In some studies third-generation oral contraceptives have been reported to be associated with a higher risk of venous thromboembolism than are second-generation oral contraceptives, whereas recent, more refined studies have not confirmed this. The reasons for the alleged differences are under discussion, and differential effects on hemostasis have been proposed. Eighteen studies comparing second- and third-generation oral contraceptives with respect to their effects on hemostasis were analyzed. Significant changes from baseline were reported for many variables with both second- and third-generation oral contraceptives without significant between-group differences. Also, in a combined analysis of nonsignificant changes, no consistent pattern of change emerged for any marker, with the exception of higher factor VII levels associated with third-generation oral contraceptives. However, factor VII is not related to venous thromboembolism risk. In addition, 1 cross-sectional study with an unvalidated assay reported a higher ratio of activated protein C sensitivity with third-generation oral contraceptives. Only 2 components of the hemostatic system (factor VII and activated protein C sensitivity ratio) emerged as potentially differentially affected by second- and third-generation oral contraceptives; the association with venous thromboembolism risk is questionable in the former case and unknown in the latter.
PIP: The initial finding of an increased risk of venous thromboembolism in users of third-generation oral contraceptives (OCs) has not been confirmed in recent, more methodologically refined studies. This article reviews 17 prospective studies with healthy volunteers and one cross-sectional study that compared second- and third-generation OCs in terms of their effects on markers of hemostasis. Significant changes from baseline were reported for many variables with both second- and third-generation OCs. For example, activated partial prothrombin clotting time, protein S, and tissue plasminogen activator and its inhibitor were reduced during OC treatment. However, none of the studies reported statistically significant differences between treatment groups for any of these markers. In a combined analysis of nonsignificant changes, no consistent pattern emerged for any coagulation or fibrinolysis parameter with the exception of higher factor VII levels (not related to venous thromboembolism risk) associated with third-generation formulations. The cross-sectional study with an unvalidated assay found a higher ratio of activated C protein sensitivity with third-generation OCs. Only two components of the hemostatic system--factor VII and activated protein C sensitivity ratio--emerged as potentially differentially affected by second- and third-generation OCs. The association with venous thromboembolism risk is questionable in the former cases and unknown in the latter.