Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.

The composition and use of oral contraceptives (OCs) have changed since their cardiovascular side-effects were established 20 years ago. This report describes the risk of idiopathic venous thromboembolic (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) in association with current use of combined OCs among 1143 cases aged 20-44 and 2998 age-matched controls, as evaluated in a hospital-based, case-control study in 21 centres in Africa, Asia, Europe, and Latin America. OC use was associated with an increased risk of VTE in Europe (odds ratio 4.15 [95% CI 3.09-5.57]) and in non-European ("developing") countries (3.25 [2.59-4.08]). Risk estimates were generally higher for DVT than for PE but no consistent trend by certainty of diagnosis (definite, probable, possible) was found. Increased risk was apparent within 4 months of starting OCs, was unaffected by duration of current episode of OC use, and had disappeared within 3 months of stopping OCs. Relative risk estimates of VTE associated with OC use were unaffected by age of user, by history of hypertension (excluding hypertension in pregnancy), or in any consistent way by smoking. However, in both groups of countries increased body mass index (BMI) was an independent risk factor for VTE, and OC-associated odds ratios were higher among those with a BMI above 25 kg/m2 than among those with smaller BMIs. OC-associated risk estimates were high among women in Europe with a history of hypertension in pregnancy. Odds ratios associated with the use of OCs containing a third-generation progestagen were higher than those observed with progestagens of the first (norethindrone type) and second (norgestrel group) generation. Odds ratios associated with first and second generation progestagens tended to be lower, though not significantly, when used in combination with low (< 50 micrograms oestrogen) rather than higher oestrogen doses. This study confirms an association between OC use and VTE in Europe and the developing countries, although overall risk estimates associated with use were lower than demonstrated in most previous studies of non-fatal idiopathic VTE.