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Incidence and relative risk for developing cancers in women with gestational diabetes mellitus: a nationwide cohort study in Taiwan
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024583
Article Type: Research
Date Submitted by the Author: 03-Jun-2018
Complete List of Authors: Peng, Yun-Shing; Chang Gung Memorial Hospital, Chiayi, Division of Endocrinology and Metabolism; Chang Gung University Lin, Jr-Rung; Chang Gung University, Clinical Informatics and Medical Statistics Research Center Cheng, Bi-Hua Ho, Cheng Lin, Yung-Hsiang Shen, Chien-Hen Tsai, Ming-Hung; Chang Gung Memorial Hospital Linkou Branch, Department of Internal Medicine; Chang Gung University
Diabetes in pregnancy < DIABETES & ENDOCRINOLOGY, cancer, http://bmjopen.bmj.com/ Keywords: population-based cohort study
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1 2 3 4 Article title 5 6 7 Incidence and relative risk for developing cancers in women with gestational diabetes 8 9 mellitus: a nationwide cohort study in Taiwan 10 11 12 13 14 15 Running title: 16 For peer review only 17 18 Increased risk of cancer with previous gestational diabetes 19 20 21 Authors: 22 23 Yun Shing Peng,1,2 Jr Rung Lin2,3, Bi Hua Cheng4, Cheng Ho1, Yung Hsiang Lin1, 24 25 26 Chien Hen Shen5, Ming Hung Tsai2,6 27 28 29 1Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, 30
31 http://bmjopen.bmj.com/ 32 Chia Yi, Taiwan. 33 34 2 35 Chang Gung University, College of Medicine, Tao Yuan, Taiwan 36 37 3 38 Clinical Informatics and Medical Statistics Research Center and Graduate Institute of
39 on September 27, 2021 by guest. Protected copyright. 40 Clinical Medicine, Chang Gung University, Taoyuan, Taiwan 41 42 43 4Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Chiayi, 44 45 46 Taiwan. 47 48 5 49 Department of internal medicine, Chang Gung Memorial Hospital, Chia Yi, Taiwan. 50 51 6 52 Department of internal medicine, Chang Gung Memorial Hospital, Lin Kuo medical 53 54 center, Taoyoun, Taiwan. 55 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 2 of 35
1 2 3 4 5 6 7 Corresponding author: 8 9 Ming Hung Tsai, MD 10 11 12 Department of internal medicine 13 14 15 Chang Gung Memorial Hospital 16 For peer review only 17 18 Chang Gung University 19 20 21 No.5, Fu Hsing Street, Guei Shan District, Taoyuan, Taiwan 22 23 Tel: +886 3 3281200 ext. 8108 24 25 26 Fax: +886 3 3288662 27 28 29 E mail: [email protected] 30
31 http://bmjopen.bmj.com/ 32 33 34 35 Word count 36 37 38 2948
39 on September 27, 2021 by guest. Protected copyright. 40 Number of tables 41 42 43 3 44 45 46 Number of Figures 47 48 49 2 50 51 52 Abbreviations 53 54 GDM, gestational diabetes; T2DM, type 2 diabetes; NHIRD, National Health 55 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 3 of 35 BMJ Open
1 2 3 4 Insurance Research Database; ICD 9 CM, International Classification of Disease, 9th 5 6 7 Revision, Clinical Modification; OPD, outpatient department; AHR, adjusted hazard 8 9 ratio. 10 11 12 13 14 15 Conflict of interest 16 For peer review only 17 18 The authors declare no conflict of interest. 19 20 21 22 23 24 25 26 27 28 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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1 2 3 4 ABSTRACT 5 6 7 Objectives: 8 9 To evaluate the risk of developing cancers, particularly site specific cancers, in 10 11 12 women with gestational diabetes mellitus (GDM) in Taiwan. 13 14 15 Setting: 16 For peer review only 17 18 The National Health Insurance Research Database (NHIRD) of Taiwan. 19 20 21 Participants 22 23 This study was conducted using the nationwide data from 2000 to 2013. In total, 24 25 26 1,466,596 pregnant women with admission for delivery were identified. Subjects with 27 28 29 GDM consisted of 47,373 women, while the control group consisted of 943,199 30
31 http://bmjopen.bmj.com/ 32 women without GDM. The participants were followed from the delivery date to the 33 34 35 diagnosis of cancer, death, the last medical claim or the end of follow up (December 36 37 38 31 2013), whichever came first.
39 on September 27, 2021 by guest. Protected copyright. 40 Primary outcome measures: 41 42 43 Patients with a new diagnosis of cancer (ICD 9 CM codes 140–208) recorded in 44 45 46 NHRID were identified. The risk of 11 major cancer types was assessed, including 47 48 49 cancers of head and neck, digestive organs, lung and bronchus, bone and connective 50 51 52 tissue, skin, breast, genital organs, urinary system, brain, thyroid and hematological 53 54 system. 55 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 5 of 35 BMJ Open
1 2 3 4 Results: 5 6 7 The rates of developing cancers were significantly higher in women with GDM 8 9 compared to non GDM group (2.24% vs. 1.96%; p<0.001). After adjusting for 10 11 12 maternal age at delivery and comorbidities, women with GDM had increased risk of 13 14 15 cancers, including cancers of nasopharynx (adjust hazard ratio (AHR), 1.739; 95 % 16 For peer review only 17 18 CI, 1.400 to 2.161; p<0.0001), kidney (AHR, 2.169; 95 % CI, 1.428 to 3.293; 19 20 21 p=0.0003), lung and bronchus (AHR, 1.372; 95 % CI, 1.044 to 1.803; p=0.0231), 22 23 breast (AHR, 1.234; 95 % CI, 1.093 to 1.393; p=0.007), and thyroid gland (AHR, 24 25 26 1.389; 95 % CI, 1.121 to 1.721; p=0.0026). 27 28 29 Conclusion: Women with GDM have a higher risk of developing cancers. Cancer 30
31 http://bmjopen.bmj.com/ 32 screening is warranted in women with GDM. Future research should be aimed to 33 34 35 establish whether this association is causal. 36 37 38 Keywords：Gestational diabetes, Cancer, National health insurance research database
39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 6 of 35
1 2 3 4 Strengths and limitations of this study 5 6 7 • Our study represents the first one to document that women with GDM have a 8 9 higher risk of developing cancers of nasopharynx, lung and bronchus, and 10 11 12 kidney. 13 14 15 • This nationwide population based cohort study included more than one million 16 For peer review only 17 18 women, making selection bias minimal. Furthermore, the use of big data from 19 20 21 Taiwan NHIRD also decreased the risk of recall bias which is inherent to 22 23 self reporting. Thus, our findings are potentially generalizable. 24 25 26 • The data from NHIRD lack information on other factors that may be 27 28 29 associated with GDM and cancer, such as smoking, alcohol consumption, 30
31 http://bmjopen.bmj.com/ 32 obesity, dietary style, environmental exposure, genetic parameters, and family 33 34 35 history of cancers. 36 37 38 • The relatively short follow up period (6.84±3.05 years) in our study may not
39 on September 27, 2021 by guest. Protected copyright. 40 have allowed some slow growing cancers to be detected. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 7 of 35 BMJ Open
1 2 3 4 INTRODUCTION 5 6 7 Pregnancy is normally accompanied by insulin resistance, which is facilitated by 8 9 placental production of diabetogenic hormones. Gestational diabetes mellitus (GDM) 10 11 12 develops in pregnant women whose pancreatic islet function is inadequate to 13 14 15 overcome the insulin resistance that accompanies pregnancy (1). GDM is associated 16 For peer review only 17 18 with adverse outcomes of pregnancy, for example, preeclampsia, macrosomia, and 19 20 21 cesarean delivery (1). The prevalence of GDM varies worldwide and among racial 22 23 and ethnic groups (2), and is generally in parallel with the prevalence of type 2 24 25 26 diabetes (T2DM). Indeed, it has been shown that women diagnosed with GDM are at 27 28 29 lifetime risk of developing T2DM subsequently (3). Lately, the prevalence of GDM 30
31 http://bmjopen.bmj.com/ 32 has been on the rise (4). The reasons for this phenomenon may be an increase in 33 34 35 maternal age, obesity issues and a decrease in daily physical activity. 36 37 38 Accumulating lines of evidence have demonstrated an association between
39 on September 27, 2021 by guest. Protected copyright. 40 T2DM and certain types of cancers. Although the exact causes for this phenomenon 41 42 43 are not yet fully understood, chronic hyperinsulinemia which is prompted by insulin 44 45 46 resistance has been proposed to be the major channel through which T2DM can 47 48 49 trigger tumor growth. Some studies, although not all, suggested that T2DM may 50 51 52 contribute to an increased mortality (5). Interestingly, the increase in cancer risk has 53 54 been found not only in T2DM but also in pre diabetes (6). GDM is characterized by 55 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 8 of 35
1 2 3 4 hyperglycemia, insulin resistance, hyperinsulinemia and increased levels of 5 6 7 Insulin like growth factor 1 (IGF 1), which can potentially lead to uncontrolled 8 9 growth of cells and cancer (1, 7). Since GDM has the same characteristics as T2DM 10 11 12 and is a predictor for subsequent overt T2DM, it is plausible that GDM may represent 13 14 15 a risk factor for the future cancers. Indeed, several studies have been conducted to 16 For peer review only 17 18 address whether GDM increases risk of cancer, but yielded mixed results probably 19 20 21 because of methodological limitations such as self reported GDM information, 22 23 relatively small population and insufficient statistical power resulting from rare 24 25 26 occurrence of cancers among young women (7 12). Most previous studies focused on 27 28 29 the association between GDM and breast cancer. Only a few have investigated the 30
31 http://bmjopen.bmj.com/ 32 relationship between GDM and other types of cancers. Moreover, few studies on the 33 34 35 association between cancer and GDM have been carried out in Asia Pacific region 36 37 38 where certain types of cancer are particularly prevalent. Therefore, it is unknown
39 on September 27, 2021 by guest. Protected copyright. 40 whether currently available data can be generalized to different ethnic groups. 41 42 43 The aim of this study was to determine the risk of developing cancers particularly 44 45 46 site specific cancers in women with prior GDM using the National Health Insurance 47 48 49 Research Database (NHIRD), which was created by National Health Research 50 51 52 Institutes (NHRI) for academic research (13). 53 54 55 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 9 of 35 BMJ Open
1 2 3 4 MATERIALS AND METHODS 5 6 7 Ethics statement 8 9 This study was granted a waiver for the requirement for informed consents by the 10 11 12 Institutional Review Board of Chang Gung memorial Hospital (IRB: 103 2572B) 13 14 15 because all data in the NHIRD were anonymized and de identified before release. 16 For peer review only 17 18 Source of data 19 20 21 Data in NHIRD were used. NHIRD contains the registration files and original 22 23 claim data for reimbursements from the national health insurance (NHI) program of 24 25 26 Taiwan; This NHI program was implemented in 1995; and covers 99.5% of the 23 27 28 29 million residents in Taiwan. NHI program offers a comprehensive, unified, and 30
31 http://bmjopen.bmj.com/ 32 universal health insurance program to all citizens. The coverage includes outpatient 33 34 35 service, inpatient care, dental care, childbirth, physical therapy, preventive health care, 36 37 38 home care, and rehabilitation for chronic mental illnesses (14). The database contains
39 on September 27, 2021 by guest. Protected copyright. 40 all dates of inpatient and outpatient services, diagnosis, prescriptions, examinations, 41 42 43 operations, and expenditures, and is updated biannually. 44 45 46 Study groups: 47 48 49 This study used data published by the NHRI in Taiwan and covered the years 50 51 52 from 2000 to 2013. The diagnostic coding of the NHI in Taiwan was performed 53 54 according to the International Classification of Disease, 9th Revision, Clinical 55 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 10 of 35
