites in the female genital tract and affects the upper part of the female reproductive system, i.e., the uterus, ovaries, and fallopian tubes, as well as other pelvic organs and even abdominal organs [ 1 ]. PID is often diagnosed among women of reproductive age. Its clinical features vary according to the patient’s immune and health status. Typically, there are no obvious symptoms and signs of PID until chronic inflammation develops in the pelvic cavity, which can lead to serious consequences, such as preterm labor [ 2 ], infertility [ 3 ], ectopic pregnancy [ 4 ], and pelvic organ adhesions [ 5 ]. Research has shown that infection and chronic inflammation play an important role in carcinogenesis, although the conclusions differ as to whether ovarian cancer is initiated by PID [ 6 – 8 ]. Ovarian cancer has a high mortality rate, due to asymptomatic tumor growth and delayed onset of symptoms, with most patients was not diagnose until they experience signs or symptoms of back pain, fatigue, constipation, abdominal discomfort, postprandial fullness sensations and urinary symptoms (urgency or frequency) [ 9 , 10 ]. Thus, almost two-thirds of patients are diagnosed with advanced disease at initial presentation [ 11 ]. Optimal treatment for advanced ovarian cancer consists of primary debulking surgery followed by platinum-based chemotherapy, although prognosis remains poor. Thus, early detection and identifying women at high risk of developing ovarian cancer are of crucial importance. Several risk factors are associated with ovarian cancer, including low parity, infertility, early age at menarche, and late age at menopause [ 12 – 15 ]. Recurrent inflammation may contribute to cancer cell formation. It is thought that chronic exposure to external or endogenous triggers of immunity and persistent immune cells injure the surrounding epithelium cells and that exposure to pathogens can lead to chronic inflammation that promotes tumor growth and progression [ 16 ]. Due to the uncertainty in the literature as to whether there is a definite association between PID and ovarian cancer risk, we examined data from Taiwan’s National Health Insurance Research Database (NHIRD) for this long-term population-based study, to examine the risk for developing ovarian cancer among women with PID. Materials And Methods Data source Taiwan launched universal health coverage in 1995 with its National Health Insurance program, which now includes over 99% of the population. Anonymized, de-identified patient data from the National Health Insurance Research Database (NHIRD) were obtained for this investigation. The NHIRD contains health insurance information covering medical procedures, prescribed medications, outpatient and inpatient records, and emergency department visits. This study was granted approval by China Medical University Hospital’s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). The main data source is the Longitudinal Health Insurance Database 2000 (LHID2000), which contains details on medical care given to a randomly selected 1 million insured individuals in the NHIRD covering the period from 1996 through 2013. It is established that the distributions of age and sex ratios are similar between the LHID2000 and NHIRD [ 17 ]. Study Participants The study population comprised women aged 18 years and older diagnosed with PID according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code 614.3-614.9, between 2000 and 2012, who served as the case cohort. The date of the PID diagnosis was defined as the index date. Each case was matched with 2 women without PID (control group) by age and index date. The index data marked the commencement of follow-up. Both study cohorts were followed-up until the first event of ovarian cancer (ICD-9-CM code 183), withdrawal from the NHI program, death, or the end of the study period (December 31, 2013) (Fig. 1 ). Participants aged younger than 18 years were excluded from the study. Comorbidities Common baseline comorbidities were identified by ICD-9 codes recorded in the LHID2000 prior to the index date and included Lynch syndrome (hereditary nonpolyposis colorectal cancer) and colon cancer (ICD-9-CM code 153.9)[ 18 , 19 ], breast cancer (ICD-9-CM code 174.9)[ 20 , 21 ], uterus cancer (ICD-9-CM codes 179 and 182)[ 20 ], rectum cancer (ICD-9-CM code 154), endometriosis (ICD-9-CM code 617)[ 22 ], infertility (ICD-9-CM code 628), and obesity (ICD-9-CM code 278). The criteria of obese defined by the Department of Health in Taiwan is BMI > or = 27[ 23 ]. Statistical analysis Baseline characteristics between the PID cohort and controls were compared using the Chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous data. The difference in age of each study cohort was determined by the t-test as your helpful suggestion. Ovarian cancer-free survival curves for the PID and control groups were calculated by Kaplan-Meier analysis and the difference was tested with the log-rank test. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios (HRs and aHRs) with their corresponding 95% confidence intervals (95% CIs) for the association of PID and ovarian cancer risk, with and without adjusting for potential confounders. All models were adjusted for age and comorbidities. All statistical analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA). A P -value of < 0.05 was considered to denote a statistically significant relationship. Results Table 1 presents comparisons of demographic and clinical variables between the PID cohort and controls. The peak age of PID development was between 20 and 30 years (31.1%). Significantly more diagnoses of uterine cancer, endometriosis, and infertility were identified among the PID cases than among controls (all P < 0.001). Mean follow-up times were 9.44 ± 3.62 years and 9.24 ± 3.71 years for the PID cohort and controls, respectively. Table 1 Baseline variables for patients with PID and women without PID (controls) Patients with PID Controls P value * ( n = 64,925) ( n = 129,850) n % n % Age, years > 0.99 < 20 4,529 6.98 9,058 6.98 20–30 20,215 31.1 40,430 31.1 30–40 18,739 28.8 37,478 28.8 40–50 14,073 21.6 28,146 21.6 50–60 4,866 7.49 9,732 7.49 ≥60 2,503 3.86 5,006 3.86 mean (SD) † 35.43 (12.1) 35.38 (12.3) 0.37 Comorbidity Lynch syndrome and colon cancer 69 0.11 108 0.08 0.11 Breast cancer 257 0.40 538 0.41 0.54 Uterine cancer 66 0.10 67 0.05 < 0.0001 Rectum cancer 52 0.08 80 0.06 0.13 Endometriosis 4,241 6.53 2,552 1.97 < 0.0001 Infertility 3,455 5.32 3,263 2.51 < 0.0001 Obesity 524 0.81 860 0.66 0.0003 Monthly income (NTD) < 0.0001 < 15,000 31,211 48.0 64,575 49.7 15,000–29,999 27,453 42.3 50,240 38.7 ≥ 30,000 6,261 9.64 15,035 11.6 Abbreviations: PID, pelvic inflammatory disease; SD, standard deviation; NTD, New Taiwan dollar. * P values were determined using the Chi-square test for comparisons between women with PID and controls. † Mean follow-up times were 9.44 years (SD, 3.62) for the PID cohort and 9.24 years (SD, 3.71) for controls. Incidence rates of ovarian cancer per 1,000 person-years were 0.27 in the PID cohort and 0.16 in the control cohort (Table 2 ). The risk of ovarian cancer was significantly higher among women with PID than among those without in both unadjusted (HR, 1.67; 95% CI, 1.36–2.05; P < 0.001) and adjusted models (aHR, 1.49; 95% CI, 1.21–1.84; P < 0.001). Several comorbidities were significantly more common among women with PID than among those without, including Lynch syndrome and colon cancer (aHR, 5.47; 95% CI, 1.48–20.1; P < 0.05), breast cancer (aHR, 1.93; 95% CI, 1.03–5.23; P < 0.05), uterine cancer (aHR, 13.9; 95% CI, 5.70–34.2; P < 0.001), endometriosis (aHR, 2.93; 95% CI, 2.09–4.12; P < 0.001), and infertility (aHR, 1.84; 95% CI, 1.21–2.80; P < 0.01). Over