Nonoral combined hormonal contraceptives and thromboembolism: a systematic review

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).

The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs.

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.

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.

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.