THE INCREASED RISK OF VENOUS THROMBOEMBOLISM AND THE USE OF 3RD GENERATION PROGESTAGENS - ROLE OF BIAS IN OBSERVATIONAL RESEARCH

A matched case-control study was undertaken in 10 centers in Germany a nd the United Kingdom to explore the association of current use of maj or combination oral contraceptives with the occurrence of venous throm boembolism. The cases recruited were 505 women aged 16-44 years with v enous thromboembolism, controls were 1877 women (at least 3 controls p er case) matched for 5-year age group and region without VTE. The main outcome measures were odds ratios derived by comparing current use of a specific oral contraceptive or group of OC against current use of o ther groups or against no current use of OC. The odds ratios (95% conf idence intervals) for venous thromboembolism were: for third generatio n products (low dose ethinyloestradiol, gestodene and desogestrel) ver sus second generation products (low dose ethinyloestradiol, no gestode ne and desogestrel, 1.5 (1.1 to 2.0), for third versus second generati on products with norgestimate included in third generation, 1.6 (1.2 t o 2.2). The odds ratios for current use for women aged 16-44 of specif ic progastagens versus levonorgestrel-containing compounds were 1.7 (1 .1 to 2.6) for gestodene, 1.8 (1.2 to 2.6) for desogestrel, 1.9 (1.0 t o 3.6) for norgestimate and 1.3 (0.7 to 2.5) for progestagen-only pill s. For women aged 25 to 44 likely to be exposed to any of these proges tagens, odds ratios for the comparison of progestagens versus levonorg estrel showed a successive increase by market introduction ranging fro m 1.5 (0.9 to 2.5) for desogestrel with 30 pg oestrogen content (intro duced 1981) to 2.8 (1.3 to 6.5) for desogestrel with 20 mu g oestrogen content (introduced 1992) significant in linear trend analysis (p=0.0 0012). The influence of norgestimate classification as third or second generation product does not significantly alter the results regarding the association of third generation products and venous thromboemboli sm. A direct comparison of current use of norgestimate (which is prima rily metabolized to levonorgestrel) versus levonorgestrel shows an inc reased odds ratio. The trend of increasing risk of progestagens by rec ency of market introduction when compared with levonorgestrel is stron gly indicative of the existence of external bias due to attrition of s usceptibles.