Venous thromboembolism and oral contraceptives

Abstract

R M C Herings and co-workers1Herings RMC Urquhart J Leufkens HGM Venous thromboembolism among new users of different oral contraceptives.Lancet. 1999; 354: 127-128Summary Full Text Full Text PDF PubMed Scopus (125) Google Scholar present high relative risks of developing venous thromboembolism (VTE) among first users of third-generation oral contraceptives compared with first users of second generation oral contraceptives. With an overall adjusted estimate of 4·2, the relative risk seems to be highest for women younger than 25 years (8·5), for duration of use of 1 year or more (8·1), especially in the absence of other disorders (14·1), and is apparently independent of the type of third generation progestagen used or the oestrogen content of the preparation. These findings were based on 27 women who developed VTE exposure to third generation and six women exposed to second generation oral contraceptives. Several issues related to this analysis should be addressed, apart from the small number of cases. Although the investigators repeatedly referred to a base population of 450 000, it was unclear how many women were included in the calculations, and there was no mention of the exact numbers of non-cases in the cohort. The accrued total exposure time was 54 939 woman-years over 10 years. Little seems to have been done to validate the data. The data on exposure and outcome were derived from different sources, with exposure measured on a regional basis and outcome on a nationwide basis. Time periods were not clearly defined in the exposure database, for which data were apparently collected retrospectively for 1986–89. Although implicitly stated, it was not entirely clear that first users actually became first users within the time period assessed, nor whether the definition of first user related to continuous use. The issue of left-censoring was unclear, and women older than 16 years in 1986 may have used oral contraceptives before the database was established. Users of second generation pills might therefore have been misclassified as first-time users. Crude and adjusted risk ratios showed little differences, despite large differences in the age structures of cases and non-cases by generation and in other variables. Furthermore, duration of use seemed not to have been adjusted for. We have shown the importance of previous exposure history and duration of use by use of a Cox's time-dependent regression model on a dataset of the transnational study, with additional information on lifetime use of oral contraceptives (hazard ratio of third vs second generation 0·79 [95% CI 0·50–1·26]).2Lewis MA MacRae KD Kuhl-Habich D Bruppacher R Heinemann LAJ Spitzer WO Transnational Research Group on Oral Contraception and the Health of Young WomenThe differential risk of oral contraceptives: the impact of full exposure history.Hum Reprod. 1999; 14: 1493-1499Crossref PubMed Scopus (79) Google Scholar For first-time users, taking into account duration of use, the hazard ratio is 1·23 (0·70–20·07). For previous users, the time-dependent model adjusts for full history of exposure, giving a hazard ratio of 0·64 (0·48–0·83). Our results do not support the suggestion that there is an increased risk of VTE in first-time users of third generation oral contraceptives compared with first-time users of second generation oral contraceptives. Data selection, small numbers of cases, and not taking into account duration of use are likely to outweigh the potential influences of changing prescribing patterns on the risk estimates.