1 2 3 4 Modification (ICD 9 CM) diagnostic criteria. 5 6 7 Inclusion and exclusion criteria: 8 9 A total of 1,466,596 pregnant women with admission for delivery were found in 10 11 12 the NHIRD between Jan 1, 2002 and Dec 31, 2012. Among these women, we 13 14 15 identified 47,373 women who had been diagnosed with gestational diabetes 16 For peer review only 17 18 (ICD 9 CM code 648, 250), and had at least 2 consensus diagnoses at prenatal 19 20 21 outpatient visits or at least one diagnosis at inpatient admissions during the prenatal 22 23 period to ensure the validity of diagnosis. (Fig.1). The remaining 943,199 women 24 25 26 without GDM, diabetes or malignancy were used as controls. The incidence of GDM 27 28 29 was 4.78 in 100 deliveries during the 11 year span (Table 1). 30
31 http://bmjopen.bmj.com/ 32 Patients with missing data (n=422,568), history of malignancy (ICD 9 CM codes 33 34 35 140 to 208) (n=9,809), or diabetes (ICD 9 CM codes 250) (n=37,026) two years 36 37 38 before pregnancy were excluded. The date of delivery was set as the index date. To
39 on September 27, 2021 by guest. Protected copyright. 40 avoid inclusion of patients with cancers that arose during or before pregnancy, GDM 41 42 43 and control participants were followed for 180 days after delivery until malignancy 44 45 46 diagnosis, death, the last medical claim or the end of study follow up (December 31 47 48 49 2013), whichever came first. We excluded the women with a cancer diagnosis during 50 51 52 pregnancy or within 180 days postpartum. (n=778). 5827 patients were also excluded 53 54 due to loss of follow up within 180 days after delivery. 55 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 11 of 35 BMJ Open
1 2 3 4 Primary outcome 5 6 7 The primary outcome was defined as a new diagnosis of any cancer (ICD 9 CM 8 9 codes 140–208) recorded in NHRID between January 1, 2002 and December 31, 10 11 12 2013. 13 14 15 Sub-classification of Cancers 16 For peer review only 17 18 We classified cancers into the 11 groups as previously described (12), on basis of 19 20 21 the ICD 9 CM (Table 3): cancers of head and neck, digestive organs, lung and 22 23 bronchus, bone and connective tissue, skin, breast, genital organs, urinary system, 24 25 26 brain, thyroid gland and hematological system. Some of these cancers were further 27 28 29 sub classified as follows: The digestive subgroup included cancers of the esophagus, 30
31 http://bmjopen.bmj.com/ 32 stomach, colon and rectum, liver, biliary system, and pancreas. The genital subgroup 33 34 35 included cancers of the cervix uteri, ovary, and uterus. The urinary subgroup included 36 37 38 cancers of urinary bladder and kidney. The head and neck subgroup included cancers
39 on September 27, 2021 by guest. Protected copyright. 40 of oral cavity and pharynx, nasopharynx, larynx, and major salivary glands. The bone 41 42 43 and connective tissue subgroup included cancers of bone and sarcoma. The 44 45 46 hematological system subgroup included lymphoma and leukemia. 47 48 49 Baseline comorbidities were assessed for 2 years and included hypertension 50 51 52 (ICD 9 CM codes 401 405), and dyslipidemia (ICD 9 CM code 272), liver disease 53 54 (ICD 9 CM codes 070, 571), infertility (ICD 9 CM codes 628), kidney disease 55 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 12 of 35
1 2 3 4 (ICD 9 CM codes 582 3, 585 6, 588). 5 6 7 Statistical analysis 8 9 Continuous variables were presented as the mean with SDs. The χ2 test was used 10 11 12 to compare categorical variables, and the differences among continuous variables 13 14 15 were compared using the Student’s t test. The proportion of patients with cancer was 16 For peer review only 17 18 plotted by Kaplan–Meier curves with log rank test constructed to compare the 19 20 21 cumulative incidence of any type of cancer between subjects with and without GDM. 22 23 The relative risk of cancer was estimated by Cox proportional regression analysis, 24 25 26 which was adjusted for potential confounding variables, such as age and 27 28 29 comorbidities. The statistical significance was inferred at a two sided p value of 30
31 http://bmjopen.bmj.com/ 32 <0.05. All statistical analyses were performed using the Statistical Analysis Software 33 34 35 (SAS) System, V.9.4 (SAS Institute, Cary, North Carolina, USA). Kaplan Meier 36 37 38 curves were plotted using Stata V.12 (Stata Corp, College Station, Texas, USA).
39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 13 of 35 BMJ Open
1 2 3 4 RESULTS 5 6 7 Table 1 lists the clinical characteristics of subjects. Overall, 990,572 women were 8 9 analyzed. Among them, 47,373 women had GDM. The remaining 943,199 women 10 11 12 without GDM served as controls. The average length of follow up was 6.84±3.05 13 14 15 years, and mean age was 28.97±4.91 years. The incidence of GDM was 4.78% during 16 For peer review only 17 18 the 11 year span. Women with GDM had a higher incidence of comorbidities than 19 20 21 those in the control group, including hypertension, dyslipidemia, liver disease, 22 23 infertility and kidney disease (Table 1). 24 25 26 Table 2 shows that the adjusted hazard ratio (AHR) of developing any type of 27 28 29 cancer among women with GDM was 1.197 (95% CI, 1.125 to 1.274) compared to 30
31 http://bmjopen.bmj.com/ 32 women without GDM after adjusting for age and comorbidities. 33 34 35 Patients with GDM were diagnosed with cancer (n=1,063, 2.24%) at a 36 37 38 significantly higher rate than those patients without GDM (n=18,444, 1.96%;
39 on September 27, 2021 by guest. Protected copyright. 40 p<0.001). (Table 3). Figure 2 shows the cumulative incidence rates of any type of 41 42 43 cancer in patients with or without GDM from the index date until the first occurrence 44 45 46 of cancer. The patients with GDM had higher cancer incidence rates compared with 47 48 49 those patients without GDM (log rank test: p<0.0001). 50 51 52 Adjusting for maternal age at delivery, and comorbidities, women with a history 53 54 of GDM had an increased risk of cancers, including cancers of nasopharynx (AHR, 55 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 14 of 35
1 2 3 4 1.739; 95 % CI, 1.400 to 2.161; p<0.0001), kidney (AHR, 2.169; 95 % CI, 1.428 to 5 6 7 3.293, p=0.0003), lung and bronchus (AHR, 1.372; 95 % CI, 1.044 to 1.803; 8 9 p=0.0231), breast (AHR, 1.234; 95 % CI, 1.093 to 1.393; p=0.0007), and thyroid 10 11 12 gland (AHR, 1.389; 95 % CI, 1.121 to 1.721; p=0.0026). (Table 3) 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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1 2 3 4 DISCUSSION 5 6 7 The major findings of this study are as follows: [1] GDM is associated with a 8 9 19.7% higher risk of developing malignancy. [2] Women with GDM are at a higher 10 11 12 risk of developing cancers of nasopharynx, lung and bronchus, kidney, breast, and 13 14 15 thyroid glands. 16 For peer review only 17 18 One of our novel findings is that women with GDM are more likely to develop 19 20 21 nasopharyngeal cancer (NPC) during the period of follow up. NPC differs from other 22 23 head and neck cancers in epidemiology, histology, natural history, and response to 24 25 26 treatment. NPC is one of the neoplasms that are linked to infectious agents and 27 28 29 displays a distinct racial and geographic distribution. While NPC is rare in Europe and 30
31 http://bmjopen.bmj.com/ 32 America, it is endemic in Southeastern Asia including Taiwan where Epstein Barr 33 34 35 virus (EBV) infection is prevalent (15). The recrudescence of EBV in 36 37 38 immunocompromised patients has been characterized by activating the expression of
39 on September 27, 2021 by guest. Protected copyright. 40 EBV latency genes, consequently immortalizing the infected cells and leading to 41 42 43 carcinogenesis (16). Indeed, the immune dysfunction inherent to T2DM increases the 44 45 46 susceptibility to various infections and risk of reactivating latent virus infections as 47 48 49 well; eventually contributing to higher rates of mortality (17 20). It is unknown 50 51 52 whether GDM, a pre diabetes condition, is pathogenetically linked to reactivation of 53 54 EBV infection and subsequent malignant transformation. 55 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 16 of 35
1 2 3 4 Another novel finding in our study is that the risk of developing kidney cancer is 5 6 7 significantly higher in women with GDM, compared to those without GDM. The 8 9 etiology of kidney cancer remains elusive, but smoking, hypertension, obesity, 10 11 12 analgesics use, chronic kidney disease (CKD), and genetic defects are potential risk 13 14 15 factors (21, 22). Of these factors, obesity and hypertension also characterize GDM 16 For peer review only 17 18 (1). Indeed, it has been shown that patients with T2DM have a higher risk of 19 20 21 developing kidney cancers (23, 24). In fact, GDM is associated with subsequent 22 23 development of T2DM and CKD (3, 25). It is unknown whether prevention of CKD 24 25 26 would reduce the risk of kidney cancer in women with GDM. 27 28 29 Our study is also the first to demonstrate the association between GDM and lung 30
31 http://bmjopen.bmj.com/ 32 cancers, which is the most common cancer around the world (26). The prevalence of 33 34 35 both lung cancer and GDM has been on the increase in Taiwan and worldwide (4, 27). 36 37 38 Whether this association is causal remains to be determined. Importantly, GDM and
39 on September 27, 2021 by guest. Protected copyright. 40 lung cancer do share common risk factors such as smoking, dietary style, and obesity 41 42 43 (26, 28). It is unknown whether modification of these risk factors could impact this 44 45 46 association. 47 48 49 In the present study, we also observed a clear association between GDM and 50 51 52 breast cancer. Previous studies on the association between GDM and breast cancer 53 54 have produced mixed results (7 12, 29 34). The reasons for the discrepancy are not 55 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 17 of 35 BMJ Open
1 2 3 4 clear. They could be explained by methodological limitations. First, most of these 5 6 7 studies were based on self reported information about GDM (9 11, 29, 31, 32, 34), 8 9 which is prone to recall bias. Secondly, small sample size and relatively rare 10 11 12 occurrence of cancer among young women may result in inadequate statistical power, 13 14 15 contributing to inconsistency. In these regards, our big database from Taiwan NHIRD 16 For peer review only 17 18 confers an advantage to overcome these methodological limitations. 19 20 21 In agreement with a previous study (8), we showed that GDM was associated with a 22 23 38.9% higher risk of developing thyroid cancer. Interestingly, a large study from 24 25 26 United States found that the risk of thyroid cancer was significantly increased in 27 28 29 women, but not in men, with diabetes (35). Taken together, women with GDM may 30
31 http://bmjopen.bmj.com/ 32 represent a readily recognizable subgroup that deserves a more intensive surveillance 33 34 35 for thyroid cancer. 36 37 38 The elucidation of the relationship between GDM and later cancer risk may not
39 on September 27, 2021 by guest. Protected copyright. 40 be straightforward. It is conceivable that GDM may impact subsequent cancer risk 41 42 43 through certain direct or indirect pathophysiological mechanisms such as 44 45 46 hyperglycemia, hyperinsulinemia secondary to insulin resistance and chronic 47 48 49 inflammation. Shared risk factors for GDM and cancers can be other explanations, for 50 51 52 example smoking, alcohol drinking, obesity, physical inactivity, hypertension and 53 54 dietary style. 55 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 18 of 35
