—The Copenhagen City heart study is a longitudinal study initiated in 1976. An age stratified random sample of 19 698 Danish men and women were invited to participate. All participants gave written informed consent. In 1981-3 the same population had additional examinations. The second examination of 7018 women included questions on stress and is therefore used as baseline for the study reported here. The response rate was 70%. We excluded women with breast cancer before baseline (n = 120) or lacking information on stress or other covariates (n = 209), leaving 6689 women. Twenty six (< 0.1%) women were lost to follow-up. A detailed description of the Copenhagen City heart study has previously been published.17
—The study participants were asked about their level of stress in terms of intensity and frequency. In the questionnaire, stress was exemplified as the sensation of tension, nervousness, impatience, anxiety, or sleeplessness. Participants were asked to report their stress intensity as none (0), light (1), moderate (2), or high (3). Frequency of stress was reported as never/hardly ever (0), monthly (1), weekly (2), or daily (3).18
We added the scores of the two questions and combined them into a continuous stress score from 0 to 6. We categorised the stress score into low (0-1 points), medium (2-4 points), and high (5-6 points) stress in order to examine differences in incidence of breast cancer for low and high levels of stress.
Covariates—We considered the following variables as potential confounders for the analyses: current oral contraceptive use (yes/no), other hormone therapy (yes/no), menopause at baseline (yes/no), body mass index (continuous), number of children (0, 1-2, ≥ 3), physical activity in leisure time (low, medium, high), alcohol consumption (0 drinks/week, 1-14 drinks/week, > 14 drinks/week), and education (< 8 years, 8-11 years, ≥ 12 years).
Follow-up—We followed participants from the date of the second examination until the date of first diagnosis of primary breast cancer (n = 251), death (n = 2224), emigration (n = 26), or the end of follow-up on 31 December 1999 (n = 4188). We used the civil registry number, which is unique to every Danish citizen, to identify primary breast cancer events through linkage to the Danish national cancer registry, which contains data on all cancer diagnoses in Denmark. We used ICD-7 codes170.0-170.5, 470.0-470.5, and 870.0-870.2 to identify cases of primary invasive breast cancer. We followed the vital status of the study population in the central death registry. Information on diagnosis of breast cancer was updated until 1999, making it possible to follow the participants from the second examination for 16-18 years for a primary diagnosis of breast cancer.
—We used Cox regression models (SAS/STAT software version 8.2) to analyse data with age as the time scale. All included variables met the assumption of proportional hazards. Initially, we estimated the age adjusted hazard ratio of primary breast cancer associated with stress intensity, stress frequency, and stress score (continuous and in categories of low, medium, and high stress). Subsequently, we fitted a multivariate Cox regression model according to the “change in estimate” method,19
with a cut-off point of 5% change, to adjust for potential confounding from baseline covariates. We used trend analyses to assess dose-response relations between stress and breast cancer. We did a χ2
test for goodness of fit before including any variables as continuous and also used it to test for linear trends. To estimate the effect of prolonged follow-up, we assessed the association in the first and last nine years of follow-up. Finally, we did subgroup analyses to assess potential effect modification.