In different international matched case control studies the altered risk of venous thromboembolic disorders (VTE, deep vein thrombosis and pulmonary embolism) is in the same direction and of about the same magnitude. First generation products were classified as containing lynestrenol or norethisterone acetate or similar, second generation products as containing low dose (<35 -g) ethinylestradiol and progestogen of the norgestrel group, and third generation products as containing low dose ethinylestradiol and gestodene or desogestrel or norgestimate. Current use was defined as use within 3 - 4 months before the event (for a case), hospital admission (for a hospital control) or date of interview (for a community control).
Spitzer et al. 1 compared 471 cases and 1 772 controls (at least three controls per case) by the use of different oral contraceptives. They were adjusted for linear age, smoking, alcohol use, study centre, BMI and duration of exposure to oral contraceptives (OC) used before the current oral contraceptive. Odds ratios for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (95% Cl 3.1 to 5.3); for second generation products (low dose ethinyloestradiol, no gestodene or desogestrel) versus no use, 3.2 (95% Cl 2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (95% Cl 3.4 to 6.7); for third generation products versus second generation products, 1.5 (95% Cl 1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (95% Cl 1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (95% Cl 1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year.
In a WHO collaborative study 2 (1 143 cases and 2 998 age-matched controls in Africa, Asia, Europe and Latin America) OC use was associated with an increased risk of VTE in Europe (OR 4.15 with 95% CI 3.09 - 5.57) and in non-European ("developing") countries (OR 3.25 and CI 2.59 - 4.08). Odds ratios associated with the use of OCs containing a third generation progestogen were higher than those observed with progestogens of the first and second generation.
A multinational hospital-based case control study 3 involving 769 cases and 1 979 age-matched hospital controls and, in one centre, 246 controls at a community centre at risk of VTE compares levonorgestel with third generation progestogens. The odds ratio compared with levonorgestel was 2.6 (95% Cl 1.4 - 4.8) for both desogestrel and gestodene separately.
In a cohort study (80 cases in a cohort of 238 130 otherwise healthy women using low dose oestrogen OC) conducted by Jick et al. 4 a nested case control analysis was performed and the adjusted matched relative risk estimates of VTE calculated: RR was 2.2 (95% CI 1.1 to 4.4) and 2.1 (95% CI 1.0 to 4.4) for desogestrel and gestodene users, respectively, compared with users of levonorgestrel.
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