Elsevier

Contraception

Volume 95, Issue 2, February 2017, Pages 130-139
Contraception

Review article
Nonoral combined hormonal contraceptives and thromboembolism: a systematic review

https://doi.org/10.1016/j.contraception.2016.10.005Get rights and content

Abstract

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.

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.

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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.

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