In this study of women of reproductive age (that is, younger than 50 years) living in Denmark, we found that ever use of any contemporary hormonal contraception was associated with a reduced risk of ovarian cancer, an effect that strengthened with longer periods of current use and persisted for several years after stopping use. Most of the hormonal contraceptive use related to combined oral contraceptives. There was little evidence of important differences between combined oral contraceptives containing different types of progestogens. The reduced risk associated with hormonal contraception was seen with nearly all types of ovarian cancer. Our data do not suggest a protective effect from progestogen-only products; however, few women were exclusive users of such products, and so we had limited statistical power to detect such an effect.

We did not have information about hormonal contraceptives prescribed before entry to the study. Some women who were classified as never users could have used hormonal contraception previously. Such misclassification would underestimate the protective risk estimates, a problem that should diminish the further a woman was from her last use. Because older women are further away from their last use, and because most instances of ovarian cancer occur in older women (71% of our events were in women older than 40 years), we do not believe that our results were seriously affected by this misclassification. Some of the effects attributed to the use of a particular product could reflect lingering effects from the use of a previous product or products. Our analysis of women followed to their first switch of hormonal contraception in the study was intended to minimise such effects, while still providing enough data for reliable risk estimates. Little evidence of important differences was seen between the combined oral contraceptives. Furthermore, when we restricted our analysis to women with complete contraceptive histories (in whom misclassification from unknown previous use could not occur), the pattern of results for individual combinations was similar, albeit with imprecise, non-significant risk estimates.

The low incidence of ovarian cancer among women followed up to their first switch in type of hormonal contraception meant that it was not possible to examine the association between duration of use and time since last current use among users of specific preparations. However, given the little evidence overall of major differences between preparations, it seems unlikely that there are important differences in these temporal associations.

The data linkage study design also enabled us to adjust for several important confounding variables. The cohort was younger than 50 years, and so few women will have used hormone replacement therapy known to increase ovarian cancer risk. 26 While this age restriction meant that we could be confident that we were examining the effects of oral contraception, it also meant that the study could not provide information on how contemporary hormonal contraceptives affected ovarian cancer risk in older women, in whom most cases of ovarian cancer occur. We were not able to adjust for some factors, such as breastfeeding, and information about endometriosis and polycystic ovary syndrome only related to women admitted to hospital for these conditions. Our findings, therefore, could be subject to residual confounding. Information on smoking and body mass index was only available in parous women for part of the study period. However, adjustment for these variables in the subset of women for whom these data were available did not materially change the risk estimates.

Strengths of our study included its nationwide coverage of nearly 1.9 million women, more than 21 million person years of prospective follow-up, and the examination of the many different forms of hormonal contraception currently available. The linkage of prescribing and cancer registration information avoided recall bias regarding patterns of hormonal contraception use. Similar to most studies of hormonal contraceptives, we have assumed that women who were dispensed a prescription subsequently used it. If some women did not (that is, they remained being a non-user when we incorrectly deemed them to be a user), such misclassification would underestimate the protective effects found. However, because of the time varying variables used in our study, this misclassification of current use would only be present for the time period of the redeemed prescription. Thereafter, the women would be classified as a non-taker.

Comparison with other studies

By contrast with most previous research, our study included women aged 15-49 years, most of whom will have been premenopausal. Thus, the periods of observation for ever users of hormonal contraceptives in this age group had a higher proportion of information relating to current or recent use than those for ever users in a study recruiting older women, because many would have stopped using hormonal contraception many years previously. The Collaborative Group on Epidemiological Studies of Ovarian Cancer’s reanalysis of oral contraception data from 45 studies included women who were generally older than our cohort (mean age of diagnosis of ovarian cancer was 56 years, with only 18% of tumours diagnosed in women younger than 45 years).4 The overall relative risk between ever and never users was 0.73 (95% confidence interval 0.70 to 0.76). The Collaborative Group’s analysis found that younger and premenopausal women seemed to have greater percentage reductions in risk of ovarian cancer per five years of oral contraceptive use.4 However, after accounting for time since last use, no significant heterogeneity by menopausal status or age was seen, demonstrating that how recent a woman last used hormonal contraceptives was more important than the other two factors. Our slightly stronger reduced risk for any ovarian cancer among ever users of any hormonal contraception (relative risk 0.66 (95% confidence interval 0.58 to 0.76)) was possibly due to 58% of the total period of observation in ever users arising from current or recent use of combined oral contraceptives.

Similar to the Collaborative Group4 and other more recent investigations,56789 we found that the risk reductions among current users of any hormonal contraception got stronger with longer durations of use and persisted for a number of years after stopping use. The apparent loss of protection 10 years after stopping hormonal contraception could be due to the loss of biological effect (assuming a causal association exists), or reduced statistical power to continue to observe a significant reduction due to the relatively small periods of observation (7% of total person years for ever use).