1 2 3 4 Insulin has mitogenic effects on cells (36). On the other hand, hyperglycemia can 5 6 7 induce production of reactive oxygen species (ROS), which can initiate 8 9 carcinogenesis by damaging cellular DNA (37, 38). 10 11 12 Recently, the role of systemic inflammation in the pathogenesis of GDM has 13 14 15 gained more and more attention. Increased circulating levels of interleukin 6 (IL 6) 16 For peer review only 17 18 and C reactive protein (CRP) have been observed in GDM independent of obesity 19 20 21 (39, 40), suggesting GDM as a state of low grade inflammation. Inflammation is also 22 23 a hallmark of cancer and is widely recognized to influence all cancer stages from cell 24 25 26 transformation to metastasis (41). Therefore, chronic and systemic inflammation may 27 28 29 represent the biological phenomenon linking GDM to cancer development. Future 30
31 http://bmjopen.bmj.com/ 32 investigations on the role of low grade inflammation in GDM may help identify 33 34 35 biomarkers that can better predict, diagnose and monitor the evolution of GDM. 36 37 38 Moreover, specific inflammatory pathways may represent novel targets for treatment
39 on September 27, 2021 by guest. Protected copyright. 40 and prevention of long term adverse outcomes of GDM, including cancer 41 42 43 development. 44 45 46 There were several strengths in this study. First, this is population based study 47 48 49 with a large nationally representative sample from Taiwan NHIRD, thus maing 50 51 52 selection bias minimized. Secondly, the use of NHIRD reduced the potential recall 53 54 bias that is inherent to self reporting. 55 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 19 of 35 BMJ Open
1 2 3 4 Limitations of this study included the lack of information about the histology and 5 6 7 staging of cancer. Secondly, our study did not have information about potential 8 9 confounders such as dietary, obesity, physical activity, smoking, alcohol consumption, 10 11 12 environmental exposure and genetic parameters. Third, the follow up period may not 13 14 15 be long enough to allow detection of cancers in young women. 16 For peer review only 17 18 19 20 21 CONCLUSIONS 22 23 This population based analysis of Taiwan NHIRD showed that women with 24 25 26 GDM in Taiwan have an increased risk of developing malignancy including cancers 27 28 29 of nasopharynx, lung, kidney, breast, and thyroid gland. Prevention of GDM may be 30
31 http://bmjopen.bmj.com/ 32 an important strategy in curbing the development of certain types of cancers in the 33 34 35 future. Our study also highlights under recognized cancers in women with GDM that 36 37 38 warrants further investigations to develop different surveillance strategies for cancer
39 on September 27, 2021 by guest. Protected copyright. 40 development in GDM patients in different ethnic groups. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 20 of 35
1 2 3 4 Acknowledgements 5 6 7 This work was supported by grants from the Chang Gung Memorial Hospital (Grant 8 9 CIRPD1D0031). The authors thank Research Services Center For Health Information, 10 11 12 Chang Gung University for statistical consultation. This study was based in part on 13 14 15 data from NHIRD. The interpretation and conclusions contained herein do not 16 For peer review only 17 18 represent those of the National Health Insurance Administration, Department of 19 20 21 Health, or National Health Research Institutes. 22 23 24 25 Contributors 26 27 28 YSP proposed and designed the study. YSP also drafted the manuscript. MHT 29 30
31 supervised the study and critically edited the manuscript; and finally approved the http://bmjopen.bmj.com/ 32 33 version to be submitted. JRL designed the study’s analytic strategy and conducted the 34 35 36 data analysis. BHC and CH contributed to study design and prepare the Methods and 37 38
39 the Discussion sections of the text, YHL and CHS conducted literature review. All on September 27, 2021 by guest. Protected copyright. 40 41 42 authors have read and approved the final manuscript. 43 44 45 46 47 Funding 48 49 50 This work was supported by the Chang Gung Memorial Hospital, grant number 51 52 53 CIRPD1D0031. 54 55 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 21 of 35 BMJ Open
1 2 3 4 Competing interests 5 6 7 The authors declare no conflict of interest. 8 9 10 11 12 Ethics approval 13 14 15 This study protocol was approved by the institutional review board of Chang Gung 16 For peer review only 17 18 Medical Foundation (IRB 103 2572B). 19 20 21 22 23 Provenance and peer review 24 25 26 Not commissioned; externally peer reviewed. 27 28 29 30 31 Data sharing statement http://bmjopen.bmj.com/ 32 33 No additional data are available. 34 35 36 37 38
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1 2 3 4 REFERENCES 5 6 7 1. International Association of Diabetes and Pregnancy Study Groups Consensus 8 9 Panel, Metzger BE, Gabbe SG, Persson B, et al. International association of 10 11 12 diabetes and pregnancy study groups recommendations on the diagnosis and 13 14 15 classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676. 16 For peer review only 17 18 2. Dornhorst A, Paterson CM, Nicholls JS, et al. High prevalence of gestational 19 20 21 diabetes in women from ethnic minority groups. Diabet Med 1992;9:820 5. 22 23 3. Chodick G, Elchalal U, Sella T, et al. The risk of overt diabetes mellitus among 24 25 26 women with gestational diabetes: a population based study. Diabet Med 27 28 29 2010;27:779 85 30
31 http://bmjopen.bmj.com/ 32 4. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health 33 34 35 perspective. Diabetes Care 2007;30(Suppl 2):P141 6， 36 37 38 5. Barone BB, Yeh HC, Snyder CF, et al. Long term all cause mortality in cancer
39 on September 27, 2021 by guest. Protected copyright. 40 patients with preexisting diabetes mellitus: a systematic review and meta 41 42 43 analysis. JAMA 2008;300:2754 64. 44 45 46 6. Stattin P, Björ O, Ferrari P, et al. Prospective study of hyperglycemia and cancer 47 48 49 risk. Diabetes Care 2007;30:561 7. 50 51 52 7. Tong GX, Cheng J, Chai J, et al. Association between gestational diabetes mellitus 53 54 and subsequent risk of cancer: a systematic review of epidemiological studies. 55 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 23 of 35 BMJ Open
1 2 3 4 Asian Pac J Cancer Prev 2014;15:4265 9. 5 6 7 8. Bejaimal SA, Wu CF, Lowe J, et al. Short term risk of cancer among women with 8 9 previous gestational diabetes: a population based study. Diabet Med 10 11 12 2016;33:39 46. 13 14 15 9. Powe CE, Tobias DK, Michels KB, et al. History of Gestational Diabetes Mellitus 16 For peer review only 17 18 and Risk of Incident Invasive Breast Cancer among Parous Women in the Nurses' 19 20 21 Health Study II Prospective Cohort. Cancer Epidemiol Biomarkers Prev 22 23 2017;26:321 7. 24 25 26 10. Park YM, O'Brien KM, Zhao S, et al. Gestational diabetes mellitus may be 27 28 29 associated with increased risk of breast cancer. Br J Cancer 2017;116:960 3. 30
31 http://bmjopen.bmj.com/ 32 11. Dawson SI. Long term risk of malignant neoplasm associated with gestational 33 34 35 glucose intolerance. Cancer 2004;100,149 55. 36 37 38 12. Sella T, Chodick G, Barchana M, et al. Gestational diabetes and risk of incident
39 on September 27, 2021 by guest. Protected copyright. 40 primary cancer: a large historical cohort study in Israel. Cancer Causes Control 41 42 43 2011;22,1513 20. 44 45 46 13. Chen YC, Yeh, H, Wu JC, et al. Taiwan’s National Health Insurance Research 47 48 49 Database: Administrative health care database as study object in bibliometrics. 50 51 52 Scientometrics 2011,86,365 80. 53 54 14. Hsing AW, Ioannidis JP. Nationwide population science: lessons from the Taiwan 55 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 24 of 35
1 2 3 4 National Health Insurance Research Database. JAMA Intern Med 5 6 7 2015;175:1527 9. 8 9 15. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer 10 11 12 Biol 2002;12:421 9. 13 14 15 16. Cohen JI. Epstein Barr virus infection. N Engl J Med 2000;343:481 92. 16 For peer review only 17 18 17. Plouffe JF, Silva J, Jr, Fekety R, et al. Cell mediated immunity in diabetes 19 20 21 mellitus. Infect Immun 1978;21:425 9. 22 23 18. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes 24 25 26 mellitus (DM) FEMS Immunol Med Microbiol. 1999;26:259 65. 27 28 29 19. Berrou J, Fougeray S, Venot M, et al. Natural killer cell function, an important 30
31 http://bmjopen.bmj.com/ 32 target for infection and tumor protection, is impaired in type 2 diabetes. PLoS One 33 34 35 2013;8:e62418. 36 37 38 20. Kumar M, Roe K, Nerurkar PV, et al. Impaired virus clearance, compromised
39 on September 27, 2021 by guest. Protected copyright. 40 immune response and increased mortality in type 2 diabetic mice infected with 41 42 43 West Nile virus. PLoS One 2012;7:e44682. 44 45 46 21. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell 47 48 49 carcinoma. Eur Urol 2011;60:615 21. 50 51 52 22. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney 53 54 cancer. Nat Rev Urol 2010;7:245 57. 55 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 25 of 35 BMJ Open
1 2 3 4 23. Larsson SC, Wolk A. Diabetes mellitus and incidence of kidney cancer: a 5 6 7 meta analysis of cohort studies. Diabetologia 2011;54:1013 8. 8 9 24. Tseng CH. Type 2 Diabetes Mellitus and Kidney Cancer Risk: A Retrospective 10 11 12 Cohort Analysis of the National Health Insurance. PLoS One 13 14 15 2015;11;10:e0142480. 16 For peer review only 17 18 25. Dehmer EW, Phadnis MA, Gunderson EP, et al. Association Between Gestational 19 20 21 Diabetes and Incident Maternal CKD: The Coronary Artery Risk Development in 22 23 Young Adults (CARDIA) Study. Am J Kidney Dis 2018;71:112 22. 24 25 26 26. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and 27 28 29 prevention. Clin Chest Med 2011;32:605 44. 30
31 http://bmjopen.bmj.com/ 32 27. Tseng CH. Diabetes but not insulin increases the risk of lung cancer: a Taiwanese 33 34 35 population based study. PLoS One 2014;9:e101553. 36 37 38 28. Solomon CG, Willett WC, Carey VJ, et al. A prospective study of pregravid
39 on September 27, 2021 by guest. Protected copyright. 40 determinants of gestational diabetes mellitus. JAMA 1997;278:1078 83. 41 42 43 29. Troisi R, Weiss HA, Hoover RN, et al. Pregnancy characteristics and maternal risk 44 45 46 of breast cancer. Epidemiology 1998;9,641 7. 47 48 49 30. Cnattingius S, Torrang A, Ekbom A, et al. Pregnancy characteristics and maternal 50 51 52 risk of breast cancer. JAMA 2005;294,2474 80. 53 54 31. Brasky TM, Li Y, Jaworowicz DJ Jr, et al. Pregnancy related characteristics and 55 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 26 of 35
1 2 3 4 breast cancer risk. Cancer Causes Control 2013;24,1675 85. 5 6 7 32. Lawlor DA, Smith GD, Ebrahim S. Hyperinsulinaemia and increased risk of 8 9 breast cancer: findings from the British Women’s Heart and Health Study. Cancer 10 11 12 Causes Control 2004;15,267 75. 13 14 15 33. Perrin MC, Terry MB, Kleinhaus K, et al. Gestational diabetes and the risk of 16 For peer review only 17 18 breast cancer among women in the Jerusalem Perinatal Study. Breast Cancer Res 19 20 21 Treat 2008;108,129 35. 22 23 34. Rollison DE, Giuliano AR, Sellers TA, et al. Population based case control study 24 25 26 of diabetes and breast cancer risk in Hispanic and non Hispanic White women 27 28 29 living in US southwestern states. Am J Epidemiol 2008;167,447 56. 30
31 http://bmjopen.bmj.com/ 32 35. Aschebrook Kilfoy B, Sabra MM, Brenner A, et al. Diabetes and thyroid cancer 33 34 35 risk in the National Institutes of Health AARP Diet and Health Study. Thyroid 36 37 38 2011;21:957 63.
