Association between contemporary hormonal contraception and ovarian cancer in women of reproductive age in Denmark: prospective, nationwide cohort study
BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3609 (Published 26 September 2018) Cite this as: BMJ 2018;362:k3609
- Lisa Iversen, research fellow1,
- Shona Fielding, senior lecturer2,
- Øjvind Lidegaard, professor3,
- Lina S Mørch, senior researcher3,
- Charlotte W Skovlund, scientific assistant3,
- Philip C Hannaford, professor1
- 1Academic Primary Care, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
- 2Medical Statistics Team, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
- 3Rigshospitalet, Juliane Marie Centre, Department of Gynaecology, University of Copenhagen, Denmark
- Correspondence to: L Iversen l.iversen{at}abdn.ac.uk
- Accepted 30 July 2018
Abstract
Objectives To investigate the association between contemporary combined hormonal contraceptives (including progestogen types in combined preparations and all progestogen-only products) and overall and specific types of ovarian cancer.
Design Prospective, nationwide cohort study.
Setting Denmark, 1995-2014.
Participants All women aged 15-49 years during 1995-2014 were eligible. Women were excluded if they immigrated after 1995, had cancer (except non-melanoma skin cancer), had venous thrombosis, or were treated for infertility before entry (final study population included 1 879 227 women). Women were categorised as never users (no record of being dispensed hormonal contraception), current or recent users (≤1 year after stopping use), or former users (>1 year after stopping use) of different hormonal contraceptives.
Main outcome measures Poisson regression was used to calculate relative risk of ovarian cancer among users of any contemporary combined hormonal contraceptives and by progestogen type in combined preparations and all progestogen-only products, including non-oral preparations. Separate analyses examined women followed up to their first contraception type switch and those with full contraceptive histories. Duration, time since last use, and tumour histology were examined and the population prevented fraction were calculated.
Results During 21.4 million person years, 1249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13 344 531 person years. Never users had 771 ovarian cancers during 8 150 250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (relative risk 0.58 (95% confidence interval 0.49 to 0.68) and 0.77 (0.66 to 0.91), respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82 (0.59 to 1.12) with ≤1 year use to 0.26 (0.16 to 0.43) with >10 years’ use; P<0.001 for trend). Similar results were achieved among women followed up to their first switch in contraceptive type. Little evidence of major differences in risk estimates by tumour type or progestogen content of combined oral contraceptives was seen. Use of progestogen-only products were not associated with ovarian cancer risk. Among ever users of hormonal contraception, the reduction in the age standardised absolute rate of ovarian cancer was 3.2 per 100 000 person years. Based on the relative risk for the never use versus ever use categories of hormonal contraception (0.66), the population prevented fraction was estimated to be 21%—that is, use of hormonal contraception prevented 21% of ovarian cancers in the study population.
Conclusions Use of contemporary combined hormonal contraceptives is associated with a reduction in ovarian cancer risk in women of reproductive age—an effect related to duration of use, which diminishes after stopping use. These data suggest no protective effect from progestogen-only products.
Footnotes
Contributors: LI conducted the literature review and wrote the first draft and subsequent revisions of the paper with input from all authors; she is guarantor for the paper. SF undertook all the statistical analyses and wrote the first draft of the methods and results. ØL is the principal investigator of the Danish Sex Hormone Register study, advised on analyses, and provided expertise regarding hormonal contraception. LSM provided expertise on ovarian cancer epidemiology, advised on the statistical analysis, and wrote the initial programmes for data management. CWS wrote the initial programmes for data management and prepared all the data from the national registries. PCH advised on analyses and provided expertise on hormonal contraception. All authors designed the study, interpreted the results, and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Funding: Supported by a grant (No 11645) from the Novo Nordisk Foundation. The funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the paper; or in the decision to submit the paper for publication.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Novo Nordisk Foundation for the submitted work; ØL reports grants from the Novo Nordisk Foundation, during the conduct of the study, and has been an expert witness in two legal cases in the United States on hormonal contraception and venous thrombosis for the plaintiff in 2011 and 2012; LSM reports grants from the Novo Nordisk Foundation, during the conduct of the study; LSM and CWS became employed by the Novo Nordisk Foundation after the work reported in the manuscript was completed; PCH, LI, and SF have nothing to disclose.
Ethical approval: The data were analysed and held within the secure data repository at Statistics Denmark. Ethical approval is not required for register based studies according to Danish Research Ethics Committee law (chapter 8, section 3). Nevertheless, approval for the work was obtained from the Danish Data Protection Agency and Health Data Board.
Data sharing: Data sharing is not available.
The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
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