Elsevier

Contraception

Volume 94, Issue 6, December 2016, Pages 678-700
Contraception

Review
Progestin-only contraception and thromboembolism: A systematic review

https://doi.org/10.1016/j.contraception.2016.04.014Get rights and content

Abstract

Background

Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about progestin-only contraceptives (POCs) and thrombosis risk.

Objectives

The objective was to identify evidence regarding the risk of venous thromboembolism (VTE) or arterial thromboembolism [stroke or acute myocardial infarction (AMI)] among women using POCs.

Methods

We searched the PubMed database for all articles published from database inception through January 2016 for studies examining thrombosis among women using POCs. We included studies which examined women with medical conditions associated with thrombosis risk, as well as studies of women in the general population (either without these conditions or who were not specified to have these conditions). Hormonal contraceptives of interest included progestin-only pills (POPs), injectables, implants and levonorgestrel-releasing intrauterine devices (LNG-IUDs). Outcomes of interest included VTE, stroke and AMI.

Results

There were 26 articles of good to poor quality that met inclusion criteria; 9 studies examined women with medical conditions and 20 examined women in the general population. Two studies found that, among smokers and women with certain thrombogenic mutations, use of depot medroxyprogesterone acetate (DMPA) had elevated odds of VTE compared with nonsmokers or those without mutations, although confidence intervals were wide and overlapped with odds among nonusers. One study found that, among women with previous VTE, use of POCs (including DMPA) was associated with a nonsignificant increased odds of recurrent VTE (all of which were among DMPA users); two other studies that examined POCs other than DMPA did not observe an association with recurrent VTE. Two studies found that use of DMPA among healthy women was also associated with increased odds of VTE. Two studies found that use of POCs for therapeutic indications was associated with increased odds of VTE. Studies did not find increased odds of VTE with POPs for contraceptive purposes, implants or LNG-IUDs nor were there increased odds of stroke or AMI with any POCs.

Conclusion

The majority of evidence identified by this systematic review did not suggest an increase in odds for venous or arterial events with use of most POCs. Limited evidence suggested increased odds of VTE with use of injectables (three studies) and use of POCs for therapeutic indications (two studies, one with POCs unspecified and the other with POPs). Any increase in risk likely translates to a small increase in absolute numbers of thrombotic events at the population level.

Introduction

The association between combined hormonal contraceptives and thrombosis is well established. Combined hormonal contraceptives, containing estrogen and progestin, are associated with a 2- to 3-fold increased risk of venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism (PE), compared with nonuse [1], [2]. Combined hormonal contraceptives are also associated with a 2-fold increased risk of arterial thromboembolism (ATE), including stroke and acute myocardial infarction (AMI), compared with nonuse [2], [3]. Although these events are overall rare among women of reproductive age [VTE 5–10/10,000 women years (WY), stroke 21/100,000 WY and AMI 10/100,000 WY], they can have devastating complications associated with significant morbidity [2], [3]. Development of thrombosis is most likely due to estrogen effects on the coagulation system [4]. Historically, progestin-only contraceptives (POCs) were not thought to be linked with thrombosis. However, evidence has demonstrated that combined oral contraceptives with the same estrogen dose but different progestins are associated with differential VTE risk, suggesting that the progestin component may play a role in thrombosis development [1]. In addition, few recent studies have found an elevated risk of VTE with use of POCs, specifically with use of depot medroxyprogesterone acetate (DMPA) that delivers a relatively higher dose and potency of progestin [5], [6].

The US Medical Eligibility Criteria for Contraceptive Use, 2010 (US MEC) provides guidance for safety of contraceptive methods among women with certain characteristics or medical conditions and includes guidance for many conditions associated with increased risk of thrombosis such as postpartum, history of thrombosis, thrombogenic mutations, systemic lupus erythematosus, diabetes, hypertension and others [7]. This systematic review was conducted to identify evidence on thrombosis risk associated with POC use among women with medical conditions that increase their baseline risk for thrombosis, as well as among women in the general population. This review was conducted as part of the process of updating the US MEC.

Section snippets

Materials and methods

We conducted this systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [8].

Results

The search identified 1035 articles, of which 21 met inclusion criteria (Fig. 1) [3], [5], [6], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. Most excluded articles addressed combined hormonal contraceptives only, did not have a comparison group of nonusers, were review articles or otherwise did not address the question of interest. Five additional articles were identified from reference lists of included articles or relevant reviews

Discussion

Evidence identified by this systematic review generally found that any risk of venous or arterial thrombosis among women with certain medical conditions was not further elevated with use of POCs. Among women with hypertension, odds of stroke were higher with use of POPs compared with nonuse, but CIs overlapped. Similar results were found among smokers using POPs. One study suggested that injectable use among women who smoke increased the odds of VTE compared with smokers who did not use

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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 US Centers for Disease Control and Prevention.

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