39 on September 27, 2021 by guest. Protected copyright. 40 36. Vigneri P, Frasca F, Siacca L, et al. Diabetes and cancer. Endocr. Relat. Cancer 41 42 43 2009;16,1103 23. 44 45 46 37. Chandrasekaran K, Swaminathan K, Chatterjee S, et al. Apoptosis in hepG2 cells 47 48 49 exposed to high glucose. Toxicol. In Vitro 2010;24,387 96. 50 51 52 38. Zhang Y, Zhou J, Wang T, Cai T. High level glucose increases mutagenesis in 53 54 human lymphoblastoid cells. Int. J. Biol. Sci. 2007;3,275 9. 55 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 27 of 35 BMJ Open
1 2 3 4 39. Ategbo JM, Grissa O, Yessoufou A, et al. Modulation of adipokines and cytokines 5 6 7 in gestational diabetes and macrosomia. J Clin Endocrinol Metab 8 9 2006;91:4137e43. 10 11 12 40. Wolf M, Sandler L, Hsu K, et al. First trimester C reactive protein and subsequent 13 14 15 gestational diabetes. Diabetes Care 2003;26:819 24. 16 For peer review only 17 18 41. Leonardi GC, Accardi G, Monastero R, et al. Ageing: from inflammation to 19 20 21 cancer. Immun Ageing 2018;15:1. 22 23 24 25 26 27 28 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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1 2 3 Table 1 Baseline characteristics 4 Pregnancy women Pregnancy women P value 5 6 with GDM without GDM 7 Number of population, n (%) 47373 (4.78) 943199 (95.22) 8 9 Age, y, mean±SD 31.61±4.54 28.83±4.89 <.0001 10 Age at pregnancy, n (%) <.0001 11 407 (0.86) 45942 (4.87) 12 ≤ 20 13 21 30 18617 (39.30) 558108 (59.17) 14 31 40 27203 (57.42) 329929 (34.98) 15 16 41 50 For peer review1146 (2.42) only 9220 (0.98) 17 Comorbidity, n (%) 18 19 Hypertension (icd9 401 405) 1479 (3.12) 7743 (0.82) <.0001 20 Dyslipidemia (icd9 272) 1132 (2.39) 8197 (0.87) <.0001 21 Liver disease (icd9 070, 571) 3165 (6.68) 44509 (4.72) <.0001 22 23 Infertility, female (icd9 628) 8001 (16.89) 94405 (10.01) <.0001 24 Kidney disease (icd9 582 3, 585 6, 588) 51 (0.11) 626 (0.07) 0.0008 25 26 SD=Standard Deviation 27 28 29 30
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1 2 3 Table 2 Hazard ratio (HR) of developing cancer in relation to baseline characteristics 4 of study participants: 5 6 Crude HR P value Adjusted HR P value 7 (95% CI) (95% CI) 8 9 Patients 10 GDM 1.421 (1.336 1.512) <0.0001 1.197 (1.125 1.274) 0.0012 11 Non GDM 1.0 (ref) 1.0 (ref) 12 13 Age 14 ≤ 20 1.0 (ref) 1.0 (ref) 15 16 21 30 For peer1.627 (1.488 1.779) review <0.0001 only 1.581 (1.446 1.729) <0.0001 17 31 40 2.843 (2.600 3.109) <0.0001 2.678 (2.448 2.930) <0.0001 18 19 41 50 4.883 (4.291 5.556) <0.0001 4.479 (3.933 5.100) <0.0001 20 Comorbidity, n (%) 21 Hypertension (icd9 401 405) 1.471 (1.291 1.677) <0.0001 1.114 (0.976 1.272) 0.1101 22 23 Dyslipidemia (icd9 272) 1.866 (1.648 2.113) <0.0001 1.395 (1.229 1.583) <0.0001 24 Liver disease (icd9 070, 571) 1.573 (1.486 1.665) <0.0001 1.432 (1.351 1.517) <0.0001 25 26 Infertility, female (icd9 628) 1.397 (1.340 1.457) <0.0001 1.185 (1.136 1.236) <0.0001 27 Kidney disease (icd9 582 3, 2.077 (1.403 3.073) 0.0003 1.623 (1.095 2.404) 0.0159 28 585 6, 588) 29 30 Model was adjusted for age, hypertension, dyslipidemia, liver disease, infertility, and kidney disease; 31 HR=Hazard Ratio. http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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1 2 3 Table 3 Hazard ratio (HR) of the first cancer diagnosis between GDM group and non GDM 4 groups 5 6 (ICD 9 code) Women Women Crude HR P value Adjusted HR P value 7 with GDM without GDM (95% CI) (95% CI) 8 9 (N=47373) (N=943199) 10 Head and neck 11 Oral & pharynx (140 1、 19 (0.04) 389 (0.04) 1.230 (0.776 1.950) 0.380 1.105 (0.695 1.759) 0.6724 12 13 143 6、148 9)* 14 Nasopharynx (147)* 90 (0.19) 1151 (0.12) 1.897 (1.530 2.351) <.0001 1.739 (1.400 2.161) <.0001 15 16 Larynx (161)* For 5 peer (0.01) 84 review (0.01) 1.494 (0.605 3.686) only 0.384 1.562 (0.628 3.877) 0.3379 17 Major salivary gland (142)* 5 (0.01) 69 (0.01) 1.774 (0.715 4.402) 0.216 1.476 (0.591 3.688) 0.4044 18 19 Digestive system 20 Esophagus (150)* 3 (0.01) 88 (0.01) 0.748 (0.237 2.363) 0.620 0.554 (0.175 1.756) 0.3157 21 Stomach (151)* 18 (0.04) 256 (0.03) 1.703 (1.056 2.749) 0.029 1.322 (0.816 2.142) 0.2570 22 23 Colorectum (153 4)* 100 (0.21) 1705 (0.18) 1.420 (1.160 1.738) 0.0007 1.180 (0.963 1.447) 0.1099 24 Liver (155)* 87 (0.18) 1393 (0.15) 1.504 (1.211 1.868) 0.0002 1.242 (0.998 1.545) 0.0521 25 26 Biliary system (156)* 4 (0.01) 43 (<0.01) 2.329 (0.835 6.496) 0.106 1.954 (0.692 5.516) 0.2058 27 Pancreas (157)* 17 (0.04) 314 (0.03) 1.316 (0.808 2.145) 0.270 1.072(0.655 1.755) 0.7807 28 Genital system 29 30 Cervix uteri (180)* 37 (0.08) 962 (0.10) 0.925 (0.666 1.285) 0.643 0.903 (0.649 1.256) 0.5438 31 Uterus (179,182)* 42 (0.09) 803 (0.09) 1.323 (0.970 1.805) 0.077 1.051 (0.769 1.437) 0.7534 http://bmjopen.bmj.com/ 32 33 Ovary (183)* 50 (0.11) 1146 (0.12) 1.061 (0.800 1.409) 0.680 0.963 (0.724 1.280) 0.7928 34 Urinary system 35 Urinary bladder (188)* 9 (0.02) 162 (0.02) 1.387 (0.709 2.715) 0.340 1.034 (0.525 2.033) 0.9236 36 37 Kidney (189)* 25 (0.05) 245 (0.03) 2.573 (1.704 3.885) <.0001 2.169 (1.428 3.293) 0.0003 38 Hematological system 39 on September 27, 2021 by guest. Protected copyright. 40 Leukemia (204 8)* 11 (0.02) 359 (0.04) 0.742 (0.407 1.352) 0.329 0.735 (0.402 1.344) 0.3169 41 Lymphoma (200 3)* 19 (0.04) 596 (0.06) 0.771 (0.488 1.217) 0.264 0.774 (0.489 1.226) 0.2754 42 43 Bone and connective tissue 44 Bone (170)* 4 (0.01) 96 (0.01) 0.992 (0.365 2.699) 0.988 0.977 (0.357 2.677) 0.9646 45 Sarcoma (171)* 3 (0.01) 175 (0.02) 0.412 (0.132 1.289) 0.128 0.387 (0.123 1.217) 0.1045 46 47 Lung and bronchus (162)* 56 (0.12) 846 (0.09) 1.666 (1.271 2.184) 0.0002 1.372 (1.044 1.803) 0.0231 48 Skin (173)* 15 (0.03) 201 (0.02) 1.834 (1.085 3.101) 0.024 1.664 (0.980 2.825) 0.0594 49 50 Breast (174)* 284 (0.60) 4373 (0.46) 1.654 (1.467 1.866) <.0001 1.234 (1.093 1.393) 0.0007 51 Brain (191)* 19 (0.04) 331 (0.04) 1.382 (0.870 2.195) 0.170 1.232 (0.772 1.968) 0.3818 52 Thyroid (193)* 91 (0.19) 1423 (0.15) 1.582 (1.279 1.956) <.0001 1.389 (1.121 1.721) 0.0026 53 54 Other sites 74 (0.16) 1435 (0.15) 1.046 (0.799 1.370) 0.743 0.967 (0.737 1.269) 0.8104 55 Total (140-208) 1063 (2.24) 18444 (1.96) 1.421 (1.336 1.512) <.0001 1.197 (1.125 1.274) <.0001 56 57 30 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 31 of 35 BMJ Open
1 2 3 LEGENDS: 4 5 Figure 1: Flow chart for selection of study population 6 7 8 Figure 2: The cumulative incidence rates of any type of cancer in patients with or 9 10 11 without GDM from the index date until the first occurrence of the cancer using 12 13 14 Kaplan Meier methods. 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30
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39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 Figure 1 46 47 209x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 33 of 35 BMJ Open
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 2 30 31 297x209mm (300 x 300 DPI) http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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Incidence and relative risk for developing cancers in women with gestational diabetes mellitus: a nationwide cohort study in Taiwan ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024583.R1
Article Type: Research
Date Submitted by the 14-Oct-2018 Author:
Complete List of Authors: Peng, Yun-Shing; Chiayi Chang Gung Memorial Hospital, Division of Endocrinology and Metabolism, Department of Internal Medicine; Chang Gung University Lin, Jr-Rung; Chang Gung University, Clinical Informatics and Medical Statistics Research Center Cheng, Bi-Hua; Chiayi Chang Gung Memorial Hospital, Department of Obstetrics and Gynecology Ho, Cheng; Chiayi Chang Gung Memorial Hospital, Division of Endocrinology and Metabolism, Department of Internal Medicine Lin, Yung-Hsiang; Chiayi Chang Gung Memorial Hospital, Division of Endocrinology and Metabolism, Department of Internal Medicine http://bmjopen.bmj.com/ Shen, Chien-Hen; Chiayi Chang Gung Memorial Hospital, Department of internal medicine Tsai, Ming-Hung; Chang Gung Memorial Hospital Linkou Branch, Department of Internal Medicine; Chang Gung University
Primary Subject Diabetes and endocrinology Heading:
Secondary Subject Heading: Public health on September 27, 2021 by guest. Protected copyright.
