Review articleNonoral combined hormonal contraceptives and thromboembolism: a systematic review☆
Introduction
Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are important methods in the array of contraceptives available to women. Globally, combined oral contraceptives (COCs) are the third most widely used contraceptive method and are used by over 100 million women [1], [2]. Nonoral formulations of CHCs, including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives, offer similar benefits and side effect profiles and may increase ease of use by eliminating need for daily intervention [3], [4], [5].
The elevated relative risk of thrombosis among women using CHCs compared with nonusers is well established [6]. Risks include venous thromboembolism (VTE), such as deep venous thrombosis (DVT) or pulmonary embolism (PE), and arterial thromboembolism (ATE), such as acute myocardial infarction (AMI) or ischemic stroke. Estrogen can promote coagulation through multiple effects on the procoagulant, anticoagulant and fibrinolytic pathways [7]. In addition, there is increasing evidence that different progestins may also independently and variably affect hemostatic factors and thrombosis risk [7], [8]. The relevant safety question for women choosing CHCs is whether certain formulations have differential risks of thrombosis. Among COCs, formulations with <50 mcg ethinyl estradiol containing levonorgestrel (LNG) appear to have the lowest risk of VTE [9]. This systematic review was conducted to examine the risk of VTE and ATE with use of nonoral CHCs. Specifically, the review sought to identify evidence comparing risks among women using nonoral CHCs with women using LNG-containing or norgestimate (NGM)-containing COCs.
Section snippets
Materials and methods
We conducted this systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [10].
Results
The search identified 504 articles. After reviewing the titles and abstracts of these articles, as well as the full articles when necessary, we determined that eight articles met criteria for inclusion in this review (Table 1) [12], [13], [14], [15], [16], [17], [18], [19]. Of the included articles, seven reported outcomes among patch users [12], [14], [15], [16], [17], [18], [19] and three reported outcomes among ring users [12], [13], [18]. If there were multiple articles reporting on the
Discussion
This systematic review identified six articles that found conflicting results on whether women using the patch have a higher risk of VTE than women using LNG or NGM COCs. The review also identified three articles which found conflicting results on whether women using the ring have a higher risk of VTE than women using LNG COCs. The review identified two articles which did not find an increased risk for ATE among women using the patch compared with NGM COCs. The review did not identify any
Acknowledgements
This review was supported by resources from the Department of Reproductive Health and Research at the World Health Organization, the Centers for Disease Control and Prevention, the US Agency for International Development, and the National Institute of Child Health and Human Development.
References (30)
History of oral contraceptive drugs and their use worldwide
Best Pract Res Clin Endocrinol Metab
(2013)- et al.
Vaginal ring contraception
Contraception
(2011) - et al.
Mechanisms of estrogen-induced venous thromboembolism
Thromb Res
(2010) - et al.
Current methods of the US preventive services task force: a review of the process
Am J Prev Med
(2001) - et al.
Extended case–control study results on thromboembolic outcomes among transdermal contraceptive users
Contraception
(2010) - et al.
Postmarketing study of ORTHO EVRA and levonorgestrel oral contraceptives containing hormonal contraceptives with 30 mcg of ethinyl estradiol in relation to nonfatal venous thromboembolism
Contraception
(2010) - et al.
ORTHO EVRA and venous thromboembolism: an update
Contraception
(2010) - et al.
Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, desogestrel-containing oral contraceptives and the contraceptive patch
Contraception
(2006) - et al.
Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol
Contraception
(2007) - et al.
Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 microg of ethinyl estradiol
Contraception
(2006)
Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users
Contraception
Comparison of ethinylestradiol pharmacokinetics in three hormonal contraceptive formulations: the vaginal ring, the transdermal patch and an oral contraceptive
Contraception
Effects of switching from oral to transdermal or transvaginal contraception on markers of thrombosis
Contraception
Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study
Thromb Res
Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables
Contraception
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Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the World Health Organization or US Centers for Disease Control and Prevention.