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Evidence summaries

Risk of Venous Thromboembolism in Users of Combined Oral Contraceptives

The use of any combined oral contraceptives may confer an increased risk of venous thromboembolism but the absolute risk increase is small. Level of evidence: "C"

In users of 2nd generation combined oral contraceptives (COCs), the incidence of venous thromboembolism (VTE) is estimated to be about 5 to 7 cases per 10 000 women-years of use. This translates into a mortality rate of 5 to 12 deaths per million women-years of use. In users of 3rd generation COCs the incidence of VTE is estimated to be about 6 to 12 cases per 10 000 women-years of use depending on the type of the progestogen used. The risk is estimated to be higher with the progestogens etonogestrel and norelgestromin, with 6 to 12 cases yearly per 10 000 women. The risk is also estimated to be higher with the progestogens gestodene, desogestrel, drospirenone, with 9 to 12 cases yearly per 10 000 women.For COCs containing chlormadinone, dienogest and nomegestrol, the available data are insufficient.

The incidence of VTE in women not using COCs and aged 15-44 years is 2 cases per 10 000 women-years. In pregnancy 2, the incidence is estimated as 10 to 20 cases per 10 000 pregnancies. It is expected that 20% of the women affected by a VTE will develop a disabling post-thrombotic syndrome. The most serious complication of VTE is pulmonary embolism which occurs in about 10% of the cases.

A Cochrane review [Abstract] 3 included 25 observational studies (13 case-control, 9 cohort, and 3 nested case-control designs) with a total over 10 000 000 women years. Incidence of venous thrombosis in non-users from two included cohorts was 0.19 and 0.37 per 1 000 person years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.

A meta-analysis 4 assessed the thrombosis risk in thrombophilic COC-users. 12 case-control and 3 cohort studies were included. A distinction was made between 'mild' (factor V Leiden and prothrombin-G20210A mutation) and 'severe' thrombophilia (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity of factor V Leiden and prothrombin-G20210A mutation). In COC-users, mild thrombophilia increased the risk of VTE almost 6-fold (rate ratio [RR], 5.89; 95%CI 4.21 to 8.23) and severe 7-fold (RR, 7.15; 95% CI, 2.93 to 17.45). The cohort studies showed that absolute VTE risk was far higher in COC-users with severe thrombophilia than in those with mild thrombophilia (4.3 to 4.6 vs. 0.49 to 2.0 per 100 pill-years, respectively), and these differences in absolute risks were also noted in non-affected women (0.48 to 0.7 vs. 0.19 to 0.0), but with the caveat that absolute risks were estimated in relatives of thrombophilic patients with VTE (i.e. with a positive family history). The investigators conclude that the additive VTE risk of mild thrombophilia is modest.

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Primary/Secondary Keywords