Studies45 have not found differences in ovarian cancer risk by oestrogen dose of combined oral contraceptives (when assessed by decade of use). The same studies were unable to investigate associations with combined pills containing different progestogens. The Nurses’ Health Study II reported that short term use of preparations containing the oestrogen mestranol (hazard ratio 1.83, 95% confidence interval 1.16 to 2.88) and first generation progestogens (1.72, 1.11 to 2.65) were associated with an increased ovarian cancer risk, but found no relation with those containing second generation progestogens (levonorgestrel and norgestrel).22 The Nurses’ study had insufficient data to provide risk estimates for products containing desogestrel, norgestimate, or drospirenone.

Although we lacked power to examine patterns of risk by duration of use and progestogen type, we had good statistical power for the most often used progestogens and found little evidence of important differences in overall ovarian cancer risk among current or recent users of combined preparations containing different progestogens. It has been suggested that combined oral contraceptives do not differ from progestogen-only pills in their risk of ovarian cancer.27 In our study, current or recent use of progestogen-only products among all women implied a smaller effect on ovarian cancer risk estimates, compared with users of combined products (table 2). In the no change cohort followed up to the first switch in hormonal contraception, no protection against ovarian cancer was seen in users of progestogen-only products (table 4). This risk estimate was based on only 26 events, and so had limited statistical power to detect a significant protective effect. Alternatively, the lack of significance could be because of an absence of biological effect from progestogen-only products, with the reduced risk estimates seen in the full cohort analysis due to lingering effects from previous combined pill usage, suggesting that the protection found in the full cohort analysis could be due to a lingering effect from previous combined pill usage.

Few studies have examined use of depot medroxyprogesterone,141516 with findings from those studies able to investigate exclusive use1416 suggesting a protective effect. Our finding of an increased risk was based on only three exposed ovarian cancers and a very small total observation period, resulting in very imprecise risk estimates.

Soini and colleagues1213 reported a standardised incidence ratio of 0.60 (95% confidence interval 0.45 to 0.76) for ovarian cancer and use of the levonorgestrel intrauterine system among women in Finland,12 with decreased risks for mucinous, endometrioid, and serous ovarian carcinomas.13 Our findings do not concur with those studies, possibly because the Finnish studies did not adjust for parity or previous use of oral contraceptives (shown to have a persisting protective effect).

The Ovarian Cancer Cohort Consortium (OC3) recently examined risk factors for different histological types of ovarian cancer among more than 1.2 million women from 21 prospective studies in Europe, Asia, and North America. The consortium found that a five year increase in duration of oral contraceptive use and more than 10 years of use were both associated with a decreased risk of serous, endometrioid, and clear cell tumours but not mucinous tumours.28 Similarly, the Collaborative Group on Epidemiological Studies of Ovarian Cancer found that oral contraceptive use was not associated with the incidence of mucinous tumours.4 It is important to note that our study investigated women of reproductive age and who were younger than those in both the OC3 (median age at diagnosis 61.3-68.9 years depending on histological tumour type) and Collaborative Group (mean age at diagnosis 56 years) studies.

Our findings suggest that the protective effects of current or recent use of hormonal contraception is similar among endometrioid, mucinous and serous types of epithelial ovarian cancer. In line with current understanding, most mucinous tumours in our study were diagnosed at FIGO stage I.29 However, only 3% of all ovarian cancers are now thought to be mucinous types,29 indicating a relatively high incidence of mucinous tumours in our cohort. This high incidence of mucinous tumours has been observed previously in Denmark30 and elsewhere,28 and it is widely recognised that improvements in pathology, imaging, and serum markers will alter the reporting of the morphological subtypes of ovarian cancer.29 Therefore, some of the epithelial tumours could have been misclassified as mucinous.30 Recent understanding suggests that although ovarian cancer is clinically considered to be one disease, it is in fact a heterogeneous group of neoplasms with different pathogenesis pathways.29 Combined hormonal contraceptives suppress ovulation so protection against neoplastic development is feasible, but the exact mechanisms by which hormonal contraceptives reduce ovarian cancer risk are unclear. Whatever the biological mechanisms, the epidemiological evidence suggests a longlasting protection against most types of ovarian cancer from combined oral contraception.428

It has been suggested that recent downward trends in ovarian cancer mortality rates in North America and Europe can be partly attributed to the use of combined oral contraceptives.31 We found a population prevented fraction of 21% with use of hormonal contraception, which supports the notion that these ovarian cancer mortality benefits are likely to continue.