follow-up, the cumulative incidence of ovarian cancer was significantly higher in the PID cohort than among controls (Log-rank test, P < 0.0001) (Fig. 2 ). Table 2 Incidence and crude and adjusted risks of ovarian cancer according to age, comorbidity and monthly income for women with PID and those without (controls) Ovarian cancer Crude HR (95% CI) Adjusted HR † (95% CI) Event PY IR Pelvic inflammatory disease 168 613,316 0.27 1.67 (1.36–2.05)*** 1.49 (1.21–1.84)*** Age, years < 20 11 123,291 0.08 1 (reference) 1 (reference) 20–30 62 559,564 0.11 1.24 (0.65–2.36) 1.16 (0.61–2.22) 30–40 109 545,092 0.19 2.26 (1.21–4.20)** 1.98 (1.04–3.78)* 40–50 121 403,108 0.30 3.38 (1.82–6.27)*** 3.01 (1.57–5.75)*** 50–60 42 125,894 0.33 3.71 (1.91–7.21)*** 3.32 (1.66–6.64)*** ≥60 20 57,330 0.34 3.82 (1.83–7.97)*** 3.31 (1.54–7.10)** Comorbidity Lynch syndrome and colon cancer 4 1,200 3.33 16.1 (6.01–43.1)*** 5.47 (1.48–20.1)* Breast cancer 4 6,104 0.65 3.20 (1.19–8.57)* 1.93 (1.03–5.23)* Uterus cancer 5 832 6.00 25.5 (11.8–69.0)*** 13.9 (5.70–34.2)*** Rectum cancer 3 864 3.47 16.6 (5.33–51.7)*** 3.25 (0.72–14.6) Endometriosis 41 54,969 0.74 3.97 (2.87–5.49)*** 2.93 (2.09–4.12)*** Infertility 25 59,497 0.42 2.15 (1.43–3.23)*** 1.84 (1.21–2.80)** Obesity 3 10,516 0.28 1.38 (0.44–4.30) 1.09 (0.35–3.40) Monthly income (NTD) < 15,000 130 836,290 0.15 1 (reference) 1 (reference) 15,000–29,999 189 763,730 0.24 1.62 (1.29–2.02)*** 1.13 (0.89–1.43) ≥ 30,000 46 214,260 0.21 1.40 (1.00–1.97)* 0.98 (0.69–1.39) Abbreviations: PID, pelvic inflammatory disease; HR, hazard ratio; PY, person-years; IR, incidence rate per 1,000 person-years; CI, confidence interval; NTD, New Taiwan dollar. † HR adjusted for age, Lynch syndrome and colon cancer, breast cancer, uterus cancer, rectum cancer, endometriosis, infertility, obesity, and monthly income. The incidence and HR of of ovarian cancer in populations with or without PID relative to those of the controls are listed in Table S. Despite the other factors, patients with a history of PID had HRs for ovarian cancer ranging from 1.37 (P < 0.05) to 5.06 (P < 0.001), which were significantly different compared with the values of those without a history of PID. Discussion International investigations, including cohort studies, have failed to establish consistent evidence for an association between PID and ovarian cancer [ 6 , 7 , 24 , 25 ]. This large-scale nationwide population-based study shows that compared with women without PID, women with PID are at higher risk of developing ovarian cancer and that this risk increases over time. Another large nationwide population-based cohort study suggests that there is no increased risk for ovarian, breast or uterine cancer among women with PID [ 8 ], in contrast to other researchers, who have described an increased risk of serous borderline ovarian tumors, but not of the mucinous type, in women with a history of PID[ 26 ]. Likewise, Rasmussen and colleagues have reported finding a positive association between low-grade, borderline ovarian tumors and PID in a pooled analysis of evidence from 13 case-control studies conducted between 1989 and 2009 [ 7 ], and a large Italian case-control study performed between 1983 and 1991 has shown an increased risk of ovarian cancer in women with a history of PID [ 12 ]. Interestingly, a meta-analysis of studies stratified by race has found a significant positive association between PID and ovarian cancer in studies conducted among Asian women, but only a slightly significant association amongst Caucasians [ 27 ]. One population-based cohort study that included 34 years of follow-up data from all women in Denmark ( n = 1,318,929) showed a statistically significantly increased risk of serous ovarian cancer in women with a PID history, although there was no statistically significant relationship between PID and overall ovarian cancer [ 6 ]. Evidence from two independent case-control studies supports the association between PID and ovarian cancer, showing that antibodies against Chlamydia trachomatis infection may double the risk of ovarian cancer [ 28 ]. One research group has suggested that not only does PID increase the risk for developing ovarian cancer, but also that the risk increases with the number of PID episodes [ 29 ]. A more recent study has reported that the risk of high-grade serous ovarian cancer was increased in women with a diagnosis of PID and also in those with a personal history of breast cancer [ 30 ]. Interestingly, that study found that the risk for developing high-grade serous ovarian cancer reduced with increased parity, but not in women with a personal history of breast cancer[ 30 ]. There are no large-scale, long-term follow-up studies that have examined the relationship between previous PID and ovarian cancer in Taiwan or other Asian countries. Although one research group from Taiwan has reported finding a significant association between PID and ovarian cancer, the 3-year follow-up is probably insufficient time to accurately determine cancer formation [ 25 ]. The evidence from our large nationwide study with approximately 10 years of follow-up reveals that PID is a significant risk factor for ovarian cancer and that women aged 40 years and older with PID are at greater risk of developing ovarian cancer than younger-aged women. An increased risk of ovarian cancer associated with PID supports the hypothesis that inflammatory processes may contribute to the etiology of ovarian cancer [ 30 , 31 ]. Since women with a history of PID appear to be at high risk for ovarian cancer, screening these women for ovarian cancer may be an effective way to detect and treat the disease early. Prophylactic salpingo-oophorectomy is recommended for the prevention of ovarian cancer in high-risk women; there is no proven overall survival benefit in women with average risk for ovarian cancer, in whom the procedure has been associated with a significant increase in mortality from cardiovascular disease [ 32 , 33 ]. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has proven to be an effective way of preventing ovarian cancer in women with the Lynch syndrome [ 34 ]. Our study also reveals an increased risk of ovarian cancer in women with histories of endometriosis, infertility, Lynch syndrome, or breast cancer, in line with evidence from large cohort studies. For instance, the risk of epithelial ovarian cancer in women with a history of endometriosis is around 1.3–1.9 times higher than the risk among women without any such history [ 35 , 36 ] The lifetime risk of ovarian cancer is 10–12% in women with the Lynch syndrome [ 34 ]. A multinational pooled analysis of infertility and fertility drug use in eight ovarian cancer case-control investigations reported that infertility increases the overall risk of ovarian cancer, whereas no association was observed between use of ovulation-inducing medications and ovarian cancer [ 37 ]. Other researchers have also reported that infertility alone is an independent risk factor for the development of ovarian cancer [ 38 ]. Finally, a personal history of breast cancer has been associated with a 3-fold increase in the rate of high-grade serous ovarian cancer [ 30 ]. Prevention of ovarian cancer is an important issue. Our study data are useful for clinicians wishing to counsel patients about the prevention and treatment of PID. The prevention of PID, including sex education and information, and the promotion of condom use, is an important issue for infectious diseases as well as future cancer risk [ 1 ]. Our study findings show that among important risk factors for ovarian cancer, the most important was PID. The strengths of our study include its population-based design, the use of well-established cohort data, a large