Combined oral contraceptives and the risk of venous thromboembolism carriers of antithrombin, protein C or S deficiency: Sub-analysis of a prospective cohort study

Antithrombin, protein C and S defects are well-recognized inherited risk factors for venous thromboembolism (VTE). Although these defects have been reported to increase the risk of VTE in fertile women under combined oral contraceptives (COCs), the magnitude of this association is uncertain. In a sub-analysis of a prospective cohort study, we evaluated the incidence of VTE occurring during treatment with COCs in fertile women who were family members of a proband with an objectively diagnosed VTE event and a documented defect of antithrombin, protein C or S. Of the 197 women of child-bearing age from 88 families who qualified for this analysis in a 17-year period, 112 (57%) were carriers of an inherited defect (23 antithrombin, 41 protein C and 48 protein S), whereas the remaining 85 were free from these abnormalities. Estrogen-progestin therapy was used by 19 of the 112 (17%) carriers of inherited thrombophilia for an overall period of 276 months, and by 17 of the 85 (20%) non-carriers for an overall period of 992 months. VTE events developed in 12 of the 19 (63%) carriers, leading to a monthly event rate of 4.3% (95% CI: 2.2 to 7.6), and in 2 of the 17 (12%) non-carriers, leading to a monthly rate of 0.2% (95% CI: 0.02 to 0.7), for a relative risk of 21 (95% CI, 4.7 to 92). Among family members of probands with inherited defects of antithrombin, protein C or S defects, the use of estrogen-progestin therapy in carriers of these abnormalities results in a risk of VTE events that is more than 20 times as high as that expected in non-carriers. Accordingly, the systematic screening for thrombophilia in these families has the potential to identify those subjects in whom this kind of hormonal treatment should be strongly discouraged.