Diabetes in pregnancy < DIABETES & ENDOCRINOLOGY, cancer, Keywords: population-based cohort study
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1 2 3 4 Article title 5 6 7 Incidence and relative risk for developing cancers in women with gestational diabetes 8 9 10 mellitus: a nationwide cohort study in Taiwan 11 12 13 14 15 16 Running title: For peer review only 17 18 19 Increased risk of cancer with previous gestational diabetes 20 21 22 Authors: 23 24 25 Yun-Shing Peng,1,2 Jr Rung Lin2,3, Bi-Hua Cheng4, Cheng Ho1, Yung-Hsiang Lin1, 26 27 28 Chien-Hen Shen5, Ming-Hung Tsai2,6 29 30 31 1Division of Endocrinology and Metabolism, Department of internal medicine, Chang http://bmjopen.bmj.com/ 32 33 34 Gung Memorial Hospital, Chiayi, Taiwan. 35 36 37 2Chang Gung University, College of Medicine, Taoyuan, Taiwan 38
39 on September 27, 2021 by guest. Protected copyright. 40 3Clinical Informatics and Medical Statistics Research Center and Graduate Institute of 41 42 43 Clinical Medicine, Chang Gung University, Taoyuan, Taiwan 44 45 46 4Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Chiayi, 47 48 49 Taiwan. 50 51 52 5Department of internal medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan. 53 54 55 6Department of internal medicine, Chang Gung Memorial Hospital, Linkuo medical 56 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 2 of 39
1 2 3 4 center, Taoyuan, Taiwan. 5 6 7 8 9 10 Corresponding author: 11 12 13 Ming-Hung Tsai, MD 14 15 16 Department of internalFor medicine peer review only 17 18 19 Chang Gung Memorial Hospital, Linkuo Medical Center 20 21 22 Chang Gung University 23 24 25 No.5, Fu-Hsing Street, Guishan District, Taoyuan, Taiwan 26 27 28 Tel: +886-3-3281200 ext. 8108 29 30 31 Fax: +886-3-3288662 http://bmjopen.bmj.com/ 32 33 34 E-mail: [email protected] 35 36 37 38
39 on September 27, 2021 by guest. Protected copyright. 40 Word count 41 42 43 2824 44 45 46 Number of tables 47 48 49 3 50 51 52 Number of Figures 53 54 55 2 56 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 3 of 39 BMJ Open
1 2 3 4 Abbreviations 5 6 7 GDM, Gestational diabetes mellitus; T2DM, type 2 diabetes mellitus; NHIRD, National 8 9 10 Health Insurance Research Database; ICD-9-CM, International Classification of Disease, 11 12 13 9th Revision, Clinical Modification; OPD, outpatient department; AHR, adjusted hazard 14 15 16 ratio. For peer review only 17 18 19 20 21 22 Conflict of interest 23 24 25 The authors declare no conflict of interest. 26 27 28 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 3 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 4 of 39
1 2 3 4 ABSTRACT 5 6 7 Objectives: 8 9 10 To evaluate the risk of developing cancers, particularly site-specific cancers, in women 11 12 13 with gestational diabetes mellitus (GDM) in Taiwan. 14 15 16 Setting: For peer review only 17 18 19 The National Health Insurance Research Database (NHIRD) of Taiwan. 20 21 22 Participants 23 24 25 This study was conducted using the nationwide data from 2000 to 2013. In total, 26 27 28 1,466,596 pregnant women with admission for delivery were identified. Subjects with 29 30 31 GDM consisted of 47,373 women, while the non-exposed group consisted of 943,199 http://bmjopen.bmj.com/ 32 33 34 women without GDM. The participants were followed from the delivery date to the 35 36 37 diagnosis of cancer, death, the last medical claim or the end of follow-up (December 31 38
39 on September 27, 2021 by guest. Protected copyright. 40 2013), whichever came first. 41 42 43 Primary outcome measures: 44 45 46 Patients with a new diagnosis of cancer (ICD-9-CM codes 140–208) recorded in NHIRD 47 48 49 were identified. The risk of 11 major cancer types was assessed, including cancers of 50 51 52 head and neck, digestive organs, lung and bronchus, bone and connective tissue, skin, 53 54 55 breast, genital organs, urinary system, brain, thyroid gland, and hematological system. 56 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 5 of 39 BMJ Open
1 2 3 4 Results: 5 6 7 The rates of developing cancers were significantly higher in women with GDM compared 8 9 10 to non-GDM group (2.24% vs. 1.96%; p<0.001). After adjusting for maternal age at 11 12 13 delivery and comorbidities, women with GDM had increased risk of cancers, including 14 15 16 cancers of nasopharynxFor (adjust peer hazard reviewratio (AHR), 1.739; only 95 % CI, 1.400 to 2.161; 17 18 19 p<0.0001), kidney (AHR, 2.169; 95 % CI, 1.428 to 3.293; p=0.0003), lung and bronchus 20 21 22 (AHR, 1.372; 95 % CI, 1.044 to 1.803; p=0.0231), breast (AHR, 1.234; 95 % CI, 1.093 to 23 24 25 1.393; p=0.007), and thyroid gland (AHR, 1.389; 95 % CI, 1.121 to 1.721; p=0.0026). 26 27 28 Conclusion: 29 30 31 Women with GDM have a higher risk of developing cancers. Cancer screening is http://bmjopen.bmj.com/ 32 33 34 warranted in women with GDM. Future research should be aimed to establish whether 35 36 37 this association is causal. 38
39 on September 27, 2021 by guest. Protected copyright. 40 Keywords：Gestational diabetes, Cancer, National health insurance research database 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 6 of 39
1 2 3 4 Strengths and limitations of this study 5 6 7 Our study represents the first one to document that women with GDM have a 8 9 10 higher risk of developing cancers of nasopharynx, lung and bronchus, and kidney. 11 12 13 This nationwide population-based cohort study included more than one million 14 15 16 women, Formaking selection peer bias minimal.review only 17 18 19 The use of big data from Taiwan NHIRD also decreased the risk of recall bias 20 21 22 which is inherent to self-reporting, thus making our findings potentially 23 24 25 generalizable. 26 27 28 The data from NHIRD lack information on other factors that may be associated 29 30 31 with GDM and cancer, such as smoking, alcohol consumption, obesity, dietary http://bmjopen.bmj.com/ 32 33 34 style, environmental exposure, genetic parameters, subtypes of cancer, and family 35 36 37 history of cancers. 38
39 on September 27, 2021 by guest. Protected copyright. 40 The relatively short follow-up period (6.84±3.05 years) in our study may not have 41 42 43 allowed some slow-growing cancers to be detected. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 7 of 39 BMJ Open
1 2 3 4 INTRODUCTION 5 6 7 Pregnancy is normally accompanied by insulin resistance, which is facilitated by 8 9 10 placental production of diabetogenic hormones. Gestational diabetes mellitus (GDM) 11 12 13 develops in pregnant women whose pancreatic islet function is inadequate to overcome 14 15 16 the insulin resistanceFor that peeraccompanies reviewpregnancy (1). GDM only is associated with adverse 17 18 19 outcomes of pregnancy, for example, preeclampsia, macrosomia, and cesarean delivery 20 21 22 (1). The prevalence of GDM varies worldwide and among racial and ethnic groups (2), 23 24 25 and is generally in parallel with the prevalence of type 2 diabetes (T2DM). Indeed, it has 26 27 28 been shown that women diagnosed with GDM are at lifetime risk of developing T2DM 29 30 31 subsequently (3). Lately, the prevalence of GDM has been on the rise (4). The reasons for http://bmjopen.bmj.com/ 32 33 34 this phenomenon may be an increase in maternal age, obesity issues and a decrease in 35 36 37 daily physical activity. 38
39 on September 27, 2021 by guest. Protected copyright. 40 Accumulating lines of evidence have demonstrated an association between T2DM 41 42 43 and certain types of cancers. Although the exact causes for this phenomenon are not yet 44 45 46 fully understood, chronic hyperinsulinemia which is prompted by insulin resistance has 47 48 49 been proposed to be the major channel through which T2DM can trigger tumor growth. 50 51 52 Some studies, although not all, suggested that T2DM may contribute to an increased 53 54 55 mortality (5). Interestingly, the increase in cancer risk has been found not only in T2DM 56 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 8 of 39
1 2 3 4 but also in pre-diabetes (6). GDM is characterized by hyperglycemia, insulin resistance, 5 6 7 hyperinsulinemia and increased levels of Insulin-like growth factor 1 (IGF-1), which can 8 9 10 potentially lead to uncontrolled growth of cells and cancer (1, 7). Since GDM has the 11 12 13 same characteristics as T2DM and is a predictor for subsequent overt T2DM, it is 14 15 16 plausible that GDMFor may representpeer a risk review factor for the future only cancers. Indeed, several 17 18 19 studies have been conducted to address whether GDM increases risk of cancer, but 20 21 22 yielded mixed results probably because of methodological limitations such as self- 23 24 25 reported GDM information, relatively small population and insufficient statistical power 26 27 28 resulting from rare occurrence of cancers among young women (7-13). 29 30 31 Most previous studies focused on the association between GDM and breast cancer. http://bmjopen.bmj.com/ 32 33 34 Only a few have investigated the relationship between GDM and other types of cancers. 35 36 37 Moreover, few studies on the association between cancer and GDM have been carried out 38
39 on September 27, 2021 by guest. Protected copyright. 40 in Asia-Pacific region where certain types of cancer are particularly prevalent. Therefore, 41 42 43 it is unknown whether currently available data can be generalized to different ethnic 44 45 46 groups. 47 48 49 The aim of this study was to determine the risk of developing cancers particularly 50 51 52 site-specific cancers in women with prior GDM using the National Health Insurance 53 54 55 Research Database (NHIRD), which was created by National Health Research Institutes 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 9 of 39 BMJ Open
1 2 3 4 (NHRI) for academic research (14). 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 10 of 39
1 2 3 4 MATERIALS AND METHODS 5 6 7 Ethics statement 8 9 10 This study was granted a waiver for the requirement for informed consents by the 11 12 13 Institutional Review Board of Chang Gung memorial Hospital (IRB: 103-2572B) because 14 15 16 all data in the NHIRDFor were peer anonymized review and de-identified only before release. 17 18 19 Source of data 20 21 22 Data in NHIRD were used. NHIRD contains the registration files and original claim 23 24 25 data for reimbursements from the national health insurance (NHI) program of Taiwan; 26 27 28 This NHI program was implemented in 1995; and covers 99.5% of the 23 million 29 30 31 residents in Taiwan. NHI program offers a comprehensive, unified, and universal health http://bmjopen.bmj.com/ 32 33 34 insurance program to all citizens. The coverage includes outpatient service, inpatient 35 36 37 care, dental care, childbirth, physical therapy, preventive health care, home care, and 38
39 on September 27, 2021 by guest. Protected copyright. 40 rehabilitation for chronic mental illnesses (15). The database provides all dates of 41 42 43 inpatient and outpatient services, diagnosis, prescriptions, examinations, operations, and 44 45 46 expenditures, and is updated biannually. 47 48 49 Patient and public involvement 50 51 52 In the present study, we used NHIRD, which is the data of insurance claims with 53 54 55 anonymised identifications. No patients or public were involved. 56 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 11 of 39 BMJ Open
1 2 3 4 5 6 7 Study groups: 8 9 10 This study used data published by the NHRI in Taiwan and covered the years from 11 12 13 2000 to 2013. The diagnostic coding of the NHI in Taiwan was performed according to 14 15 16 the InternationalFor Classification peer of Disease, review 9th Revision, Clinicalonly Modification (ICD-9- 17 18 19 CM) diagnostic criteria. 20 21 22 Inclusion and exclusion criteria: 23 24 25 A total of 1,466,596 pregnant women with admission for delivery were found in the 26 27 28 NHIRD between Jan 1, 2000 and Dec 31, 2013 (Figure 1). Subjects were traced back 2 29 30 31 years before delivery to identify if there was a past history of malignancy or diabetes and http://bmjopen.bmj.com/ 32 33 34 assess baseline comorbidities which may confound the association between GDM and 35 36 37 malignancy. In this context, women with admission for delivery between Jan 1, 2002 and 38
