Third-generation oral contraceptive and deep venous thrombosis: From epidemiologic controversy to new insight in coagulation

Four epidemiologic studies showed a twofold increase in risk of deep venous thrombosis with the use of oral contraceptives containing third-generation progestins, relative to second-generation products. These findings have been strongly debated ever since, and new studies have been added. In the current article we examine whether the findings can be explained by potential biases or other shortcomings of the epidemiologic studies. We conclude that complete certainty cannot exist but that the most rational conclusion from the epidemiologic findings and their discussion is that an increased risk of deep venous thrombosis with third-generation contraceptives is likely, especially in first-time and young users. The controversy has recently led to new insights in coagulation: Women who use third-generation contraceptives acquire a resistance to the blood's own anticoagulation system, similar to the activated protein C resistance that is seen in persons who carry the factor V Leiden mutation but different from that in women using second-generation contraceptives.