Affiliations of authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (KZ, ON, HOA, AE, WY); Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Stockholm (CGÖ); Endocrine and Metabolism Research Center and Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran (KZ); Department of Epidemiology, Harvard School of Public Health, Boston, MA (HOA).
Correspondence to: Weimin Ye, MD, MSc, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE 171 77, Stockholm, Sweden (e-mail: Weimin.Ye{at}meb.ki.se)
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ABSTRACT |
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We used the Swedish Inpatient Register created by the National Board of Health and Welfare to identify the study cohort (10). Each record in this register includes the patient's national registration number and the discharge diagnoses coded throughout the study period according to the 7th through 10th revised versions of the International Classification of Diseases (ICD) (1114). The coding for diabetes in ICD versions 7 through 9 did not allow us to distinguish between patients with type 1 diabetes and those with type 2 diabetes because unique codes for insulin-dependent diabetes were not introduced until 1997, when the ICD-10 became effective. In addition, many elderly patients diagnosed with insulin-dependent diabetes after 1997 had previously been diagnosed with type 2 diabetes that had become insulin-dependent. Therefore, we defined patients with type 1 diabetes as those who were 30 years old or younger at first hospitalization for diabetes (15,16). We initially selected the records of 30 072 patients who were diagnosed with diabetes mellitus and were 30 years old or younger when discharged from the hospital. The records were then linked to the Swedish Cancer, Total Population, Migration, and Death Registers. We excluded 159 records with erroneous national registration numbers and records for 122 patients who were diagnosed with cancer before the first hospitalization for type 1 diabetes (index hospitalization), 18 patients who underwent a renal transplantation during or before the index hospitalization, and 22 patients hospitalized after 1996 with a diagnosis of noninsulin-dependent diabetes during the subsequent or previous hospitalization, and 564 records with other inconsistencies. We used the records of the remaining 29 187 patients, who were presumed to have type 1 diabetes, in our study.
The number of person-years at risk for each patient was calculated from the date of discharge from the index hospitalization until the date of the first malignant cancer diagnosis, renal transplantation, death, emigration, or December 31, 1999, whichever came first. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs), adjusted for age, sex, and calendar year at follow-up, were calculated to estimate relative risks by using the entire population of Sweden as reference group (17). To minimize the impact of selection bias, we excluded person-time accrued and cancer events observed during the first year of follow-up. The Regional Research Ethics Committee at Karolinska Institutet approved this register-based study.
The mean age of patients with type 1 diabetes upon index hospitalization was 17.1 years. Patients were followed for a mean of 14.4 years and accrued a total of 415 838 person-years at risk. More males than females were hospitalized for type 1 diabetes, and females were first hospitalized at an older age and were followed up for a longer period of time than males (Table 1).
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Although two Swedish studies (7,19) have reported that patients with type 1 diabetes have an increased risk of endometrial cancer, an Italian study (20) reported no such increased risk. However, all of those studies defined patients with type 1 diabetes by using a cutoff age that was higher than the one used in our study. Several mechanisms could underlie the association between type 1 diabetes and endometrial cancer observed in our study. First, obesity is a recognized risk factor for endometrial cancer (19). Long-term insulin therapy used to treat diabetes patients may be responsible both for the weight gain these patients experience and the deposition of abdominal fat that leads to insulin resistance in later stages of the disease (21). Our finding, that patients with type 1 diabetes had a greater risk of endometrial cancer during the early follow-up period than during the late follow-up period, however, seems inconsistent with this hypothesis. Second, results of several studies have suggested that, compared with women without type 1 diabetes, women with type 1 diabetes have higher incidence of nulliparity, irregular menstruation, and fertility disorders (22,23), which are probable risk factors for endometrial cancer (24) and conceivable effect modifiers of the positive association(s) between endometrial cancer and other risk factors.
An unexpected finding in this study was that the risk of stomach cancer among type 1 diabetes patients increased with follow-up time. This finding may be related to the high prevalence of Helicobacter pylori infection among patients with type 1 diabetes (25,26) or the high incidence of pernicious anemia, a condition associated with a high risk of stomach cancer, because parietal cell antibodies are more common in type 1 diabetes patients than in the general population (27,28).
Our study has several limitations. We cannot exclude the possibility that our results are chance findings due to multiple comparisons; thus, these results should be interpreted with caution. Additional limitations include the possibility that some type 2 diabetes patients were misclassified as type 1 diabetes patients, the lack of information about several potential confounding factors and, despite the large number of observed person-years, the modest number of observed cancers for each specific site.
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Manuscript received April 30, 2003; revised September 22, 2003; accepted September 26, 2003.
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