The differential risk of oral contraceptives: the impact of full exposure history

Previous discussions have indicated that the small increases of risk of venous thromboembolism (VTE) associated with newer combined oral contraceptives (third generation, containing desogestrel and gestodene) may be attributed to bias due to cohort effects. In a case-control analysis, this may produce an overestimate of risk of newer preparations. In 10 centres in Germany and the UK, the Transnational Study analysed data from 502 women aged 16-44 years with VTE, and from 1864 controls matched for 5-year age group and region. Information on lifetime exposure history from all subjects was added to the dataset used in previous analyses and entered into a Cox regression model with time-dependent covariates. Based on 17 622 continuous exposure episodes comprising 47 914 person-years of observation, the adjusted hazard ratio (equivalent to odds ratio, OR) of VTE for the comparison of current users of third-generation versus current users of second-generation (primarily levonorgestrel compounds) combined oral contraceptives was 0.8 (0.5 to 1.3). The OR obtained in standard case-control analysis had been 1.5 (1.1 to 2.1). Adjustment for past exposures includes more information and appears more valid than the standard cross-sectional analysis. Using this approach, the Transnational Study data show no evidence for an increased risk of VTE with third- compared with second-generation combined oral contraceptives.