According to the EMA’s Pharmacovigilance Risk Assessment the overall adjusted odds ratio for 3rd and 4th versus 2nd generation oral contraceptives (COCs) was 1.5 to 2.0 fold. The risk is lowest with the COCs containing the progestogens levonorgestrel, norgestimate and norethisterone: it is estimated that each year there will be 5 to 7 cases of VTE per 10 000 women who use these COCs. 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. For comparison, in women who are not using COCs and who are not pregnant, there will be around 2 cases of VTE each year per 10000 women.
The incidence of VTE in women not using COCs and aged 15–44 years is 2 cases per 10 000 women-years. In pregnancy , the incidence is estimated as 10-20 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.
The excess risk for users of third generation oral contraceptives over second generation preparations was estimated to be 1.5 per 10 000 woman years. Among new users the incidence would be 6.6 per 10 000 woman years.
Another meta-analysis from similar study material confirms these conclusions. The summary relative risk (95% CI) was 1.7 (1.3–2.1). The incremental risk of VTE was estimated to be about 1.1 per 10 000 women per year. An association was present when accounting for duration of use and when restricted to the first year of use in new users.
Another Cochrane review included 25 observational studies (13 case-control, 9 cohort, and 3 nested case-control designs) with a total over 10 000 000 women years. The relative risk of venous thrombosis for combined oral contraceptives with 30-35 μg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.
This increase of incidence of VTE would translate into an additional 20 to 40 cases of disabling post-thrombotic syndrome, 10 to 20 cases of pulmonary embolism and 1 to 4 deaths per million women-years of use .