Risk of Venous Thromboembolism in Users of Combined Oral Contraceptives

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.

References

• The EMA's Pharmacovigilance Risk Assessment CommitteePharmacovigilance Risk Assessment Committee(PRAC). PRAC confirms that benefits of all combined hormonal contraceptives (CHCs) continueto outweigh risksEMA/607314/2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/10/news_detail_001916.jsp&mid=WC0b01ac058004d5c1
• Bain E, Wilson A, Tooher R et al. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev 2014;(2):CD001689. [PubMed]
• de Bastos M, Stegeman BH, Rosendaal FR et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014;(3):CD010813. [PubMed]
• van Vlijmen EF, Wiewel-Verschueren S, Monster TB et al. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2016;14(7):1393-403.[PubMed]