Secondhand Smoke Exposure, Diabetes, Elevated Glucose Level Are Risk Factors for Uterine Cervical Cancer: A Cross-Sectional Study From the Korea National Health and Nutrition Examination Survey (2010-2018)

Background: Human papilloma virus infection and tobacco smoking are the major risk factors for cervical cancer. There are limited studies searching other risk factors for cervical cancer and the results are not consistent. This study investigated the relations between cervical cancer and possible risk factors, including secondhand cigarette smoke exposure, diabetes, work schedule. Methods: In this cross-sectional study, 29,557 women completed a cervical cancer questionnaire and were selected using 2010–2018 data from the Korea National Health and Nutrition Examination Survey. Details in secondhand smoke exposure, diabetes, work schedule were assessed from participants’ health interviews and blood test results were used for fasting glucose level and hemoglobin A1c (HbA1c) level. Results: Two hundred sixty-two women (0.89%) in the sample were diagnosed with cervical cancer. Domestic secondhand smoke exposure, diabetes, high fasting glucose level, and high HbA1c signicantly increased cervical cancer risk. The respective odd ratios and 95% condence intervals were: 1.488 (1.002–2.207), 2.369 (1.713–3.274), 1.008 (1.005–1.009), and 1.304 (1.193–1.425). Weekly work hours and work schedule were not signicantly related to cervical cancer incidence. Conclusion: Among Korean women, passive exposure to cigarette smoke at home, diabetes, elevated fasting glucose level, and high HbA1c level all increase risk for cervical cancer. analyzed separately. Passive smoke exposure at work was negatively related to cervical cancer risk. Incidence of cervical cancer among women exposed to secondhand smoking at work was 0.57%, whereas 0.95% of unexposed women ha d cervical cancer (χ2 = 6.835, p = 0.009). Domestic passive smoke exposure was related with increased cervical cancer incidence. Cervical cancer was present among 1.26% of women exposed domestic secondhand smoke, but only 0.85% of those living in a smoke-free home (χ2 4.017, p 0.045). Among women exposed to secondhand smoke in public places, 0.84% cervical cancer, which did not differ signicantly from the rate of 1.01% among those who were unexposed (χ2 p 0.05). that it was based on extensive nationwide survey data, including 29,557 women in Korea. Furthermore, relatively recent data (2010–2018) were used, reecting current disease patterns and trends. There are also several limitations. The study was cross-sectional; thus, exposure and outcomes were assessed simultaneously and deductions about interrelated courses are dicult. Finally, most of these data were derived from self-report questionnaires based on participant recall.


Background
Cervical cancer is the fourth most common and the third most lethal female malignancy worldwide [1]. Cervical cancer is caused by human papilloma virus (HPV) infection, which is one of the most powerful human carcinogens and has been implicated in several cancers, including uterine cervix, anorectum and oropharynx [2]. In addition to HPV infection, young age at rst intercourse, multiple sexual partners, cigarette smoking, race, high parity, low socioeconomic status, and chronic immune suppression are also risk factors for cervical cancer [3].
Tobacco smoking is a strong risk factor for cervical neoplasia. Smoking status, duration, and intensity are associated with twofold increase in risk for highgrade cervical dysplasia and invasive carcinoma, independent of HPV infection [4]. Passive cigarette smoking, or secondhand smoke exposure is also considered a risk factor for cervical carcinogenesis, although related study results have been inconsistent. Su et al. reported a 1.7-fold increase in cervical cancer risk among those exposed to secondhand smoke, whereas Louie et al. concluded that passive smoking is not an independent risk factor for invasive cervical cancer in the absence of active smoking [5,6].
Diabetes mellitus (DM), especially type 2 diabetes, is a major risk factor for many cancers. The association between endometrial cancer and diabetes is well-established, and some have shown weak correlations between ovarian cancer and diabetes [7,8]. However, the relationship between cervical cancer incidence and type 2 diabetes remains unclear and relevant studies have been limited.
Socioeconomic disparities among women also affect cervical cancer occurrence. Cervical cancer incidence and mortality are much higher in low-and middle-income countries compared with high-income countries [9]. In Korea, women with lower education levels and lower household income have signi cantly lower cervical cancer screening rates than do highly educated and high-earning females [10,11]. Regarding occupation, service and sales workers appear to have a higher risk of cervical cancer compared with those in other elds. [12]. To our knowledge, the relationship between work schedule and cervical neoplasm has not been addressed.
To better prevent cervical cancer, and raise public health awareness, risk factors other than HPV infection and smoking must be identi ed. Thus, the study purpose was to determine the relationships between cervical cancer and potential risk factors, including passive cigarette smoking, diabetes-related factors and work schedule, using data from the Korea National Health and Nutrition Examination Survey (KNHANES).

