Oral contraceptives and cardiovascular outcomes: cause or bias?

The 1995-1996 "pill" scare, which suggested that third-generation oral contraceptives (OCs) were associated with a greater risk of venous thromboembolism (VTE) than second-generation OCs, had serious social and public health consequences, as women discontinued OCs, resulting in unwanted pregnancies and unnecessary abortions. This article uses the Bradford Hill criteria, for diagnosing causality from an observed association, to interpret evidence from recent studies as to whether there is any difference in the risk of VTE between third- and second-generation OCs. Bias and the influence of confounders have also been examined in relation to the difference in the risk of VTE between third- and second-generation OCs reported in the 1995-1996 studies. It is clear from the results of this analysis that none of the Bradford Hill criteria are fulfilled. Thus, a causal relationship cannot be inferred from the alleged association of third-generation OCs with VTE. Indeed, it would appear that the unavoidable bias in observational research is a more likely explanation for the apparent difference in the risk of VTE between third- and second-generation OCs in the 1995-1996 studies. Recent studies, which employed more appropriate controls for these biases showed no difference in the risk of VTE between third- and second-generation OCs. A Danish study (1994-1996) demonstrated a lower risk of thrombotic morbidity and mortality with third-generation OCs compared with second-generation OCs. In addition, the Transnational study has shown that third-generation OCs have a significantly lower relative risk (0.3 [0.1-0.9]) for acute myocardial infarction (MI) compared with second-generation products. In conclusion, there is no convincing evidence for a difference in the risk of stroke or VTE between third- and second-generation OCs. Moreover, third-generation OCs may be associated with a lower risk of MI than second-generation OCs.