nationwide sample and an approximate 10-year follow-up period that identifies PID as a crucial risk factor in the development of ovarian cancer. Some limitations must be noted with this study. First, the NHIRD database does not code for the severity of PID, nor does it provide details of the pathogenesis and microbiology of PID, what types of infertility, or details about the cell types of ovarian cancers. Thus, we were unable to analyze any details concerning the pathophysiological relationship between ovarian cancer and PID. Second, the NHIRD registry lacks detailed records about laboratory results, parity, health-related habits or personal histories of patients, such as oral contraception use, family history and gynecological history, some of which are recognized risk factors for ovarian cancer. Third, the general incidence of PID may be underestimated if calculations fail to account for women with subclinical PID, or if women with PID fail to make a hospital visit due to personal or cultural reasons [ 39 ]. Fourth, this study was based on inpatient and outpatient data on the NHIRD database. Although the annual coverage rate of the NHI program has been estimated at 99.6%, under lack of 100% coverage, some bias may still exist of the general population. Fifth, comorbidities that happen prior to diagnosis of PID but after entry to the cohort study was not able to involved in this study. Sixth, the mean follow-up time is about 10 years, some of the ovarian cancer happened at advanced age might be miss. Conclusions This study revealed that PID is an independent and significant risk factor for ovarian cancer. Compared with women without PID disease, those with a history of PID had a 1.49-fold higher risk of developing ovarian cancer ( P < 0.001). More international study data are needed to verify this finding in our Taiwanese population. Our findings suggest that gynecologists should undertake careful assessments and closely follow patients with PID, who are at long-term risk of developing ovarian cancer. Abbreviations PID:Pelvic inflammatory disease NHIRD:National Health Insurance Research Database LHID:Longitudinal Health Insurance Database HRs:hazard ratios Declarations Ethics approval and consent to participate : This study was granted approval by China Medical University Hospital’s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). The informed consent for the study was waived off by China Medical University Hospital’s Review Board and Ethics Committee.( For the study purpose, the small databank from NHIRD is form one million individuals randomly recruited as subjects obtained from NHIRD. The use of data for our study was permitted by the National Health Research Institute. Protocol for the protection of subjects' privacy already under de-link and unable to identify personally. This study was granted approval by China Medical University Hospital’s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). Consent for publication Not applicable. Availability of data and materials :The data that support the findings of this study are available from the National Health Insurance Research Database (NHIRD) in Taiwan, but restrictions apply regarding the availability of these data, which were used under license for the current study and thus are not publicly available. The data are, however, available from the authors upon reasonable request and with permission of the National Health Insurance Research Database (NHIRD) in Taiwan. All experimental protocols were approved by China Medical University Hospital’s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). all methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki). Competing interests : The authors declare that they have no competing interests. Funding : Not applicable Authors' contributions Conception and design: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin Diabetes mellitusinistrative support: Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin Collection and assembly of data: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Data analysis and interpretation: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin Manuscript writing: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin Final approval of manuscript: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin Acknowledgments : Not applicable References Workowski, K.A. and G.A. Bolan, Sexually transmitted diseases treatment guidelines (2015) . Reproductive Endocrinology, 2015(24): p. 51–56. Toth, M., et al., Pregnancy outcome following pelvic infection . Infect Dis Obstet Gynecol, 1993. 1 (1): p. 12–5. Westrom, L., Effect of pelvic inflammatory disease on fertility . 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Supplementary Files TableS.docx TableS.docx TableS.docx Cite Share Download PDF Status: Published Journal Publication published 28 Jul, 2021 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Major revision 08 Jun, 2021 Reviews received at journal 12 Jan, 2021 Reviewers agreed at journal 01 Jan, 2021 Reviewers invited by journal 07 Dec, 2020 Editor assigned by journal 07 Dec, 2020 Editor invited by journal 03 Dec, 2020 Submission checks completed at journal 03 Dec, 2020 First submitted to journal 20 Nov, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-112758","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":5784403,"identity":"607e7057-fb22-4b92-b246-514a9a0a6b6d","order_by":0,"name":"Cherry Chang","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cherry","middleName":"","lastName":"Chang","suffix":""},{"id":5784404,"identity":"35de8369-5a01-44ac-9fba-13d11f0c8be6","order_by":1,"name":"Kent Lin","email":"","orcid":"","institution":"Royal North Shore Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kent","middleName":"","lastName":"Lin","suffix":""},{"id":5784405,"identity":"f690a01c-70dd-41fe-a324-92e490f77ed8","order_by":2,"name":"Chien-Chu Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACHhhDgrHhQEKFDZDF2HiASC3MjQcenEkDaWkgVgt788GHLYfBbLxa+HsOP93wc89heX7pxoYDiQ3n7da2HwbaUmMTjUuLxNk2s5s9zw4bzpxzEKhlx+3kbWcSgVqOpeU24NJznsHsBs+BwwkGN4AqE8/cTjYD2nWAseEwTi3y59m/3fwD19J2Ltns/EP8WgzO9pjdRtjSdsDO7AYBWwzPnCm7LXMg3XDmDKDKhDPJCWY3gLYk4PGL3Jn0bTffHLCW55dIf/zxR4Wdvdn59IcPPtTY4PY+OkgEq0wgVjkI2JOieBSMglEwCkYGAADsvXTs7BJEGgAAAABJRU5ErkJggg==","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chien-Chu","middleName":"","lastName":"Huang","suffix":""},{"id":5784406,"identity":"8b34d56d-a9b2-429e-b7af-b823a23671a9","order_by":3,"name":"Wu-Chou Lin","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wu-Chou","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2020-11-20 15:59:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-112758/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-112758/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-021-01413-2","type":"published","date":"2021-07-28T15:07:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":4068727,"identity":"43463366-74de-4b59-85d1-d5dbfe060668","added_by":"auto","created_at":"2020-12-07 15:22:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65816,"visible":true,"origin":"","legend":"The flowchart of study sample selection from National Health Insurance Research Database in Taiwan","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/5edd2f0ebe8e23e0cdb12f8c.JPG"},{"id":4068723,"identity":"e6d46ca8-4ced-4d3f-9ead-f344a16cabb7","added_by":"auto","created_at":"2020-12-07 15:22:14","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65816,"visible":true,"origin":"","legend":"The flowchart of study sample selection from National Health Insurance Research Database in Taiwan","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/f4018dfbcaf76a981796ac64.JPG"},{"id":4068719,"identity":"076be344-e36d-488a-8896-530fbc15510c","added_by":"auto","created_at":"2020-12-07 