Frequency of Pregnancy-Related Venous Thromboembolism in Anticoagulant Factor-Deficient Women: Implications for Prophylaxis

Deep venous thrombosis is an important, although relatively infrequent, problem during pregnancy and the postpartum period. Pulmonary embolism, a much-dreaded complication of deep venous thrombosis of the leg, is one of the most frequent causes of maternal illness and death [1, 2]. Among women in the general population between 20 and 40 years of age, the annual frequency of deep venous thrombosis is 1.8% [3]. In other observational studies [4-7], the frequency of venous thromboembolism has varied from 1.3% to 7% during pregnancy and from 6.1% to 23% during the postpartum period. These findings indicate that the risk for venous thromboembolism might be increased only moderately during pregnancy but that it is clearly enhanced during the postpartum period. However, the absolute frequencies during both of these periods remain low. In contrast, in women who have an inherited deficiency of a naturally occurring anticoagulant-antithrombin, protein C, or protein S-it has been reported that pregnancy and the postpartum period are associated with a greatly increased risk for venous thromboembolism [8-11]. During pregnancy, the observed frequency of venous thromboembolism per woman per pregnancy varied from 12% to 48% in antithrombin-deficient women and from 2% to 8% in protein C-deficient women; no thrombosis was seen in protein S-deficient women [8-11]. During the postpartum period, the following frequencies were seen: 28% to 47% in antithrombin-deficient women, 11% to 20% in protein C-deficient women, and 14% in protein S-deficient women [8-11]. However, the usefulness of these data for clinical decision making is limited because the studies that produced the data lacked appropriate control groups and included many patients who were identified because they presented with venous thrombosis, either associated with or unrelated to pregnancy. In addition, most of the identified thrombotic events were diagnosed on the basis of clinical findings only, which are known to be nonspecific, particularly during pregnancy [12]. Hence, the frequencies reported previously are likely to be overestimates. As a result, the best approach to anticoagulative prophylaxis for venous thromboembolism in anticoagulant factor-deficient women during pregnancy and the postpartum period is actively debated. Advocated regimens range from surveillance combined with noninvasive tests for deep venous thrombosis only to prophylaxis with therapeutic doses of heparin and oral anticoagulants throughout pregnancy and the postpartum period [13, 14] combined with intravenous administration of the lacking proteins. Also debated are the maternal and fetal adverse effects associated with the use of heparin and oral anticoagulants during pregnancy. The administration of coumarins during pregnancy may cause embryopathy [15], and the use of heparin has been associated with osteoporosis, which may result in bone fractures [16, 17]. Both of these drugs may also induce hemorrhagic complications, especially during delivery [15, 18]. Because the lack of accurate clinical data on the frequency of venous thromboembolism contributes to a wide variation in clinical practice regarding this event, physicians obviously need better information about the frequency of venous thromboembolism in anticoagulant factor-deficient women. We therefore sought to determine the frequency of venous thromboembolism during pregnancy and the postpartum period among otherwise asymptomatic women with a deficiency of antithrombin, protein C, or protein S. We investigated all female family members of probands known to have a deficiency of one of these factors and assessed the frequency of pregnancy-related venous thromboembolism in this group. The deficiency status of the female family members was determined only after a careful, structured history was obtained. The female family members found to be nondeficient were used as a representative control group. Methods Patients Female members of 69 families that had a documented deficiency of antithrombin, protein C, or protein S were investigated. The study participants were identified through the family trees of unselected patients who had an objective diagnosis of venous thromboembolism and were referred to the participating study centers (Academic Medical Center, Amsterdam, the Netherlands; Institute of Medical Semeiotics, Padua, Italy). These probands were excluded from further study. All of the women were interviewed by an investigator blinded to anticoagulant factor-deficiency status. A medical history, with attention to episodes of venous thromboembolism and to events in the obstetric history (such as pregnancy, childbirth, and postpartum periods), was obtained from each participant. An episode of venous thromboembolism was considered to have occurred only if it had been documented by objective tests (ultrasonography, impedance plethysmography, or venography for deep venous