39 on September 27, 2021 by guest. Protected copyright. 40 Dec 31, 2012 were further analyzed to avoid pre-existing malignancy and ensure 41 42 43 adequate period of time in follow-up. Among these women, we identified 47,373 women 44 45 46 who had been diagnosed with gestational diabetes (ICD-9-CM code 648, 250), and had at 47 48 49 least 2 consensus diagnoses at prenatal outpatient visits or at least one diagnosis at 50 51 52 inpatient admissions during the prenatal period to ensure the validity of diagnosis. 53 54 55 (Fig.1). The remaining 943,199 women without GDM, diabetes or malignancy were used 56 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 12 of 39
1 2 3 4 as the non-exposed group. The incidence of GDM was 4.78 in 100 deliveries during the 5 6 7 11-year span (Table 1). 8 9 10 Those women who were not admitted for delivery within the time frame between Jan 11 12 13 1, 2002 and Dec 31, 2012 were excluded (n=422,568). Subjects with a history of 14 15 16 malignancy (ICD-9-CMFor codespeer 140 to 208)review (n=9,809) two only years before delivery, or 17 18 19 diabetes (ICD-9-CM codes 250) (n=37,026) before pregnancy were excluded. The date of 20 21 22 delivery was set as the index date. To avoid inclusion of patients with cancers that arose 23 24 25 during or before pregnancy, GDM and the non-exposed participants were followed for 26 27 28 180 days after delivery until malignancy diagnosis, death, the last medical claim or the 29 30 31 end of study follow-up (December 31, 2013), whichever came first. We excluded the http://bmjopen.bmj.com/ 32 33 34 women with a cancer diagnosis during pregnancy or within 180 days postpartum. 35 36 37 (n=778). 5,827 patients were also excluded due to loss of follow-up within 180 days after 38
39 on September 27, 2021 by guest. Protected copyright. 40 delivery. 41 42 43 Primary outcome 44 45 46 The primary outcome was defined as a new diagnosis of any cancer (ICD-9-CM 47 48 49 codes 140–208) recorded in NHIRD between Jan 1, 2002 and Dec 31, 2013. 50 51 52 Sub-classification of Cancers 53 54 55 We classified cancers into the 11 groups as previously described (12), on basis of the 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 13 of 39 BMJ Open
1 2 3 4 ICD-9-CM: cancers of head and neck, digestive organs, lung and bronchus, bone and 5 6 7 connective tissue, skin, breast, genital organs, urinary system, brain, thyroid gland, and 8 9 10 hematological system. 11 12 13 Baseline comorbidities were assessed for 2 years and included hypertension (ICD-9-CM 14 15 16 codes 401-405),For and dyslipidemia peer (ICD-9-CM review code 272), only liver disease (ICD-9-CM codes 17 18 19 070, 571), infertility (ICD-9-CM codes 628), and kidney disease (ICD-9-CM codes 582- 20 21 22 3, 585-6, 588). These comorbidities were selected because they have been shown to be 23 24 25 associated with both GDM and risk of cancers (16-25). 26 27 28 Statistical analysis 29 30 31 Continuous variables were presented as the mean with SDs. The χ2 test was used to http://bmjopen.bmj.com/ 32 33 34 compare categorical variables, and the differences among continuous variables were 35 36 37 compared using the Student’s t-test. The proportion of patients with cancer was plotted 38
39 on September 27, 2021 by guest. Protected copyright. 40 by Kaplan–Meier curves with log-rank test constructed to compare the cumulative 41 42 43 incidence of any type of cancer between subjects with and without GDM. The hazard 44 45 46 ratio of cancer was estimated by Cox proportional regression analysis, which was 47 48 49 adjusted for potential confounding variables, such as age and comorbidities. The 50 51 52 predictors satisfied the proportional hazard assumption in Cox model. The statistical 53 54 55 significance was inferred at a two-sided p value of <0.05. All statistical analyses were 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 14 of 39
1 2 3 4 performed using the Statistical Analysis Software (SAS) System, V.9.4 (SAS Institute, 5 6 7 Cary, North Carolina, USA). Kaplan-Meier curves were plotted using Stata V.12 (Stata 8 9 10 Corp, College Station, Texas, USA). 11 12 13 14 15 16 RESULTS For peer review only 17 18 19 Table 1 lists the clinical characteristics of subjects. Overall, 990,572 women were 20 21 22 analyzed. Among them, 47,373 women had GDM. The remaining 943,199 women 23 24 25 without GDM served as the non-exposed group. The average length of follow-up was 26 27 28 6.84±3.05 years, and mean age was 28.97±4.91 years. The incidence of GDM was 4.78% 29 30 31 during the 11-year span. Women with GDM had a higher rate of comorbidities than those http://bmjopen.bmj.com/ 32 33 34 in the non-exposed group, including hypertension, dyslipidemia, liver disease, infertility 35 36 37 and kidney disease (Table 1). 38
39 on September 27, 2021 by guest. Protected copyright. 40 Table 2 shows that the adjusted hazard ratio (AHR) of developing any type of cancer 41 42 43 among women with GDM was 1.197 (95% CI, 1.125 to 1.274) compared to women 44 45 46 without GDM after adjusting for age and comorbidities. 47 48 49 Patients with GDM were diagnosed with cancer (n=1,063, 2.24%) at a significantly 50 51 52 higher rate than those without GDM (n=18,444, 1.96%; p<0.001) (Table 3). Figure 2 53 54 55 shows the cumulative incidence rates of any type of cancer in patients with or without 56 57 14 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 15 of 39 BMJ Open
1 2 3 4 GDM from the index date until the first occurrence of cancer. The patients with GDM 5 6 7 had higher cancer incidence rates compared with those patients without GDM (log-rank 8 9 10 test: p<0.0001). 11 12 13 Adjusting for maternal age at delivery, and comorbidities, women with a history of 14 15 16 GDM had an increasedFor risk peer of cancers, review including cancers onlyof nasopharynx (AHR, 1.739; 17 18 19 95 % CI, 1.400 to 2.161; p<0.0001), kidney (AHR, 2.169; 95 % CI, 1.428 to 3.293, 20 21 22 p=0.0003), lung and bronchus (AHR, 1.372; 95 % CI, 1.044 to 1.803; p=0.0231), breast 23 24 25 (AHR, 1.234; 95 % CI, 1.093 to 1.393; p=0.0007), and thyroid gland (AHR, 1.389; 95 % 26 27 28 CI, 1.121 to 1.721; p=0.0026). (Table 3) 29 30
31 http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 16 of 39
1 2 3 4 DISCUSSION 5 6 7 The major findings of this study are as follows: [1] GDM is associated with a 19.7% 8 9 10 higher risk of developing malignancy. [2] Women with GDM are at a higher risk of 11 12 13 developing cancers of nasopharynx, lung and bronchus, kidney, breast, and thyroid 14 15 16 glands. For peer review only 17 18 19 One of our novel findings is that women with GDM are more likely to develop 20 21 22 nasopharyngeal cancer (NPC) during the period of follow-up. NPC differs from other 23 24 25 head and neck cancers in epidemiology, histology, natural history, and response to 26 27 28 treatment. NPC is one of the neoplasms that are linked to infectious agents and displays a 29 30 31 distinct racial and geographic distribution. While NPC is rare in Europe and America, it http://bmjopen.bmj.com/ 32 33 34 is endemic in Southeastern Asia including Taiwan where Epstein-Barr virus (EBV) 35 36 37 infection is prevalent (26). The recrudescence of EBV in immunocompromised patients 38
39 on September 27, 2021 by guest. Protected copyright. 40 has been characterized by activating the expression of EBV latency genes, consequently 41 42 43 immortalizing the infected cells and leading to carcinogenesis (27). Indeed, the immune 44 45 46 dysfunction inherent to T2DM increases the susceptibility to various infections and risk 47 48 49 of reactivating latent virus infections as well; eventually contributing to higher rates of 50 51 52 mortality (28-31). It is unknown whether GDM, a pre-diabetes condition, is 53 54 55 pathogenetically linked to reactivation of EBV infection and subsequent malignant 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 17 of 39 BMJ Open
1 2 3 4 transformation. It is also unknown whether shared environmental risk factors and genetic 5 6 7 susceptibility can be other explanations. 8 9 10 Another novel finding in our study is that the risk of developing kidney cancer is 11 12 13 significantly higher in women with GDM, compared to those without GDM. The etiology 14 15 16 of kidney cancerFor remains peerelusive, but smoking,review hypertension, only obesity, analgesics use, 17 18 19 chronic kidney disease (CKD), and genetic defects are potential risk factors (32, 33). Of 20 21 22 these factors, obesity and hypertension also characterize GDM (1). Indeed, it has been 23 24 25 shown that patients with T2DM have a higher risk of developing kidney cancers (34, 35). 26 27 28 In fact, GDM is associated with subsequent development of T2DM and CKD (3, 25). It is 29 30 31 unknown whether prevention of CKD would reduce the risk of kidney cancer in women http://bmjopen.bmj.com/ 32 33 34 with GDM. 35 36 37 Our study is also the first to demonstrate the association between GDM and lung 38
39 on September 27, 2021 by guest. Protected copyright. 40 cancers, which is the most common cancer around the world (36). The prevalence of both 41 42 43 lung cancer and GDM has been on the increase in Taiwan and worldwide (4, 37). 44 45 46 Whether this association is causal remains to be determined. Importantly, GDM and lung 47 48 49 cancer do share common risk factors such as smoking, dietary style, and obesity (36, 38). 50 51 52 It is unknown whether modification of these risk factors could impact this association. 53 54 55 In the present study, we also observed a clear association between GDM and breast 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 18 of 39
1 2 3 4 cancer. Previous studies on the association between GDM and breast cancer have 5 6 7 produced mixed results (7-13, 39-44). The reasons for the discrepancy are not clear. They 8 9 10 could be explained by methodological limitations. First, most of these studies were based 11 12 13 on self-reported information about GDM (9-11, 39, 41, 42, 44), which is prone to recall 14 15 16 bias. Secondly, smallFor sample peer size and relativelyreview rare occurrence only of cancer among young 17 18 19 women may result in inadequate statistical power, contributing to inconsistency. In these 20 21 22 regards, our big database from Taiwan NHIRD confers an advantage to overcome these 23 24 25 methodological limitations. 26 27 28 In agreement with a previous study (8), we showed that GDM was associated with a 29 30 31 38.9% higher risk of developing thyroid cancer. Interestingly, a large study from United http://bmjopen.bmj.com/ 32 33 34 States found that the risk of thyroid cancer was significantly increased in women, but not 35 36 37 in men, with diabetes (45). Taken together, women with GDM may represent a readily 38
39 on September 27, 2021 by guest. Protected copyright. 40 recognizable subgroup that deserves a more intensive surveillance for thyroid cancer. 41 42 43 The elucidation of the relationship between GDM and later cancer risk may not be 44 45 46 straightforward. It is conceivable that GDM may impact subsequent cancer risk through 47 48 49 certain direct or indirect pathophysiological mechanisms such as hyperglycemia, 50 51 52 hyperinsulinemia secondary to insulin resistance and chronic inflammation. Shared risk 53 54 55 factors for GDM and cancers can be other explanations, for example smoking, alcohol 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 19 of 39 BMJ Open