15:22:08","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65816,"visible":true,"origin":"","legend":"The flowchart of study sample selection from National Health Insurance Research Database in Taiwan","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/affba36e5c14c83d194a9b62.JPG"},{"id":4068728,"identity":"6e7c1001-0caf-45fc-878d-99e76ad54681","added_by":"auto","created_at":"2020-12-07 15:22:39","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66503,"visible":true,"origin":"","legend":"Using Kaplan-Meier survival statistics, it showed crude overall survival curves by with and without pelvic inflammatory disease. Over follow-up, the cumulative incidence of ovarian cancer was significantly higher in the PID cohort than among controls. (log-rank P\u003c0.0001)","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/a12e4b2e9129741793e818d6.JPG"},{"id":4068724,"identity":"a125a7f2-c63c-413f-ac16-ac36316f8ced","added_by":"auto","created_at":"2020-12-07 15:22:14","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66503,"visible":true,"origin":"","legend":"Using Kaplan-Meier survival statistics, it showed crude overall survival curves by with and without pelvic inflammatory disease. Over follow-up, the cumulative incidence of ovarian cancer was significantly higher in the PID cohort than among controls. (log-rank P\u003c0.0001)","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/0ef8ef47849eab0b6f930609.JPG"},{"id":4068720,"identity":"491bc002-5025-4abf-9205-71ae52171ff2","added_by":"auto","created_at":"2020-12-07 15:22:08","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66503,"visible":true,"origin":"","legend":"Using Kaplan-Meier survival statistics, it showed crude overall survival curves by with and without pelvic inflammatory disease. Over follow-up, the cumulative incidence of ovarian cancer was significantly higher in the PID cohort than among controls. (log-rank P\u003c0.0001)","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/6e19ca0d50e78ecf2024d4ef.JPG"},{"id":13625321,"identity":"e67abb48-5084-4f97-81f0-0f0b43ddbaf0","added_by":"auto","created_at":"2021-09-17 07:25:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":709686,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/22b7d1d7-d056-4446-bc92-6ee1d8f4c208.pdf"},{"id":4068729,"identity":"fcd3e131-1cad-4df2-a509-00885c3c0187","added_by":"auto","created_at":"2020-12-07 15:22:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20926,"visible":true,"origin":"","legend":"","description":"","filename":"TableS.docx","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/235077d90aa3870de87d6a49.docx"},{"id":4068725,"identity":"d291f612-f228-47e6-9dc7-30a4c6242fcd","added_by":"auto","created_at":"2020-12-07 15:22:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20926,"visible":true,"origin":"","legend":"","description":"","filename":"TableS.docx","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/96acef9fbadf0b58842554ce.docx"},{"id":4068721,"identity":"f206fcaf-fbb7-4110-8d3d-1155f6af4dea","added_by":"auto","created_at":"2020-12-07 15:22:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20926,"visible":true,"origin":"","legend":"","description":"","filename":"TableS.docx","url":"https://assets-eu.researchsquare.com/files/rs-112758/v1/742a465ed9c4ee51f8ac4136.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAssociation of Pelvic Inflammatory Disease (PID) with Ovarian Cancer: A Nationwide Population-Based Retrospective Cohort Study from Taiwan\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003ePelvic inflammatory disease (PID) is caused by sexually transmitted infections at various sites in the female genital tract and affects the upper part of the female reproductive system, i.e., the uterus, ovaries, and fallopian tubes, as well as other pelvic organs and even abdominal organs [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. PID is often diagnosed among women of reproductive age. Its clinical features vary according to the patient\u0026rsquo;s immune and health status. Typically, there are no obvious symptoms and signs of PID until chronic inflammation develops in the pelvic cavity, which can lead to serious consequences, such as preterm labor [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], infertility [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], ectopic pregnancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], and pelvic organ adhesions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Research has shown that infection and chronic inflammation play an important role in carcinogenesis, although the conclusions differ as to whether ovarian cancer is initiated by PID [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOvarian cancer has a high mortality rate, due to asymptomatic tumor growth and delayed onset of symptoms, with most patients was not diagnose until they experience signs or symptoms of back pain, fatigue, constipation, abdominal discomfort, postprandial fullness sensations and urinary symptoms (urgency or frequency) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Thus, almost two-thirds of patients are diagnosed with advanced disease at initial presentation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Optimal treatment for advanced ovarian cancer consists of primary debulking surgery followed by platinum-based chemotherapy, although prognosis remains poor. Thus, early detection and identifying women at high risk of developing ovarian cancer are of crucial importance. Several risk factors are associated with ovarian cancer, including low parity, infertility, early age at menarche, and late age at menopause [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Recurrent inflammation may contribute to cancer cell formation. It is thought that chronic exposure to external or endogenous triggers of immunity and persistent immune cells injure the surrounding epithelium cells and that exposure to pathogens can lead to chronic inflammation that promotes tumor growth and progression [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to the uncertainty in the literature as to whether there is a definite association between PID and ovarian cancer risk, we examined data from Taiwan\u0026rsquo;s National Health Insurance Research Database (NHIRD) for this long-term population-based study, to examine the risk for developing ovarian cancer among women with PID.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eTaiwan launched universal health coverage in 1995 with its National Health Insurance program, which now includes over 99% of the population. Anonymized, de-identified patient data from the National Health Insurance Research Database (NHIRD) were obtained for this investigation. The NHIRD contains health insurance information covering medical procedures, prescribed medications, outpatient and inpatient records, and emergency department visits. This study was granted approval by China Medical University Hospital\u0026rsquo;s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). The main data source is the Longitudinal Health Insurance Database 2000 (LHID2000), which contains details on medical care given to a randomly selected 1\u0026nbsp;million insured individuals in the NHIRD covering the period from 1996 through 2013. It is established that the distributions of age and sex ratios are similar between the LHID2000 and NHIRD [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eStudy Participants\u003c/h2\u003e\n \u003cp\u003eThe study population comprised women aged 18\u0026nbsp;years and older diagnosed with PID according to the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code 614.3-614.9, between 2000 and 2012, who served as the case cohort. The date of the PID diagnosis was defined as the index date. Each case was matched with 2 women without PID (control group) by age and index date. The index data marked the commencement of follow-up. Both study cohorts were followed-up until the first event of ovarian cancer (ICD-9-CM code 183), withdrawal from the NHI program, death, or the end of the study period (December 31, 2013) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Participants aged younger than 18\u0026nbsp;years were excluded from the study.