The study was conducted within the population of North Jutland, a county with nearly 500
000 inhabitants, representing approximately 9% of the total Danish population. The National Health Service in Denmark provides tax supported health care for all inhabitants, guaranteeing free access to general practitioners, hospitals and public clinics, and refunds a variable proportion of the costs of medication prescribed by physicians through a computerised accounting system. In North Jutland, this accounting system also provides prescription data to the Pharmaco-Epidemiologic Prescription Database, which was initiated in 1989 (Gaist et al, 1997
) and by 1991 covered all pharmacies in the county. The Database includes the civil personal registration number (a unique number assigned to all Danish residents that encodes gender and date of birth) of the patient, type of drug prescribed according to Anatomical Therapeutical Chemical (ATC) Classification System (Capellá, 1993
) and the date of prescription (date of dispensing the drug). The civil personal identification number is maintained by the Central Population Register (CPR), which updates information on vital status (dates of death or emigration), address (date of migration from the county), and the civil personal identification numbers of all offspring. Thus, information on parity can be obtained for all women since the establishment of the CPR in 1968.
From the files of the CPR, we identified 83
873 women who were 40–66 years of age at any time during the period 1 January 1989 to 31 December 2002 and resident in the county of North Jutland. These women were linked to the Danish Cancer Registry to identify cases of breast cancer occurring through 2002. The Danish Cancer Registry has recorded incident cases of cancer on a nation-wide basis since 1943 with accurate and virtually complete ascertainment (Storm et al, 1997
). Tumours are classified according to a revised version of ICD-7 (Danish National Board of Health, 2003
), and since 1978, also according to ICD-O (WHO, 1976
). We excluded 1444 women who had a cancer diagnosis (except nonmelanoma skin cancer) before 1989 or before age 40 (if later than 1989).
The remaining 82
429 women were linked to the Pharmaco-Epidemiologic Prescription Database. We excluded 1079 women who received prescriptions for sex hormones other than those used in HRT (ATC codes: G03B, G03G, G03H, G03X) including androgens, during 1989–2002, and 2970 women who had used systemic HRT before the age of 40 years. Among the remaining 78
380 women, we identified 17
466 who received at least two prescriptions for systemic HRT (G03A, G03C, G03D and G03F) from 1 January 1989 until 31 December 2002. In Denmark, there is normally no reimbursement for oral contraceptives, but we included women recorded with reimbursed prescriptions for oral contraceptives, since this indicates that the hormones were given for reasons other than contraception. Prescription of nonsystemic HRT was not judged as HRT exposure for the purposes of the present study.
The follow-up for breast cancer started on 1 January 1989 or at age 40 years, whichever occurred later, and continued until the date of breast cancer diagnosis, of cancer other than breast (except) for nonmelanoma skin cancer), date of death, of migration from North Jutland, or 31 December 2002, whichever came first. Since women with only one prescription may never have actually taken the drug, we classified such women as nonexposed. The follow-up time was stratified according to use of HRT in unexposed time (less than two prescriptions) and exposed time (two or more prescriptions) (). The exposed time was further stratified into:
- recency of use (current use of HRT with less than 2 years since last prescription, recent use with 2–5 years since last prescription and former use with more than 5 years since last prescription);
- number of prescriptions (2–4, 5–9, 10–19, and 20 or more prescriptions);
- type of first prescription of HRT (oestrogen only, sequentially combined oestrogen–testosterone derived progestin (levonorgestrel, norethisteron, norgestimat, desogestrel, gestoden), sequentially combined oestrogen–progesterone derived progestin (medroxyprogesteron), continuously combined oestrogen–testosterone derived progestin (norethisteron), tibolone, and progestins. Users contributed person-years to the appropriate group until they received a prescription for HRT from one of the other groups, and from that time on they contributed person-years to a category of mixed use.
Illustration of the method of calculation of exposure to HRT in the cohort of women aged 40–67 years in North Jutland county, Denmark, 1989–2002.
We computed rate ratios as the breast cancer incidence rate for HRT exposure divided by the breast cancer incidence rate for nonexposure (<two prescriptions). Age-specific as well as age-standardised (direct standardisation in 5-year age-groups to the age distribution in the total cohort of women) rate ratios were calculated. In addition, we performed analyses based on Cox proportional hazards models with age as the time scale. These analyses were adjusted for calendar-period as a time-dependent covariate with two levels (1989–1996 and 1997–2002) and number of children and age at first child obtained from the CPR as time-dependent linear variables. Tests were based on the likelihood ratio test statistics calculated from Cox's partial likelihood. Confidence intervals were based on Wald's test of the corresponding regression parameters, that is, on the log scale for the rate ratios. The statistical analyses were performed using SAS version 8.02. The proportional hazards assumption of the Cox models was tested by visual inspection of transformations of the survival function using standard techniques.