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Am Fam Physician. 2015;91(5):287-288

Author disclosure: No relevant financial affiliations.

Clinical Question

Which combined oral contraceptives carry the greatest risk of venous thromboembolism (VTE)?

Evidence-Based Answer

All combined oral contraceptives increase VTE risk. The risk is greater for those containing desogestrel, drospirenone, gestodene (not available in the United States), and cyproterone acetate (not available in the United States) when compared with levonorgestrel. All combined oral contraceptives are effective in preventing pregnancy. (Strength of Recommendation: B, based on inconsistent or limited-quality patient-oriented evidence.)

Practice Pointers

The first combined oral contraceptives debuted in 1960 and are now used by 17% of women 15 to 44 years of age. In the United States, more women use combined oral contraceptives than any other contraceptive method.1 However, studies have demonstrated an up to fourfold increase in the risk of VTE among combined oral contraceptive users compared with nonusers (pregnancy carries a slightly greater than fourfold risk).2,3 Over time, the hormone formulations and dosages of combined oral contraceptives have changed in an effort to decrease thrombogenic risk. The authors of this review looked at studies featuring multiple combined oral contraceptive formulations and dosages to determine the relative risk associated with each.

This Cochrane review included nine cohort and 17 case-control studies. The authors found no pertinent randomized controlled trials. Only five studies objectively confirmed VTE in all study patients, raising concern that ascertainment bias influenced the outcomes of the other studies. The absolute risk of VTE in nonusers was 0.19 to 0.37 per 1,000 woman-years. The risk of VTE with combined oral contraceptive use (15 studies) was 3.5 times greater than with nonuse (95% confidence interval [CI], 2.9 to 4.3).

Compared with that of nonusers, the risk of VTE was 3.2 times greater (95% CI, 2.0 to 5.1) with first-generation progestins, 2.8 times greater (95% CI, 2.0 to 4.1) with second-generation progestins, and 3.8 times greater (95% CI, 2.7 to 5.4) with third-generation progestins. This corresponds to absolute risk increases of 0.61 to 1.18 per 1,000 woman-years for first-generation progestins, 0.55 to 1.04 per 1,000 woman-years for second-generation progestins, and 0.72 to 1.41 per 1,000 woman-years for third-generation progestins. Risk of VTE was similar among the third- and fourth-generation progestins desogestrel, drospirenone, gestodene, and cyproterone acetate, each of which carried a risk of VTE that was 50% to 80% higher than that associated with the second-generation progestin levonorgestrel.

The Centers for Disease Control and Prevention (CDC) recommends against combined oral contraceptive use in those who smoke more than 15 cigarettes per day, who have a blood pressure equal to or greater than 160 mm Hg systolic or 100 mm Hg diastolic, or who have multiple risk factors for or a history of vascular disease. Likewise, the CDC strongly recommends against the use of combined oral contraceptives in those who have a history of VTE or known thrombophilia.4

All women should be counseled on the risk of VTE with combined oral contraceptive use vs. the risk of VTE in pregnancy (1.4%; 95% CI, 1.0% to 1.8%).5 As much as possible, physicians should try to use lower-dose hormone formulations to decrease the risk of VTE. Based on this review, levonorgestrel has a lower risk than desogestrel, drospirenone, gestodene, or cyproterone acetate.

These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at

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