\u003c/p\u003e\n\u003ch2\u003eComorbidities\u003c/h2\u003e\n \u003cp\u003eCommon baseline comorbidities were identified by ICD-9 codes recorded in the LHID2000 prior to the index date and included Lynch syndrome (hereditary nonpolyposis colorectal cancer) and colon cancer (ICD-9-CM code 153.9)[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], breast cancer (ICD-9-CM code 174.9)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], uterus cancer (ICD-9-CM codes 179 and 182)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], rectum cancer (ICD-9-CM code 154), endometriosis (ICD-9-CM code 617)[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], infertility (ICD-9-CM code 628), and obesity (ICD-9-CM code 278). The criteria of obese defined by the Department of Health in Taiwan is BMI\u0026thinsp;\u0026gt;\u0026thinsp;or =\u0026thinsp;27[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eBaseline characteristics between the PID cohort and controls were compared using the Chi-square test for categorical variables and the Wilcoxon rank-sum test for continuous data. The difference in age of each study cohort was determined by the t-test as your helpful suggestion. Ovarian cancer-free survival curves for the PID and control groups were calculated by Kaplan-Meier analysis and the difference was tested with the log-rank test. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios (HRs and aHRs) with their corresponding 95% confidence intervals (95% CIs) for the association of PID and ovarian cancer risk, with and without adjusting for potential confounders. All models were adjusted for age and comorbidities. All statistical analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA). A \u003cem\u003eP\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered to denote a statistically significant relationship.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents comparisons of demographic and clinical variables between the PID cohort and controls. The peak age of PID development was between 20 and 30\u0026nbsp;years (31.1%). Significantly more diagnoses of uterine cancer, endometriosis, and infertility were identified among the PID cases than among controls (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Mean follow-up times were 9.44\u0026thinsp;\u0026plusmn;\u0026thinsp;3.62\u0026nbsp;years and 9.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.71\u0026nbsp;years for the PID cohort and controls, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline variables for patients with PID and women without PID (controls)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePatients with PID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eControls\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003en\u003c/span\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;64,925)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003e(\u003c/b\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003en\u003c/span\u003e\u0026thinsp;\u003cb\u003e=\u0026thinsp;129,850)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003en\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e%\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003en\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e%\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9,058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20,215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40,430\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18,739\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37,478\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14,073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28,146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9,732\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2,503\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5,006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emean (SD)\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e35.43 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e35.38 (12.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLynch syndrome and colon cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterine cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectum cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,241\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2,552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3,455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3,263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e524\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e860\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMonthly income (NTD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;15,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31,211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64,575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15,000\u0026ndash;29,999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27,453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50,240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;30,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6,261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15,035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: PID, pelvic inflammatory disease; SD, standard deviation; NTD, New Taiwan dollar.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*\u003cem\u003eP\u003c/em\u003e values were determined using the Chi-square test for comparisons between women with PID and controls.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e Mean follow-up times were 9.44\u0026nbsp;years (SD, 3.62) for the PID cohort and 9.24\u0026nbsp;years (SD, 3.71) for controls.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIncidence rates of ovarian cancer per 1,000 person-years were 0.27 in the PID cohort and 0.16 in the control cohort (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The risk of ovarian cancer was significantly higher among women with PID than among those without in both unadjusted (HR, 1.67; 95% CI, 1.36\u0026ndash;2.05; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and adjusted models (aHR, 1.49; 95% CI, 1.21\u0026ndash;1.84; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Several comorbidities were significantly more common among women with PID than among those without, including Lynch syndrome and colon cancer (aHR, 5.47; 95% CI, 1.48\u0026ndash;20.1; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), breast cancer (aHR, 1.93; 95% CI, 1.03\u0026ndash;5.23; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), uterine cancer (aHR, 13.9; 95% CI, 5.70\u0026ndash;34.2; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), endometriosis (aHR, 2.93; 95% CI, 2.09\u0026ndash;4.12; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and infertility (aHR, 1.84; 95% CI, 1.21\u0026ndash;2.80; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Over follow-up, the cumulative incidence of ovarian cancer was significantly higher in the PID cohort than among controls (Log-rank test, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIncidence and crude and adjusted risks of ovarian cancer according to age, comorbidity and monthly income for women with PID and those without (controls)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eOvarian cancer\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCrude HR\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdjusted HR\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEvent\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003ePY\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eIR\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePelvic inflammatory disease\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e613,316\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.67 (1.36\u0026ndash;2.05)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.49 (1.21\u0026ndash;1.84)***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123,291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (reference)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e559,564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.24 (0.65\u0026ndash;2.