Prothrombin and Factor V Mutations in Women With a History of Thrombosis During Pregnancy and the Puerperium

Although venous thromboembolism remains a prominent cause of illness and death during and after pregnancy, the role of genetic abnormalities remains incompletely understood. This study measured antithrombin, protein C, protein S, and lupus anticoagulant in 119 women with a history of thromboembolism during pregnancy or the puerperium and in 233 age-matched women without a history of thromboembolism (control subjects). In addition, genetic analyses were performed detect the factor V Leiden mutation (G1691A mutation in the factor V gene), the G20210A mutation in the prothrombin gene, and the C677T mutation in the gene for methylenetetrahydrofolate reductase. The factor V Leiden mutation is found in 20 percent of patients with initial venous thrombosis and in as many as half of those with recurrences. The other mutations are both associated with an increased risk of venous thrombosis. About half of the study group had deep venous thromboembolism during pregnancy, most often during the third trimester, and the rest were affected during the postpartum period. The factor V Leiden mutation was identified significantly more often in women with a history of thromboembolism than in the control group. The same was true for the prothrombin gene mutation, and both mutations were found in 9.3 percent of the study group. None of the control women had this combination of mutations. The prevalence of deficient antithrombin, protein C, or protein S was 25 percent in the study group and 11 percent in the control group. Antithrombin deficiency was documented in nearly one in five women with a history of thromboembolism. On logistic regression analysis, the only independent risk factors predicting thrombosis in women with a history of thromboembolism were antithrombin deficiency and the factor V Leiden and G20210A mutations. Women with recurrent thromboembolism were significantly more likely to have combined genetic effects than those having a first episode. Assuming an overall risk of 1 in 1500 pregnancies, the estimated risk of thrombosis was 0.2 percent for carriers of the factor V Leiden mutation, 0.5 percent for carriers of the prothrombin gene mutation, and 4.6 percent for those carrying both defects. The factor V Leiden mutation and other inherited markers of thrombotic risk have low predictive value in pregnant women. Only women with both the factor V Leiden and prothrombin gene mutations have a significant risk of venous thromboembolism. N Engl J Med 2000;342:374–380