1 2 3 4 drinking, obesity, physical inactivity, hypertension and dietary style. 5 6 7 Insulin has mitogenic effects on cells (46). On the other hand, hyperglycemia can 8 9 10 induce production of reactive oxygen species (ROS), which can initiate carcinogenesis by 11 12 13 damaging cellular DNA (47, 48). 14 15 16 Recently, theFor role of systemicpeer inflammation review in the pathogenesis only of GDM has gained 17 18 19 more and more attention. Increased circulating levels of interleukin-6 (IL-6) and C- 20 21 22 reactive protein (CRP) have been observed in GDM independent of obesity (49, 50), 23 24 25 suggesting GDM as a state of low grade inflammation. Inflammation is also a hallmark of 26 27 28 cancer and is widely recognized to influence all cancer stages from cell transformation to 29 30 31 metastasis (51). Therefore, chronic and systemic inflammation may represent the http://bmjopen.bmj.com/ 32 33 34 biological phenomenon linking GDM to cancer development. Future investigations on 35 36 37 the role of low-grade inflammation in GDM may help identify biomarkers that can better 38
39 on September 27, 2021 by guest. Protected copyright. 40 predict, diagnose and monitor the evolution of GDM. Moreover, specific inflammatory 41 42 43 pathways may represent novel targets for treatment and prevention of long-term adverse 44 45 46 outcomes of GDM, including cancer development. 47 48 49 There were several strengths in this study. First, this is population-based study with a 50 51 52 large nationally representative sample from Taiwan NHIRD, thus making selection bias 53 54 55 minimized. Secondly, the use of NHIRD reduced the potential recall bias that is inherent 56 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 20 of 39
1 2 3 4 to self-reporting. 5 6 7 Limitations of this study included the lack of information about parity, multiple 8 9 10 GDM pregnancy and the histology, subtype and staging of cancer. Secondly, our study 11 12 13 did not have information about potential confounders such as dietary, obesity, physical 14 15 16 activity, smoking,For alcohol peer consumption, review environmental exposure, only and genetic parameters. 17 18 19 Third, the follow-up period may not be long enough to allow detection of cancers in 20 21 22 young women. 23 24 25 26 27 28 CONCLUSIONS 29 30 31 This population-based analysis of Taiwan NHIRD showed that women with GDM in http://bmjopen.bmj.com/ 32 33 34 Taiwan have an increased risk of developing malignancy including cancers of 35 36 37 nasopharynx, lung, kidney, breast, and thyroid gland. Prevention of GDM may be an 38
39 on September 27, 2021 by guest. Protected copyright. 40 important strategy in curbing the development of certain types of cancers in the future. 41 42 43 Our study also highlights under-recognized cancers in women with GDM that warrants 44 45 46 further investigations to develop different surveillance strategies for cancer development 47 48 49 in GDM patients in different ethnic groups. 50 51 52 53 54 55 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 21 of 39 BMJ Open
1 2 3 4 Acknowledgements 5 6 7 This work was supported by grants from the Chang Gung Memorial Hospital (Grant 8 9 10 CIRPD1D0031). The authors thank Research Services Center For Health Information, 11 12 13 Chang Gung University for statistical consultation. This study was based in part on data 14 15 16 from NHIRD. TheFor interpretation peer and conclusions review contained only herein do not represent those 17 18 19 of the National Health Insurance Administration, Department of Health, or National 20 21 22 Health Research Institutes. 23 24 25 26 27 Contributors 28 29 30 YSP proposed and designed the study. YSP also drafted the manuscript. MHT supervised
31 http://bmjopen.bmj.com/ 32 33 the study and critically edited the manuscript; and finally approved the version to be 34 35 36 submitted. JRL designed the study’s analytic strategy and conducted the data analysis. 37 38
39 BHC and CH contribute the study design and prepare the Methods and the Discussion on September 27, 2021 by guest. Protected copyright. 40 41 42 sections of the text, YHL and CHS helped conduct the literature review. All authors read 43 44 45 and approved the final manuscript. 46 47 48 49 50 51 Funding 52 53 54 This work was supported by the Chang-Gung Memorial Hospital, grant number 55 56 57 21 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 22 of 39
1 2 3 4 CIRPD1D0031. 5 6 7 8 9 10 Competing interests 11 12 13 The authors declare no conflict of interest. 14 15 16 For peer review only 17 18 19 Ethics approval 20 21 22 This study protocol was approved by the institutional review board of Chang Gung 23 24 25 Medical Foundation (IRB 103-2572B). 26 27 28 29 30 31 Provenance and peer review http://bmjopen.bmj.com/ 32 33 34 Not commissioned; externally peer reviewed. 35 36 37 38 39 Data sharing statement on September 27, 2021 by guest. Protected copyright. 40 41 42 No additional data are available. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 23 of 39 BMJ Open
1 2 3 4 REFERENCES 5 6 7 1. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, 8 9 10 Metzger BE, Gabbe SG, Persson B, et al. International association of diabetes and 11 12 13 pregnancy study groups recommendations on the diagnosis and classification of 14 15 16 hyperglycemiaFor in pregnancy. peer Diabetes review Care 2010;33:676. only 17 18 19 2. Dornhorst A, Paterson CM, Nicholls JS, et al. High prevalence of gestational diabetes 20 21 22 in women from ethnic minority groups. Diabet Med 1992;9:820-5. 23 24 25 3. Chodick G, Elchalal U, Sella T, et al. The risk of overt diabetes mellitus among 26 27 28 women with gestational diabetes: a population-based study. Diabet Med 2010;27:779- 29 30 31 85. http://bmjopen.bmj.com/ 32 33 34 4. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health 35 36 37 perspective. Diabetes Care 2007;30(Suppl 2):P141-6. 38
39 on September 27, 2021 by guest. Protected copyright. 40 5. Barone BB, Yeh HC, Snyder CF, et al. Long-term all-cause mortality in cancer 41 42 43 patients with preexisting diabetes mellitus: a systematic review and meta- analysis. 44 45 46 JAMA 2008;300:2754-64. 47 48 49 6. Stattin P, Björ O, Ferrari P, et al. Prospective study of hyperglycemia and cancer risk. 50 51 52 Diabetes Care 2007;30:561-7. 53 54 55 7. Tong GX, Cheng J, Chai J, et al. Association between gestational diabetes mellitus 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 24 of 39
1 2 3 4 and subsequent risk of cancer: a systematic review of epidemiological studies. Asian 5 6 7 Pac J Cancer Prev 2014;15:4265-9. 8 9 10 8. Bejaimal SA, Wu CF, Lowe J, et al. Short-term risk of cancer among women with 11 12 13 previous gestational diabetes: a population-based study. Diabet Med 2016;33:39-46. 14 15 16 9. Powe CE, TobiasFor DK, peer Michels KB, review et al. History of Gestationalonly Diabetes Mellitus 17 18 19 and Risk of Incident Invasive Breast Cancer among Parous Women in the Nurses' 20 21 22 Health Study II Prospective Cohort. Cancer Epidemiol Biomarkers Prev 23 24 25 2017;26:321-7. 26 27 28 10. Park YM, O'Brien KM, Zhao S, et al. Gestational diabetes mellitus may be associated 29 30 31 with increased risk of breast cancer. Br J Cancer 2017;116:960-3. http://bmjopen.bmj.com/ 32 33 34 11. Dawson SI. Long-term risk of malignant neoplasm associated with gestational 35 36 37 glucose intolerance. Cancer 2004;100,149-55. 38
39 on September 27, 2021 by guest. Protected copyright. 40 12. Sella T, Chodick G, Barchana M, et al. Gestational diabetes and risk of incident 41 42 43 primary cancer: a large historical cohort study in Israel. Cancer Causes Control 44 45 46 2011;22,1513-20. 47 48 49 13. Xie C, Wang W, Li X, Shao N, et al. Gestational diabetes mellitus and maternal 50 51 52 breast cancer risk: a meta-analysis of the literature. J Matern-Fetal Neonatal Med 53 54 55 2017;7:1–11. 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 25 of 39 BMJ Open
1 2 3 4 14. Chen YC, Yeh, H, Wu JC, et al. Taiwan’s National Health Insurance Research 5 6 7 Database: Administrative health care database as study object in bibliometrics. 8 9 10 Scientometrics 2011,86,365-80. 11 12 13 15. Hsing AW, Ioannidis JP. Nationwide population science: lessons from the Taiwan 14 15 16 National HealthFor Insurance peer Research review Database. JAMA onlyIntern Med 2015;175:1527-9. 17 18 19 16. Kuzu OF, Noory MA, Robertson GP. The Role of Cholesterol in Cancer. Cancer Res 20 21 22 2016;76:2063-70. 23 24 25 17. Stocks T, Van Hemelrijck M, Manjer J, et al. Blood pressure and risk 26 27 28 of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project. 29 30 31 Hypertension 2012;59:802-10. http://bmjopen.bmj.com/ 32 33 34 18. Yang HP, Cook LS, Weiderpass E, et al. Infertility and incident endometrial cancer 35 36 37 risk: a pooled analysis from the epidemiology of endometrial cancer consortium. Br J 38
39 on September 27, 2021 by guest. Protected copyright. 40 Cancer 2015;112:925-33. 41 42 43 19. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, et al. 44 45 46 The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 47 48 49 at the Global, Regional, and National Level: Results From the Global Burden of 50 51 52 Disease Study 2015. JAMA Oncol 2017;3:1683. 53 54 55 20. Lowrance WT, Ordoñez J, Udaltsova N, et al. CKD and the risk of incident cancer. J 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 26 of 39
1 2 3 4 Am Soc Nephrol 2014;25:2327-34. 5 6 7 21. Baumfeld Y, Novack L, Wiznitzer A, et al. Pre-Conception Dyslipidemia Is 8 9 10 Associated with Development of Preeclampsia and Gestational Diabetes Mellitus. 11 12 13 PLoS One 2015;10:e0139164. 14 15 16 22. Tobias DK, ForChavarro peerJE, Williams review MA, et al. History only of infertility and risk of 17 18 19 gestational diabetes mellitus: a prospective analysis of 40,773 pregnancies. Am J 20 21 22 Epidemiol 2013;178:1219-25. 23 24 25 23. Sridhar SB, Xu F, Darbinian J, et al. Pregravid liver enzyme levels and risk of 26 27 28 gestational diabetes mellitus during a subsequent pregnancy. Diabetes Care 29 30 31 2014;37:1878-84. http://bmjopen.bmj.com/ 32 33 34 24. Mirghani Dirar A, Doupis J. Gestational diabetes from A to Z. World J Diabetes 35 36 37 2017;8:489-511. 38
39 on September 27, 2021 by guest. Protected copyright. 40 25. Dehmer EW, Phadnis MA, Gunderson EP, et al. Association Between Gestational 41 42 43 Diabetes and Incident Maternal CKD: The Coronary Artery Risk Development in 44 45 46 Young Adults (CARDIA) Study. Am J Kidney Dis 2018;71:112-22. 47 48 49 26. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Semin Cancer Biol 50 51 52 2002;12:421-9. 53 54 55 27. Cohen JI. Epstein-Barr virus infection. N Engl J Med 2000;343:481-92. 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 27 of 39 BMJ Open
1 2 3 4 28. Plouffe JF, Silva J, Jr, Fekety R, et al. Cell-mediated immunity in diabetes mellitus. 5 6 7 Infect Immun 1978;21:425-9. 8 9 10 29. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus 11 12 13 (DM) FEMS Immunol Med Microbiol. 1999;26:259-65. 14 15 16 30. Berrou J, FougerayFor S, peerVenot M, et reviewal. Natural killer cell only function, an important target 17 18 19 for infection and tumor protection, is impaired in type 2 diabetes. PLoS One 20 21 22 2013;8:e62418. 23 24 25 31. Kumar M, Roe K, Nerurkar PV, et al. Impaired virus clearance, compromised 26 27 28 immune response and increased mortality in type 2 diabetic mice infected with West 29 30 31 Nile virus. PLoS One 2012;7:e44682. http://bmjopen.bmj.com/ 32 33 34 32. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell 35 36 37 carcinoma. Eur Urol 2011;60:615-21. 38