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.16 (0.61\u0026ndash;2.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e545,092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.26 (1.21\u0026ndash;4.20)**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.98 (1.04\u0026ndash;3.78)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e403,108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.38 (1.82\u0026ndash;6.27)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.01 (1.57\u0026ndash;5.75)***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125,894\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.71 (1.91\u0026ndash;7.21)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.32 (1.66\u0026ndash;6.64)***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57,330\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.82 (1.83\u0026ndash;7.97)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.31 (1.54\u0026ndash;7.10)**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eLynch syndrome and colon cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.1 (6.01\u0026ndash;43.1)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.47 (1.48\u0026ndash;20.1)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBreast cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6,104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.20 (1.19\u0026ndash;8.57)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.93 (1.03\u0026ndash;5.23)*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterus cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e832\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.5 (11.8\u0026ndash;69.0)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13.9 (5.70\u0026ndash;34.2)***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRectum cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e864\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16.6 (5.33\u0026ndash;51.7)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.25 (0.72\u0026ndash;14.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometriosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54,969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.97 (2.87\u0026ndash;5.49)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.93 (2.09\u0026ndash;4.12)***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e59,497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.15 (1.43\u0026ndash;3.23)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.84 (1.21\u0026ndash;2.80)**\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10,516\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.38 (0.44\u0026ndash;4.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.09 (0.35\u0026ndash;3.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMonthly income (NTD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;15,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e836,290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (reference)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (reference)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15,000\u0026ndash;29,999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e763,730\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.62 (1.29\u0026ndash;2.02)***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.13 (0.89\u0026ndash;1.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;30,000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e214,260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.40 (1.00\u0026ndash;1.97)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.98 (0.69\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviations: PID, pelvic inflammatory disease; HR, hazard ratio; PY, person-years; IR, incidence rate per 1,000 person-years; CI, confidence interval; NTD, New Taiwan dollar.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003eHR adjusted for age, Lynch syndrome and colon cancer, breast cancer, uterus cancer, rectum cancer, endometriosis, infertility, obesity, and monthly income.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe incidence and HR of of ovarian cancer in populations with or without PID relative to those of the controls are listed in Table S. Despite the other factors, patients with a history of PID had HRs for ovarian cancer ranging from 1.37 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) to 5.06 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which were significantly different compared with the values of those without a history of PID.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eInternational investigations, including cohort studies, have failed to establish consistent evidence for an association between PID and ovarian cancer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This large-scale nationwide population-based study shows that compared with women without PID, women with PID are at higher risk of developing ovarian cancer and that this risk increases over time. Another large nationwide population-based cohort study suggests that there is no increased risk for ovarian, breast or uterine cancer among women with PID [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], in contrast to other researchers, who have described an increased risk of serous borderline ovarian tumors, but not of the mucinous type, in women with a history of PID[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Likewise, Rasmussen and colleagues have reported finding a positive association between low-grade, borderline ovarian tumors and PID in a pooled analysis of evidence from 13 case-control studies conducted between 1989 and 2009 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and a large Italian case-control study performed between 1983 and 1991 has shown an increased risk of ovarian cancer in women with a history of PID [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Interestingly, a meta-analysis of studies stratified by race has found a significant positive association between PID and ovarian cancer in studies conducted among Asian women, but only a slightly significant association amongst Caucasians [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. One population-based cohort study that included 34\u0026nbsp;years of follow-up data from all women in Denmark (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1,318,929) showed a statistically significantly increased risk of serous ovarian cancer in women with a PID history, although there was no statistically significant relationship between PID and overall ovarian cancer [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEvidence from two independent case-control studies supports the association between PID and ovarian