thrombosis; ventilation-perfusion lung scanning or pulmonary angiography for pulmonary embolism) or if it had been clinically diagnosed and the patient had been treated with anticoagulative drugs for at least 3 months. If a patient reported having had a venous thromboembolic event, further medical information was sought and reviewed by one of the investigators to establish the methods that had been used to diagnose the event. A venous thromboembolic event was considered to be pregnancy related if it occurred during pregnancy or within 3 months after childbirth. Episodes of pregnancy-related venous thromboembolism were classified according to the period in which they occurred: first trimester of pregnancy, second trimester of pregnancy, third trimester of pregnancy, puerperium ( 7 days after delivery), and the remaining postpartum period. If a patient had an episode of venous thromboembolism, all subsequent pregnancies were excluded from the analysis to avoid risk enhancement and because anticoagulative prophylaxis is often given after such an episode. After the history was recorded, blood samples were collected for the determination of anticoagulant factor status. Blood samples (20 mL) were collected by venipuncture with 21-gauge butterfly infusion sets into a plastic syringe containing 3.8% sodium citrate; the ratio of the volume of anticoagulant to the volume of blood was 0.1:0.9. Plateletpoor plasma was obtained by using centrifugation at 2000 g for 20 minutes and was stored at 80C until it was analyzed. Antithrombin antigen concentrations were measured using the Asseraplate Antithrombin III Kit (Boehringer Mannheim, Mannheim, Germany); antithrombin activity was measured using Berichrom ATIII (Behringwerke, Marburg, Germany). Protein C antigen concentrations were measured with enzyme-linked immunosorbent assay (ELISA) using rabbit anti-protein C polyclonal antibody (DAKO, Glostrup, Denmark) as catching antibody. Rabbit anti-protein C polyclonal horseradish peroxidase conjugated antibody (DAKO) was used as the second antibody according to the manufacturer's instructions. Protein C activity was measured using the Protein C Reagent Kit (Behringwerke). Concentrations of total and free protein S were measured by ELISA using rabbit anti-protein S polyclonal antibody (DAKO). The 15C4 anti-protein S monoclonal antibody (Serbio, Gennevilliers, France) was used as catching antibody, and the rabbit anti-protein S polyclonal horseradish peroxidase conjugated antibody (DAKO), diluted 1:1000, was used as the second antibody. The 15C4 anti-protein S monoclonal antibody recognized only free protein S antigen. Protein S activity was measured using the Protein S IL-Kit (Instrumentation Laboratories, Milan, Italy). A participant was considered to be deficient if repeated tests done 1 month apart showed values that were subnormal for the protein deficiency in that participant's family. The following reference values were used: antithrombin antigen concentration, 0.80 to 1.20 U/mL; antithrombin activity, 0.80 to 1.20 U/mL; protein C antigen concentration, 0.70 to 1.30 U/mL; protein C activity, 0.70 to 1.30 U/mL; total protein S concentration, 0.70 to 1.20 U/mL; and free protein S concentration, 0.26 to 1.08 U/mL. The criteria used to classify antithrombin, protein C, and protein S deficiencies accord with those reported in the current literature [19]. Activated partial thromboplastin time and prothrombin time were determined in an effort to exclude vitamin K deficiency. Activated partial thromboplastin time was measured by using ActinFS (Dade, Miami, Florida) (normal range, 25 to 36 seconds); prothrombin time was measured by using Thromboplastin IS (Dade) (normal range, 11 to 14 seconds). During the time of the laboratory investigation, none of the study participants were pregnant or in the postpartum period [20-23]. The participants were categorized according to deficiency status into a nondeficient group and a deficient group. The deficient group was further subdivided according to specific deficiency. Statistical Analysis In each group, the frequency of venous thromboembolism was calculated by dividing the number of pregnancy-related venous thromboembolic episodes by the total number of recorded pregnancies and by the total number of women. The percentages of deficient and nondeficient women who had thromboembolic episodes were compared using the Fisher exact test. Using a Cox model, we calculated the hazard ratio (and its mid-p corrected 95% CI) for pregnancy-related venous thromboembolism in deficient women compared with nondeficient women (SAS, Inc., version 6.11, Cary, North Carolina). The P values were calculated by using the exact log-rank test. For this purpose, a pregnancy was regarded as the unit of time and women who had not had a venous thromboembolic event by the end of their last pregnancy were considered to be censored. Results Of the female members of the 69 families, 282 women were potentially eligible for the study. Of these, 52 could not be contacted because they lived