39 on September 27, 2021 by guest. Protected copyright. 40 33. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. 41 42 43 Nat Rev Urol 2010;7:245-57. 44 45 46 34. Larsson SC, Wolk A. Diabetes mellitus and incidence of kidney cancer: a meta- 47 48 49 analysis of cohort studies. Diabetologia 2011;54:1013-8. 50 51 52 35. Tseng CH. Type 2 Diabetes Mellitus and Kidney Cancer Risk: A Retrospective 53 54 55 Cohort Analysis of the National Health Insurance. PLoS One 2015;11;10:e0142480. 56 57 27 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 28 of 39
1 2 3 4 36. Dela Cruz CS, Tanoue LT, Matthay RA. Lung cancer: epidemiology, etiology, and 5 6 7 prevention. Clin Chest Med 2011;32:605-44. 8 9 10 37. Tseng CH. Diabetes but not insulin increases the risk of lung cancer: a Taiwanese 11 12 13 population-based study. PLoS One 2014;9:e101553. 14 15 16 38. Solomon CG,For Willett WC,peer Carey VJ,review et al. A prospective only study of pregravid 17 18 19 determinants of gestational diabetes mellitus. JAMA 1997;278:1078-83. 20 21 22 39. Troisi R, Weiss HA, Hoover RN, et al. Pregnancy characteristics and maternal risk of 23 24 25 breast cancer. Epidemiology 1998;9,641-7. 26 27 28 40. Cnattingius S, Torrang A, Ekbom A, et al. Pregnancy characteristics and maternal 29 30 31 risk of breast cancer. JAMA 2005;294,2474-80. http://bmjopen.bmj.com/ 32 33 34 41. Brasky TM, Li Y, Jaworowicz DJ Jr, et al. Pregnancy-related characteristics and 35 36 37 breast cancer risk. Cancer Causes Control 2013;24,1675-85. 38
39 on September 27, 2021 by guest. Protected copyright. 40 42. Lawlor DA, Smith GD, Ebrahim S. Hyperinsulinaemia and increased risk of breast 41 42 43 cancer: findings from the British Women’s Heart and Health Study. Cancer Causes 44 45 46 Control 2004;15,267-75. 47 48 49 43. Perrin MC, Terry MB, Kleinhaus K, et al. Gestational diabetes and the risk of breast 50 51 52 cancer among women in the Jerusalem Perinatal Study. Breast Cancer Res Treat 53 54 55 2008;108,129-35. 56 57 28 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 29 of 39 BMJ Open
1 2 3 4 44. Rollison DE, Giuliano AR, Sellers TA, et al. Population-based case-control study of 5 6 7 diabetes and breast cancer risk in Hispanic and non-Hispanic White women living in 8 9 10 US southwestern states. Am J Epidemiol 2008;167,447-56. 11 12 13 45. Aschebrook-Kilfoy B, Sabra MM, Brenner A, et al. Diabetes and thyroid cancer risk 14 15 16 in the NationalFor Institutes peer of Health-AARP review Diet and Health only Study. Thyroid 17 18 19 2011;21:957-63. 20 21 22 46. Vigneri P, Frasca F, Siacca L, et al. Diabetes and cancer. Endocr. Relat. Cancer 23 24 25 2009;16,1103-23. 26 27 28 47. Chandrasekaran K, Swaminathan K, Chatterjee S, et al. Apoptosis in hepG2 cells 29 30 31 exposed to high glucose. Toxicol. In Vitro 2010;24,387-96. http://bmjopen.bmj.com/ 32 33 34 48. Zhang Y, Zhou J, Wang T, Cai T. High level glucose increases mutagenesis in human 35 36 37 lymphoblastoid cells. Int. J. Biol. Sci. 2007;3,275-9. 38
39 on September 27, 2021 by guest. Protected copyright. 40 49. Ategbo JM, Grissa O, Yessoufou A, et al. Modulation of adipokines and cytokines in 41 42 43 gestational diabetes and macrosomia. J Clin Endocrinol Metab 2006;91:4137e43. 44 45 46 50. Wolf M, Sandler L, Hsu K, et al. First-trimester C-reactive protein and subsequent 47 48 49 gestational diabetes. Diabetes Care 2003;26:819-24. 50 51 52 51. Leonardi GC, Accardi G, Monastero R, et al. Ageing: from inflammation to cancer. 53 54 55 Immun Ageing 2018;15:1. 56 57 29 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 30 of 39
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1 2 3 Table 1 Baseline characteristics 4 5 Pregnancy women Pregnancy women P value 6 with GDM without GDM 7 8 Number of population, n (%) 47373 (4.78) 943199 (95.22) 9 Age, y, mean±SD 31.61±4.54 28.83±4.89 <.0001 10 11 Age group, n (%) <.0001 12 20 407 (0.86) 45942 (4.87) 13 14 21-30 18617 (39.30) 558108 (59.17) 15 31-40 27203 (57.42) 329929 (34.98) 16 For peer review only 17 41-50 1146 (2.42) 9220 (0.98) 18 Comorbidity, n (%) 19 20 Hypertension (ICD-9: 401-405) 1479 (3.12) 7743 (0.82) <.0001 21 Dyslipidemia (ICD-9: 272) 1132 (2.39) 8197 (0.87) <.0001 22 23 Liver disease (ICD-9: 070, 571) 3165 (6.68) 44509 (4.72) <.0001 24 Infertility, female (ICD-9: 628) 8001 (16.89) 94405 (10.01) <.0001 25 26 Kidney disease (ICD-9:582-3, 585-6, 588) 51 (0.11) 626 (0.07) 0.0008 27 28 GDM= Gestational diabetes; SD=Standard Deviation; ICD-9= International Classification of Disease, 9th 29 Revision 30
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1 2 3 Table 2 Hazard ratio (HR) of developing cancer in relation to baseline characteristics of 4 5 study participants: 6 Crude HR P value Adjusted HR P value 7 8 (95% CI) (95% CI) 9 Patients 10 11 GDM 1.421 (1.336-1.512) <0.0001 1.197 (1.125-1.274) 0.0012 12 Non-GDM 1.0 (ref) 1.0 (ref) 13 14 Age 15 20 1.0 (ref) 1.0 (ref) 16 For peer review only 17 21-30 1.627 (1.488-1.779) <0.0001 1.581 (1.446-1.729) <0.0001 18 31-40 2.843 (2.600-3.109) <0.0001 2.678 (2.448-2.930) <0.0001 19 20 41-50 4.883 (4.291-5.556) <0.0001 4.479 (3.933-5.100) <0.0001 21 Comorbidity, n (%) 22 23 Hypertension (ICD-9: 401-405) 1.471 (1.291-1.677) <0.0001 1.114 (0.976-1.272) 0.1101 24 Dyslipidemia (ICD-9: 272) 1.866 (1.648-2.113) <0.0001 1.395 (1.229-1.583) <0.0001 25 26 Liver disease (ICD-9: 070, 571) 1.573 (1.486-1.665) <0.0001 1.432 (1.351-1.517) <0.0001 27 Infertility, female (ICD-9: 628) 1.397 (1.340-1.457) <0.0001 1.185 (1.136-1.236) <0.0001 28 29 Kidney disease (ICD-9: 582-3, 2.077 (1.403-3.073) 0.0003 1.623 (1.095-2.404) 0.0159 30 585-6, 588) 31 http://bmjopen.bmj.com/ 32 HR=Hazard Ratio; GDM= Gestational diabetes; ICD-9= International Classification of Disease, 9th 33 34 Revision 35 36 37 38
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1 2 3 4 5 Table 3 Hazard ratio (HR) of the first cancer diagnosis between GDM group and non GDM group 6 (ICD-9 code) Women Women Crude HR P value Adjusted HR P value 7 8 with GDM without GDM (95% CI) (95% CI) 9 (N=47373) (N=943199) 10 11 Head and neck 12 Oral & pharynx (140- 19 (0.04) 389 (0.04) 1.230 (0.776-1.950) 0.3792 1.105 (0.695-1.759) 0.6724 13 14 1,143-6,148-9) 15 Nasopharynx (147) 90 (0.19) 1151 (0.12) 1.897 (1.530-2.351) <.0001 1.739 (1.400-2.161) <.0001 16 For peer review only 17 Digestive system 18 Stomach (151) 18 (0.04) 256 (0.03) 1.703 (1.056-2.749) 0.0291 1.322 (0.816-2.142) 0.2570 19 20 Colorectum (153-4) 100 (0.21) 1705 (0.18) 1.420 (1.160-1.738) 0.0007 1.180 (0.963-1.447) 0.1099 21 Liver (155) 87 (0.18) 1393 (0.15) 1.504 (1.211-1.868) 0.0002 1.242 (0.998-1.545) 0.0521 22 23 Pancreas (157) 17 (0.04) 314 (0.03) 1.316 (0.808-2.145) 0.2699 1.072(0.655-1.755) 0.7807 24 Genital system 25 26 Cervix uteri (180) 37 (0.08) 962 (0.10) 0.925 (0.666-1.285) 0.6429 0.903 (0.649-1.256) 0.5438 27 Uterus (179,182) 42 (0.09) 803 (0.09) 1.323 (0.970-1.805) 0.0768 1.051 (0.769-1.437) 0.7534 28 29 Ovary (183) 50 (0.11) 1146 (0.12) 1.061 (0.800-1.409) 0.6797 0.963 (0.724-1.280) 0.7928 30 Urinary system 31 http://bmjopen.bmj.com/ 32 Urinary bladder (188) 9 (0.02) 162 (0.02) 1.387 (0.709-2.715) 0.3395 1.034 (0.525-2.033) 0.9236 33 Kidney (189) 25 (0.05) 245 (0.03) 2.573 (1.704-3.885) <.0001 2.169 (1.428-3.293) 0.0003 34 35 Hematological system 36 Leukemia (204-8) 11 (0.02) 359 (0.04) 0.742 (0.407-1.352) 0.3293 0.735 (0.402-1.344) 0.3169 37 38 Lymphoma (200-3) 19 (0.04) 596 (0.06) 0.771 (0.488-1.217) 0.2641 0.774 (0.489-1.226) 0.2754
39 on September 27, 2021 by guest. Protected copyright. Bone and connective tissue 7 (0.01) 271 (0.03) 0.618 (0.292-1.309) 0.0708 0.582 (0.274-1.236) 0.1590 40 41 (170-1) 42 Lung and bronchus (162) 56 (0.12) 846 (0.09) 1.666 (1.271-2.184) 0.0002 1.372 (1.044-1.803) 0.0231 43 44 Skin (173) 15 (0.03) 201 (0.02) 1.834 (1.085-3.101) 0.0236 1.664 (0.980-2.825) 0.0594 45 Breast (174) 284 (0.60) 4373 (0.46) 1.654 (1.467-1.866) <.0001 1.234 (1.093-1.393) 0.0007 46 47 Brain (191) 19 (0.04) 331 (0.04) 1.382 (0.870-2.195) 0.1703 1.232 (0.772-1.968) 0.3818 48 Thyroid (193) 91 (0.19) 1423 (0.15) 1.582 (1.279-1.956) <.0001 1.389 (1.121-1.721) 0.0026 49 50 Other sites 91 (0.16) 1719 (0.18) 1.251 (0.989-1.583) 0.0619 1.154 (0.910-1.462) 0.2373 51 Total (140-208) 1063 (2.24) 18444 (1.96) 1.421 (1.336-1.512) <.0001 1.197 (1.125-1.274) <.0001 52 53 Model was adjusted for age, hypertension, dyslipidemia, liver disease, infertility, and kidney disease; HR=Hazard 54 55 Ratio; GDM= Gestational diabetes; ICD-9= International Classification of Disease, 9th Revision 56 57 33 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from BMJ Open Page 34 of 39
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1 2 3 LEGENDS: 4 5 6 Figure 1: Flow chart for population selection 7 8 9 Figure 2: The cumulative incidence rates of any type of cancer in patients with or without 10 11 12 GDM from the index date until the first occurrence of the cancer using Kaplan-Meier 13 14 15 methods. 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30
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39 on September 27, 2021 by guest. Protected copyright. 40 41 42 43 44 45 Figure 1 46 47 209x297mm (300 x 300 DPI) 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-024583 on 21 February 2019. Downloaded from Page 37 of 39 BMJ Open
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 Figure 2 30 31 297x209mm (300 x 300 DPI) http://bmjopen.bmj.com/ 32 33 34 35 36 37 38
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For peer review only For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml ) Report category boundariescontinuous when variables categorized were ) unadjustedGive estimates ifand, applicable, confounder-adjusted estimates and their precision (eg, confidence95% ) If relevant, If ) consider translating estimates of relative risk into absolute for risk meaningful periodtime a c b a similar studies, other relevantand evidence confounders eligible, includedeligible, in study,the follow-up,completing analysedand interval). Make interval). clear confounderswhich andwere foradjusted they why were included which thewhich article presentis based
( ( Summarise (c) follow-up time (eg, average total and amount) (b)number Indicate of participants missingwith data eachof interestfor variable Consider (c) diagram flow use of a (b)reasons Give non-participationfor each at stage 18 18 results Summarise key to reference with study objectives 20 20 Give cautiousa interpretationoverall of results considering objectives, limitations, of multiplicity resultsanalyses, from 16 16 ( 22 22 the Give of fundingsource and role the of fundersthe presentthe for if study theforand, applicable, original study on 13* (a) numbersReport of individuals each at of stage study—eg numbers potentially eligible, eligibility,examined for confirmed
An Explanation and Elaboration article discussesitem each checklist and gives backgroundmethodological and published examples of transparent reporting. The STROBE checklist is best used in this(freelywith conjunction available onarticle sites the Medicine of PLoS http://www.plosmedicine.org/,Web at Annals of Internal Medicine at http://www.annals.org/, http://www.epidem.com/).Epidemiology at and Information on InitiativeSTROBE the is www.strobe-statement.org.available at information*Give separately cases for and controls studiesin forcase-control applicable, if and, exposedunexposed and groups in cohort and studies.cross-sectional Note: Funding Other information Generalisability 21 Discuss (external generalisability the of thevalidity) study results Interpretation Limitations Key Key results Discussion Other analyses 17 Report other analyses done—eg analyses of subgroupsinteractions, sensitivity and and analyses
Main resultsMain Outcome Outcome data 15* Report numbers of outcome events or summary timemeasures over
Descriptive data 14* characteristics (a) Give participantsof study (eg clinical,demographic, social) informationand exposureson and potential
Participants 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 39 of