cancer, showing that antibodies against \u003cem\u003eChlamydia trachomatis\u003c/em\u003e infection may double the risk of ovarian cancer [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. One research group has suggested that not only does PID increase the risk for developing ovarian cancer, but also that the risk increases with the number of PID episodes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A more recent study has reported that the risk of high-grade serous ovarian cancer was increased in women with a diagnosis of PID and also in those with a personal history of breast cancer [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Interestingly, that study found that the risk for developing high-grade serous ovarian cancer reduced with increased parity, but not in women with a personal history of breast cancer[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. There are no large-scale, long-term follow-up studies that have examined the relationship between previous PID and ovarian cancer in Taiwan or other Asian countries. Although one research group from Taiwan has reported finding a significant association between PID and ovarian cancer, the 3-year follow-up is probably insufficient time to accurately determine cancer formation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe evidence from our large nationwide study with approximately 10\u0026nbsp;years of follow-up reveals that PID is a significant risk factor for ovarian cancer and that women aged 40\u0026nbsp;years and older with PID are at greater risk of developing ovarian cancer than younger-aged women. An increased risk of ovarian cancer associated with PID supports the hypothesis that inflammatory processes may contribute to the etiology of ovarian cancer [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Since women with a history of PID appear to be at high risk for ovarian cancer, screening these women for ovarian cancer may be an effective way to detect and treat the disease early. Prophylactic salpingo-oophorectomy is recommended for the prevention of ovarian cancer in high-risk women; there is no proven overall survival benefit in women with average risk for ovarian cancer, in whom the procedure has been associated with a significant increase in mortality from cardiovascular disease [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has proven to be an effective way of preventing ovarian cancer in women with the Lynch syndrome [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study also reveals an increased risk of ovarian cancer in women with histories of endometriosis, infertility, Lynch syndrome, or breast cancer, in line with evidence from large cohort studies. For instance, the risk of epithelial ovarian cancer in women with a history of endometriosis is around 1.3\u0026ndash;1.9 times higher than the risk among women without any such history [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] The lifetime risk of ovarian cancer is 10\u0026ndash;12% in women with the Lynch syndrome [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. A multinational pooled analysis of infertility and fertility drug use in eight ovarian cancer case-control investigations reported that infertility increases the overall risk of ovarian cancer, whereas no association was observed between use of ovulation-inducing medications and ovarian cancer [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Other researchers have also reported that infertility alone is an independent risk factor for the development of ovarian cancer [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Finally, a personal history of breast cancer has been associated with a 3-fold increase in the rate of high-grade serous ovarian cancer [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrevention of ovarian cancer is an important issue. Our study data are useful for clinicians wishing to counsel patients about the prevention and treatment of PID. The prevention of PID, including sex education and information, and the promotion of condom use, is an important issue for infectious diseases as well as future cancer risk [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Our study findings show that among important risk factors for ovarian cancer, the most important was PID.\u003c/p\u003e \u003cp\u003eThe strengths of our study include its population-based design, the use of well-established cohort data, a large nationwide sample and an approximate 10-year follow-up period that identifies PID as a crucial risk factor in the development of ovarian cancer. Some limitations must be noted with this study. First, the NHIRD database does not code for the severity of PID, nor does it provide details of the pathogenesis and microbiology of PID, what types of infertility, or details about the cell types of ovarian cancers. Thus, we were unable to analyze any details concerning the pathophysiological relationship between ovarian cancer and PID. Second, the NHIRD registry lacks detailed records about laboratory results, parity, health-related habits or personal histories of patients, such as oral contraception use, family history and gynecological history, some of which are recognized risk factors for ovarian cancer. Third, the general incidence of PID may be underestimated if calculations fail to account for women with subclinical PID, or if women with PID fail to make a hospital visit due to personal or cultural reasons [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Fourth, this study was based on inpatient and outpatient data on the NHIRD database. Although the annual coverage rate of the NHI program has been estimated at 99.6%, under lack of 100% coverage, some bias may still exist of the general population. Fifth, comorbidities that happen prior to diagnosis of PID but after entry to the cohort study was not able to involved in this study. Sixth, the mean follow-up time is about 10 years, some of the ovarian cancer happened at advanced age might be miss.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eThis study revealed that PID is an independent and significant risk factor for ovarian cancer. Compared with women without PID disease, those with a history of PID had a 1.49-fold higher risk of developing ovarian cancer (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). More international study data are needed to verify this finding in our Taiwanese population. Our findings suggest that gynecologists should undertake careful assessments and closely follow patients with PID, who are at long-term risk of developing ovarian cancer.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003ePID:Pelvic inflammatory disease\u003c/p\u003e\n\u003cp\u003eNHIRD:National Health Insurance Research Database\u003c/p\u003e\n\u003cp\u003eLHID:Longitudinal Health Insurance Database\u003c/p\u003e\n\u003cp\u003eHRs:hazard ratios\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This study was granted approval by China Medical University Hospital\u0026rsquo;s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)).\u003c/p\u003e\n\u003cp\u003eThe informed consent for the study was waived off by China Medical University Hospital\u0026rsquo;s Review Board and Ethics Committee.