In this prospective cohort study, the current or recent use of hormonal contraception was associated with a higher risk of breast cancer than the risk among women who had never used hormonal contraceptives, with little evidence of major differences between specific combined oral contraceptives. The risk increased with the duration of use.

The collaborative reanalysis of data from individual women5 showed that among the women who were currently using combined oral contraceptives, the relative risk of breast cancer was 1.24 (95% CI, 1.15 to 1.33), which is close to our estimate of 1.19 (95% CI, 1.13 to 1.26) for all combined oral products. In line with our data, other studies have not shown consistent differences among women who used older combined oral contraceptives (from the 1970s and 1980s) that had a different progestin content.13,15,16,18,25,29

Our data showed a higher risk of breast cancer with a longer duration of use of combined products with various progestins, although the effect of duration was only significant for the largest product group containing gestodene. A duration-of-use relationship has not been shown in most studies assessing long-term contraceptive use,5,21 possibly because many included a large proportion of postmenopausal women whose past use of oral contraceptives before menopause was unlikely to influence the breast-cancer risk estimates greatly.5,13,27 Studies that have stratified data according to menopausal status have also shown a higher risk of breast cancer among premenopausal woman who have used hormonal contraceptives for long periods of time than among those who have used them for short periods of time.22,24,25

Our results suggest the rapid disappearance of excess risk of breast cancer after discontinuation of use among women who have used hormonal contraceptives for short periods, whereas the risk among women who have used these contraceptives for longer periods may persist for at least 5 years after discontinuation. In the collaborative reanalysis, the slightly higher risk among former users of combined oral contraceptives disappeared within 5 years.5 Other studies have shown no evidence of persisting risk several years after the discontinuation of oral contraception.22,24,25 Study differences may be due to variations in the mean duration of use. Since our data mostly comprised women who used hormonal contraception for less than 5 years, our overall results indicated only a slightly higher risk of breast cancer among past users than among women who had never used hormonal contraception.

Few studies have assessed progestin-only contraception and breast-cancer risk. In a cohort of 93,843 women who used the levonorgestrel-releasing intrauterine system, a relative risk of breast cancer of 1.19 (95% CI, 1.13 to 1.25) was found, as compared with the general incidence rate among Finnish women younger than 55 years of age35; we found a similar risk estimate. The absence of an association between the duration of use of the levonorgestrel-releasing intrauterine system and breast-cancer risk might be explained by the system providing a decreasing dose of progestin released according to the time since insertion. Studies suggest a considerable systemic uptake of levonorgestrel in women who use the intrauterine system, with plasma concentrations in some women that are similar to those in women who use levonorgestrel-only pills.36-38

Our nationwide prospective study involving 1.8 million Danish women who were followed for almost 11 years adds substantively to the sparse evidence base about contemporary hormonal contraception. The linkage of cancer and pharmacy records allowed us to incorporate time-varying exposure information about changes in contraceptives used and discontinuation of use. The large number of events allowed for assessment of recently marketed combined preparations, various durations of use, progestin-only products, and various routes of administration, including the intrauterine system.

This study had some limitations. We were not able to adjust for age at menarche, breast-feeding, alcohol consumption, or physical activity, and we had information on body-mass index only for parous women. Although some of these variables may be correlated with both breast-cancer risk and hormonal contraception, they would be expected to continue to influence a woman’s risk after discontinuation of hormonal contraceptives; in contrast, we found that risks among women who used hormonal contraception for less than 5 years rapidly decreased after discontinuation of hormonal contraception.

Furthermore, we would not expect differences in the levels of these potential confounding factors with various durations of hormonal contraceptive use. Information about some of the potential confounders that we included in our models was not available for the oldest women, because the Danish National Health Register started in 1976. Analyses that were restricted to women younger than 35 years of age showed larger risk estimates for combined products with levonorgestrel and for the levonorgestrel-releasing intrauterine system, suggesting that missing information about potential confounders in older women is unlikely to have led to overestimation of overall risk estimates for these products. Residual confounding is also possible; for example, information about the polycystic ovary syndrome and endometriosis was available only for women who had been hospitalized with these conditions, and we adjusted only for a family history of premenopausal breast or ovarian cancer. Women with any family history of breast cancer might be less likely to use hormonal contraception, which might underestimate the risk estimate.4,6-11 Quantitative bias analysis, however, suggests that to explain the main finding, a confounder would need to be highly prevalent in the population (50%) and strongly associated with breast cancer (by a factor of 3) and use of hormonal contraception (an odds ratio of 2.5) (Fig. S1 in the Supplementary Appendix); such an unknown confounder appears to be unlikely.

Information was not available about exposure to hormonal contraceptives before study entry. Some women who did not purchase a hormonal contraceptive during the study period (and so were classified as never having used hormonal contraception) may have used hormonal contraception beforehand. Such misclassification (left censor bias) would underestimate breast-cancer risk among women who used hormonal contraceptives. Analyses that were restricted to women with at least 5 years of contraceptive history before inclusion in the analysis generally produced results that were similar to those of the main analysis. Some women might have stopped taking hormonal contraception even though their prescription length indicated that they were still users; such misclassification would also be expected to lead to underestimates of the risk of breast cancer among women who use hormonal contraception.

If women who were currently using hormonal contraception were screened for breast cancer more often than those who were not, we would expect to see a decreased breast-cancer risk among former users because of a reduced detection rate after the more intensive screening while the women were current users. This was not apparent in our data. Finally, we did not adjust for multiple statistical testing in the main analyses, and this might explain some of the associations observed. However, the findings were consistent across many analyses including various types of hormonal contraception.

The estimated number of additional breast cancers that were associated with hormonal contraception did not include extra cases diagnosed after the discontinuation of long-term use. Even so, the estimated number of additional breast cancers among premenopausal women that were attributable to hormonal contraception is likely to be low. This risk should be weighed against important benefits of hormonal contraceptives such as good contraceptive efficacy and reduced risks of ovarian, endometrial, and perhaps colorectal cancer (at least for combined oral contraceptives that were commonly used in the 1970s and 1980s).39