Systemic hormonal contraception and risk of venous thromboembolism
Open accessAbstract
INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.
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In the general population, CPA increases the risk of venous thromboembolism compared with other COCP.
“General population studies have shown that CPA increases the risk of venous thromboembolism compared with other COCP (71, 72); hence, COCPs containing CPA are currently not recommended as first-line treatments for PCOS (20).”
From Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis (2024) · cites this paper as [72]
The Discussion (page unavailable) reports a slightly increased VTE risk with cyproterone-and-estrogen contraceptives, and the Results show an adjusted odds ratio of 1.50 versus non-use. The paper does not establish that CPA-containing pills have a higher risk than other combined oral contraceptives; it reports a higher estimate for EE-containing combined preparations as a group, also versus non-use. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNew data suggest that the effects on coagulation and the risk for thromboembolism might be lower with natural estrogen combinations.
“Interestingly, new data suggest that the effects on coagulation and the risk for thromboembolism might be lower with natural estrogen combinations (Sitruk-Ware, 2016; Kluft et al., 2017; Heikinheimo et al., 2022; Haverinen et al., 2022b)”
From Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial (2023) · cites this paper as Heikinheimo et al., 2022
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Self-citation
- Authors
- Heikinheimo, O., Toffol, E., Partonen, T., But, A., Latvala, A., & Haukka, J.
- Affiliations
- University of Helsinki (FI)
- Finnish Institute for Health and Welfare (FI)
- Corresponding author
- Toffol, Elena
- Venue
- Acta Obstetricia Et Gynecologica Scandinavica
- Publisher
- Wiley
- Published
- 2022-05-27
- Volume
- 101
- Issue
- 8
- Pages
- 846-855
- ISSN
- 0001-6349 (ISSN-L)
- 1600-0412
- PMC
- PMC9564731
- OpenAlex
- W4281705751
- Cited by
- 58
- References
- 29
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 13 · 2023: 12 · 2022: 2
- FWCI
- 11.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Acta Obstetricia Et Gynecologica Scandinavica (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Jane ja Aatos Erkon Säätiö (#170062)
- Yrjö Jahnssonin Säätiö (20207328)
- Topics
- Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Keywords
- venous thromboembolism, hormonal contraception, gestodene, ethinyl estradiol, drospirenone, desogestrel, transdermal patch, contraceptive use patterns, thrombosis risk, women of reproductive age, Finland, prescription data, incidence rate ratio, odds ratio
- MeSH terms
- Acetates, Aged, Contraception, Contraceptives, Oral, Combined, Contraceptives, Oral, Hormonal, Cyproterone, Estradiol, Estrogens, Female, Humans, Progestins, Prospective Studies, Progesterone Congeners, Venous Thromboembolism
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