( For the study purpose, the small databank from NHIRD is form one million individuals randomly recruited as subjects obtained from NHIRD. The use of data for our study was permitted by the National Health Research Institute. Protocol for the protection of subjects' privacy already under de-link and unable to identify personally. This study was granted approval by China Medical University Hospital\u0026rsquo;s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e :The data that support the findings of this study are available from the National Health Insurance Research Database (NHIRD) in Taiwan, but restrictions apply regarding the availability of these data, which were used under license for the current study and thus are not publicly available. The data are, however, available from the authors upon reasonable request and with permission of the National Health Insurance Research Database (NHIRD) in Taiwan. All experimental protocols were approved by China Medical University Hospital\u0026rsquo;s Review Board and Ethics Committee (CMUH number: CMUH-104-REC2-115 (CR-4)). all methods were performed in accordance with the relevant guidelines and regulations (Declaration of Helsinki).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin\u003c/p\u003e\n\u003cp\u003eDiabetes mellitusinistrative support: Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin\u003c/p\u003e\n\u003cp\u003eCollection and assembly of data: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang,\u003c/p\u003e\n\u003cp\u003eData analysis and interpretation: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin\u003c/p\u003e\n\u003cp\u003eManuscript writing: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin\u003c/p\u003e\n\u003cp\u003eFinal approval of manuscript: Cherry Yin-Yi Chang, Kent Yu-Hsien Lin, Chien-Chu Huang, Wu-Chou Lin\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorkowski, K.A. and G.A. 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Case Rep Med, 2014. \u003cb\u003e2014\u003c/b\u003e: p.\u0026nbsp;645045.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLipschutz, D.I., \u003cem\u003eLong-term mortality associated with oophorectomy compared with ovarian conservation in the Nurses' Health Study.\u003c/em\u003e Obstetrics \u0026amp; Gynecology, 2013. \u003cb\u003e122\u003c/b\u003e(2 PART 1): p.\u0026nbsp;395\u0026ndash;396.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEvans, E.C., et al., \u003cem\u003eSalpingo-oophorectomy at the time of benign hysterectomy: a systematic review\u003c/em\u003e. Obstetrics \u0026amp; Gynecology, 2016. \u003cb\u003e128\u003c/b\u003e(3): p.\u0026nbsp;476\u0026ndash;485.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmeler, K.M., et al., \u003cem\u003eProphylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome\u003c/em\u003e. New England Journal of Medicine, 2006. \u003cb\u003e354\u003c/b\u003e(3): p.\u0026nbsp;261\u0026ndash;269.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark, H.K., et al., \u003cem\u003eBenign gynecologic conditions are associated with ovarian cancer risk in African-American women: a case-control study\u003c/em\u003e. Cancer Causes Control, 2018. \u003cb\u003e29\u003c/b\u003e(11): p.\u0026nbsp;1081\u0026ndash;1091.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSomigliana, E., et al., \u003cem\u003eAssociation between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence\u003c/em\u003e. Gynecologic oncology, 2006. \u003cb\u003e101\u003c/b\u003e(2): p.\u0026nbsp;331\u0026ndash;341.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNess, R.B., et al., \u003cem\u003eInfertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies\u003c/em\u003e. American journal of epidemiology, 2002. \u003cb\u003e155\u003c/b\u003e(3): p.\u0026nbsp;217\u0026ndash;224.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallach, E.E., R.E. Bristow, and B.Y. Karlan, \u003cem\u003eOvulation induction, infertility, and ovarian cancer risk\u003c/em\u003e. Fertility and sterility, 1996. \u003cb\u003e66\u003c/b\u003e(4): p.\u0026nbsp;499\u0026ndash;507.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWiesenfeld, H.C., et al., \u003cem\u003eSubclinical pelvic inflammatory disease and infertility\u003c/em\u003e. Obstetrics \u0026amp; Gynecology, 2012. \u003cb\u003e120\u003c/b\u003e(1): p.\u0026nbsp;37\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PID, NHIRD, Database, patients","lastPublishedDoi":"10.21203/rs.3.rs-112758/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-112758/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePelvic inflammatory disease (PID) is an important health issue for women. Infection and inflammation play an important role in carcinogenesis and PID has been reported to be associated with ovarian cancer, although the evidence is controversial.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e We sought to determine whether PID is associated with an elevated risk of ovarian cancer in Asian women.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Using data from Taiwan’s National Health Insurance Research Database (NHIRD), our retrospective cohort study included women diagnosed with PID (cases) between the years of 2000 till 2013. Each case was matched with two women without PID (controls) by age and the year of first entry into the database. Both study cohorts were followed-up until the first event of ovarian cancer, withdrawal from the NHI program, death, or the end of the study period (December 31, 2013). Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios (HRs and aHRs) with their corresponding 95% confidence intervals (95% CIs) for the association of PID and ovarian cancer risk, with and without adjusting for potential confounders. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e During an approximate 10 years of follow-up, cases were significantly more likely than controls to develop ovarian cancer (incidence rates of 0.27 and 0.16 per 1,000 person-years, respectively; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001). Women with a history of PID had a 1.49-fold elevated risk for ovarian cancer (aHR, 1.49; 95% CI, 1.21–1.84; \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eOur study evidence supports the contention that PID increases the risk of developing ovarian cancer amongst Taiwanese women. Gynecologists should undertake careful assessments and closely follow patients with PID, who are at long-term risk of developing ovarian cancer. Our findings need further verification in other international cohorts. \u003c/p\u003e","manuscriptTitle":"Association of Pelvic Inflammatory Disease (PID) with Ovarian Cancer: A Nationwide Population-Based Retrospective Cohort Study from Taiwan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-12-07 15:22:07","doi":"10.21203/rs.3.rs-112758/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-06-08T13:02:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-01-12T08:23:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8cb5f544-be29-44b9-a72a-815191b210f4","date":"2021-01-01T21:34:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-12-07T13:36:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-12-07T13:09:53+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-12-03T12:31:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-12-03T12:17:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2020-11-20T15:58:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"75dbf791-feed-4386-aa42-cd4ccc3e91c3","owner":[],"postedDate":"December 7th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1354964,"name":"Internal Medicine"},{"id":1354965,"name":"Preventive Medicine"}],"tags":[],"updatedAt":"2021-08-22T15:24:54+00:00","versionOfRecord":{"articleIdentity":"rs-112758","link":"https://doi.org/10.1186/s12905-021-01413-2","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2021-07-28 15:07:02","publishedOnDateReadable":"July 28th, 2021"},"versionCreatedAt":"2020-12-07 15:22:07","video":"","vorDoi":"10.1186/s12905-021-01413-2","vorDoiUrl":"https://doi.org/10.1186/s12905-021-01413-2","workflowStages":[]},"version":"v1","identity":"rs-112758","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-112758","identity":"rs-112758","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}