Nonoral combined hormonal contraceptives and thromboembolism: a systematic review
Open accessAbstract
Background Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) compared with nonuse. Few studies have examined whether nonoral formulations (including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives) increase the risk of thrombosis compared with combined oral contraceptives (COCs).Objectives The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs.Methods We searched the PubMed database for all English language articles published from database inception through May 2016. We included primary research studies that examined women using the patch, ring or combined injectables compared with women using levonorgestrel-containing or norgestimate-containing COCs. Outcomes of interest included VTE (deep venous thrombosis or pulmonary embolism) or ATE (acute myocardial infarction or ischemic stroke). We assessed the quality of each individual piece of evidence using the system developed by the United States Preventive Services Task Force.Results Eight studies were identified that met inclusion criteria. Of seven analyses from six studies examining VTE among patch users compared with levonorgestrel- or norgestimate-containing COC users, two found a statistically significantly elevated risk among patch users (risk estimates 2.2-2.3), one found an elevated risk that did not meet statistical significance (risk estimate 2.0), and four found no increased risk. Of three studies examining VTE among ring users compared with levonorgestrel COC users, one found a statistically significantly elevated risk among patch users (risk estimate 1.9) and two did not. Two studies did not find an increased risk for ATE among women using the patch compared with norgestimate COCs. We did not identify any studies examining combined injectable contraceptives.Conclusion Limited Level II-2 good to fair evidence demonstrated conflicting results on whether women using the patch or the ring have a higher risk of VTE than women using COCs. Evidence did not demonstrate an increased risk of ATE among women using the patch. Overall, any potential elevated risk likely represents a small number of events on a population level. Additional studies with standard methodology are needed to further clarify any associations and better understand mechanisms of hormone-induced thrombosis among users of nonoral combined hormonal contraception.
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The increased risk of estrogen-associated thrombosis depends on both the dose and the mode of delivery of the hormone.
“The increased risk is dependent both on the dose and well as the mode of delivery of the hormone, and studies identify alterations in numerous aspects of the hemostatic and fibrinolytic pathways that contribute to the generation of a prothrombotic milieu.”
From Estrogen and thrombosis: a bench to bedside review (2020) · cites this paper as [86]
Oral contraceptives and non-oral forms of combined hormonal contraceptives are associated with an increased risk of arteriothrombotic events.
“Oral contraceptives and non-oral forms of combined hormonal contraceptives were associated with an increased risk of arteriothrombotic events (table 1).55 67 79”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [79]
Comparing users of non-oral combined hormonal contraceptive agents with users of combined oral contraceptives, no association with stroke is seen.
“Comparing users of non-oral combined hormonal contraceptive agents with users of combined oral contraceptives,79 no association with the development of myocardial infarction (the results were not meta-analysed, but odds ratios from individual primary studies ranged from 0.2 to 1.6) or stroke (odds ratio 0.8 to 1.2) was seen but the review was rated as low quality (table 1 and supplementary table 4”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [79]
The review comparing non-oral combined hormonal contraceptives with combined oral contraceptives was rated as low quality.
“Comparing users of non-oral combined hormonal contraceptive agents with users of combined oral contraceptives,79 no association with the development of myocardial infarction (the results were not meta-analysed, but odds ratios from individual primary studies ranged from 0.2 to 1.6) or stroke (odds ratio 0.8 to 1.2) was seen but the review was rated as low quality (table 1 and supplementary table 4”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [79]
Comparing users of non-oral combined hormonal contraceptive agents with users of combined oral contraceptives, no association with development of myocardial infarction is seen.
“Comparing users of non-oral combined hormonal contraceptive agents with users of combined oral contraceptives,79 no association with the development of myocardial infarction (the results were not meta-analysed, but odds ratios from individual primary studies ranged from 0.2 to 1.6) or stroke (odds ratio 0.8 to 1.2) was seen but the review was rated as low quality (table 1 and supplementary table 4”
From Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review (2020) · cites this paper as [79]
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References 33 · Cited by 73
- Authors
- Tepper, N. K., Dragoman, M. V., Gaffield, M. E., & Curtis, K. M.
- Affiliations
- Centers for Disease Control and Prevention (US)
- World Health Organization (CH)
- Corresponding author
- Tepper, Naomi K.
- Venue
- Contraception
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 95
- Issue
- 2
- Pages
- 130-139
- ISSN
- 0010-7824 (ISSN-L)
- PMC
- PMC11025291
- OpenAlex
- W2532488743
- Cited by
- 73
- References
- 33
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 4 · 2020: 16 · 2019: 8 · 2018: 5 · 2017: 2
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Contraception (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Department of Reproductive Health and Research at the World Health Organization
- Centers for Disease Control and Prevention
- US Agency for International Development
- National Institute of Child Health and Human Development
- 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, arterial thromboembolism, contraceptive patch, vaginal ring, combined oral contraceptives, deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, levonorgestrel, norgestimate
- MeSH terms
- Administration, Cutaneous, Adolescent, Adult, Contraceptive Devices, Female, Contraceptives, Oral, Combined, Contraceptives, Oral, Hormonal, Estrogens, Female, Humans, Norgestrel, Progestins, Risk Factors, Thromboembolism, Levonorgestrel, Venous Thromboembolism, Young Adult
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