Detailed descriptions of the IWHS cohort have been published previously (32
). In brief, IWHS was initiated in 1986 when a baseline questionnaire was mailed to 98,030 women aged 55 to 69 years, randomly selected from the Iowa driver’s license list. The 41,836 women who completed the questionnaire (42.7%) constituted the cohort.
Five follow-up questionnaires were mailed to cohort subjects to update vital status, residence, and exposure information; the response rates were 91% in 1987, 90% in 1989, 83% in 1992, 79% in 1997, and 70% in 2004. Data from follow-up surveys indicated that the migration rate from Iowa among cohort members is <1% annually, allowing nearly complete follow-up for cancer incidence end points (35
). The vital status of all non-responders to follow-up questionnaires was identified by linkage with the National Death Index.
The current use of aspirin and non-aspirin NSAIDs in the cohort was ascertained on the 1992 questionnaire. Respondents were asked: “How often do you take aspirin? Examples of aspirin included Bufferin, Anacin, enteric-coated aspirin, Ecotrin, and Excedrin: never, less than one per week, one per week, 2 – 5 per week, and 6+ per week.” Use of non-aspirin NSAIDs was assessed by asking: “How often do you take other nonsteroidal anti-inflammatory drugs or arthritis medicines? Examples included Ibuprofen, Advil, Nuprin, Motrin, Naprosyn, Feldene, and Clinoril: never, less than one per week, one per week, 2 – 5 per week, and 6+ per week.” Respondents were instructed to exclude acetaminophen and Tylenol use in both questions. Data on dose and duration were not available.
The baseline questionnaire asked standard information about lifestyle behaviors and sociodemographic factors, medical histories, and anthropometric factors. The participants reported their current weight and height, and their hip and waist circumferences measured by a friend, using a paper tape measure provided with the questionnaire. Detailed information about their reproductive history was collected: age at menarche, age at menopause and the reason for it, details of each pregnancy (up to 10), and whether or not they had had their uterus and/or one or both ovaries surgically removed (updated in 1992). In addition, they were asked about their family history of cancer, the history of endometriosis, history of oral contraceptive use and duration, and history of hormone replacement therapy (HRT). Information about weight, alcohol intake and smoking status was updated in 1992, and questions about heart disease, diabetes, hypertension, and HRT use were asked at each follow up. The 1992 survey also queried whether participants had been diagnosed with migraines, rheumatoid arthritis and osteoarthritis. Data about hysterectomy and oophorectomy status were collected at a third time in 2004.
Ovarian and endometrial cancer cases were ascertained through the State Health Registry of Iowa, part of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER), via an annual computer match of name, maiden name, date of birth, address, and social security number. Primary site, morphology, extent of disease, and date of diagnosis were obtained for each incident cancer case from 1992 through 2006. Only cases diagnosed within the state of Iowa were captured.
We firstly excluded participants if they did not complete 1992 survey (n=8,819), then if they had cancer at baseline or were diagnosed with cancer other than skin cancer before 1992 (n=4,439), and if they did not complete both questions about NSAIDs (n=540). In addition, women with full oophorectomy and unknown oophorectomy status were excluded for ovarian cancer analysis (n=6,338), and women with hysterectomy and unknown hysterectomy status were excluded for endometrial cancer analysis (n=10,328). Among ovarian cancer cases, non-epithelial cancer cases were excluded (n=6); and among endometrial cancer cases, endometrial sarcomas and Muellerian mixed tumors (n=13) were excluded.
As a result, 21,694 women were available for the ovarian cancer analysis, with 157 epithelial ovarian cancers detected over 15 years of follow-up. For the endometrial cancer analysis, the cohort consisted of 17,697 women and 311 endometrial cancers.
Person-years of follow-up for endometrial and ovarian cancer cases were calculated as the time between 1992 to endometrial or ovarian cancer, respectively. All other participants were followed up to the date of death, the estimated date of emigration from Iowa (assigned as midpoint between the last completed questionnaire in Iowa and the next follow-up questionnaire completed elsewhere or non-Iowa death), or December 31, 2006, whichever occurred first.
We used SAS (SAS Institute Inc., Cary, NC) for analysis. Chi-square tests were performed to determine whether or not characteristics differed according to frequency of aspirin and non-aspirin NSAIDs use. Age-adjusted and multivariate-adjusted hazard ratios (HR) of ovarian and endometrial cancers and their 95% confidence intervals (CIs) were computed by proportional hazards regression (program PHREG) separately for aspirin and non-aspirin NSAIDs. For each exposure, women who reported using NSAIDs less than or equal to one time per week were combined into one group, resulting in categories of never (reference), less than 2 times per week, 2 – 5 times per week, and 6+ times per week.
Potential covariates in a multivariate-adjusted model were tested if they were associated with ovarian or endometrial cancer (depending on the analysis) or NSAIDs use in this analysis. The final model for ovarian cancer included age, body mass index (BMI) (continuous), history of HRT use (yes/no), number of live births (0, 1–2, 3–4, >4), history of heart disease (yes/no), and partial oophorectomy (yes/no). Alcohol, physical activity, smoking status and pack-years of smoking, education, waist-to-hip ratio, age at menopause, and age at menarche, endometriosis, hysterectomy status, family history of breast and/or ovarian cancer were not associated with ovarian cancer in this analysis and were not included. In addition, we adjusted for personal history of migraines and history of either rheumatoid arthritis or osteoarthritis. Since they did not markedly change the estimates, they were not included in the final model. In order to minimize potential confounding by indication, we also examined associations after excluding women who had reported heart disease, arthritis and migraines.
The final model for endometrial cancer included age, BMI (less than 25, 25–29.9 and ≥30 kg/m2
), alcohol use (never/ever), age at menopause (≤44, 45–49, 50–54, ≥ 55 years), age at menarche (≤11, 12, 13, ≥14 years), history of oral contraceptive and HRT use (yes/no), history of diabetes and hypertension (yes/no). Physical activity, education, smoking status and pack-years, number of live births, age at first live birth, and family history of uterine cancer were not associated with endometrial cancer and were not included. In order to compare our results with Moysich et al  and Viswanathan et al  (30
), who reported associations between NSAIDs and endometrial cancer for obese women, and Viswanathan et al  who observed an association for never users of HRT (31
), the analysis was repeated after stratifying by BMI categories (normal, <25 kg/m2
; overweight, 25–29.9 kg/m2
; and obese, ≥30 kg/m2
) and HRT use (yes/no).
We also repeated analyses after excluding ovarian or endometrial cancer cases (depending on the analysis) diagnosed within two and three years after start of follow-up to exclude women who may have used NSAIDs more frequently to treat symptoms of preclinical cancer. In addition, we stratified the time of follow-up approximately at midpoint (1992–1999 and 2000–2006) and compared hazard risk of ovarian or endometrial cancer in relation to NSAIDs use in each period. Because we did not know the dates of oophorectomy and hysterectomy during the follow-up, we were not able to censor participants at the time of their surgery. So, we conducted a sensitivity analysis among respondents to 2004 surveys to allow us to exclude women who reported a bilateral oophorectomy or hysterectomy in 2004 in the analysis of ovarian or endometrial cancer, respectively. Although the power was decreased, all associations were similar before and after exclusions. In our primary analysis, all women at risk in 1992 were included.
The IWHS was approved by the University of Minnesota’s Institutional Review Board and return of the questionnaire was considered informed consent.