Methods
The analyses presented herein are based on data collected during the 2010-2018 KNHANES, which began in 1998 and is administered by the Division of Health and Nutrition Survey under the Korea Disease Control and Prevention Agency. KNHANES is an ongoing population-based cross-sectional survey designed to assess the health and nutritional status of Koreans. The study monitors trends in health risk factors, assesses the prevalence of major chronic diseases, and provides data for the development and evaluation of health policies and programs in Korea [13].
The health interviews and examinations were conducted in mobile examination centers, while the nutritional surveys were performed by trained physicians or nurses who visited each household. Participants were asked to complete the cervical cancer, diabetes, smoking, and working conditions questionnaire during their health interviews. Fasting glucose and hemoglobin A1c (HbA1c) levels were assessed via blood samples. Written informed consent was acquired from all participants before the survey was administered. Institutional Review Board of the Catholic University of Korea, Bucheon, Republic of Korea approved this study (HC20ZASI0107). Statistical analyses conducted using Stata (v. 16.1; StataCorp LLC, College Station, TX, USA), re ect the complex sampling design and sampling weights of the KNHANES, and were chosen to provide nationally representative prevalence estimates. Fisher's exact probability tests were performed to identify distribution patterns by cervical cancer occurrence and odds ratios (OR), along with 95% con dence intervals (CI), were calculated using logistic regression models with respective independent variables. To compare mean fasting glucose, HbA1c, and weekly work hours, independent samples t-test were applied.

Results
Distribution patterns by categories are shown in Table 2. To investigate the relations between passive smoke exposure and cervical cancer occurrence, secondhand smoke in the workplace, home, and public places were analyzed separately. Passive smoke exposure at work was negatively related to cervical cancer risk. Incidence of cervical cancer among women exposed to secondhand smoking at work was 0.57%, whereas 0.95% of unexposed women ha d cervical cancer (χ2 = 6.835, p = 0.009). Domestic passive smoke exposure was related with increased cervical cancer incidence. Cervical cancer was present among 1.26% of women exposed domestic secondhand smoke, but only 0.85% of those living in a smoke-free home (χ2 = 4.017, p = 0.045). Among women exposed to secondhand smoke in public places, 0.84% had cervical cancer, which did not differ signi cantly from the rate of 1.01% among those who were unexposed (χ2 = 0.569, p > 0.05). The relationships between cervical cancer and passive smoking, diabetes, fasting glucose, HbA1c, weekly work hours, and work schedule are shown in Regarding weekly work hours and work schedule, there were fewer than expected participants in many cells, which thus failed to meet the analysis criteria. Consequently, the omnibus analyses for these factors were not statistically meaningful.

Discussion
This study investigated whether secondhand smoke exposure, diabetes-related factors, or work schedule are risk factors for cervical carcinogenesis.
The role of passive cigarette smoking in cervical neoplasia is controversial. Herein, secondhand smoke exposure at home was meaningfully related to cervical cancer. This nding is consistent with most studies, which have shown that secondhand smoke exposure is positively correlated with cervical cancer [5,[14][15][16]. Some studies have also reported passive smoking as an independent risk factor for abnormal cervical cytology or cervical intraepithelial neoplasm (CIN) [17][18][19]. However, most reports did not adjust for covariates like dose of tobacco exposure, sexual behavior, socioeconomic conditions, and (especially important) HPV infection status. A few investigators have proposed that passive smoking is statistically unrelated to CIN or cervical cancer after accounting for HPV infection status [6,20,21]. Interestingly, we identi ed that workplace secondhand smoke exposure is associated with lower cervical cancer risk. Considering the KNHANES data characteristics, it is possible that women diagnosed with cervical cancer may seek out smoke-free work environment and move to such jobs. There was a substantial connection between diabetes and cervical cancer. Several studies have reported increased risk for and mortality from many cancer types among patients with diabetes, especially type 2 DM [7,8,[22][23][24]. Some characteristics of diabetes may explain this carcinogenic tendency, including hyperinsulinemia, hyperglycemia, and chronic in ammatory status. These conditions all encourage cellular proliferative, angiogenetic, antiapoptotic, and metastatic activities [7,25]. This too is consistent with our ndings that elevated fasting glucose and HbA1c levels increase cervical cancer risk. Some researchers have reported that exogenous insulin treatment for DM increases overall cancer risk [26,27]. Although statistically nonsigni cant and based on low case numbers, our results also show that injected insulin is related to cervical cancer incidence. Since insulin treatment is used in response to poorly controlled glucose levels, this may explain the connection between higher fasting glucose and cervical cancer. Regarding oral antidiabetic agent, researchers have suggested that metformin therapy lowers cancer risk, while sulfonylureas increase carcinogenesis risk [26,28,29]. Herein, use of antidiabetic drugs increased cervical cancer risk. Because these data did not include which diabetic drugs were used, it is di cult to either determine the effects of individual drugs or interpret these ndings more generally.
No notable results were found regarding work hours and schedule. Few studies have explored the potential connections between night shift work and cancer risk, reporting lack of evidence or few correlations [30,31]. Since our data were cross-sectional, it is di cult to suggest causal relations. For example, women who were diagnosed with cervical cancer may have reduced their work hours or moved to a shift that carried fewer burdens. Further prospective studies are needed to assess a broad range of occupations and various socioeconomic characteristics.
A major strength of this study is that it was based on extensive nationwide survey data, including 29,557 women in Korea. Furthermore, relatively recent data (2010-2018) were used, re ecting current disease patterns and trends. There are also several limitations. The study was cross-sectional; thus, exposure and outcomes were assessed simultaneously and deductions about interrelated courses are di cult. Finally, most of these data were derived from self-report questionnaires based on participant recall.

Conclusion
Several factors, including passive cigarette smoking at home, diabetes, high fasting glucose level, and elevated HbA1c, are related to increased risk of cervical cancer among women in South Korea.

Competing interests
None.

Funding
None.

Authors' contributions
All authors contributed to the study design and execution. JY, HN collected the data and wrote the manuscript. DW, MJ, and JE analyzed the data. YJ reviewed the data and wrote manuscript. All authors have read and approved the nal manuscript.