The current confusion about the clinical management of thromboembolic disease during pregnancy reflects our incomplete understanding of the molecular biology and natural history of coagulation during gestation. The discovery that vasoprotective and thromboresistant molecules are membrane constituents synthesized by endothelial cells points to the enormous surface area of the vascular endothelium as an important territory still to be explored [2, 3].

Understanding the epidemiology of thromboembolic disease during pregnancy is also made difficult by inadequate definition of clinically important events and their time course. What do we know and not know about this vexing clinical area? We know that superficial phlebitis is a common nuisance that almost never progresses to deep venous disease during gestation or the postpartum period. Deep venous thrombophlebitis is a relatively infrequent complication of pregnancy, but pulmonary embolism as a complication of deep venous thrombosis is one of the most frequent causes of maternal illness and death. The converse, however, is not true: That is, it is inaccurate to conclude that serious thromboembolic disease during pregnancy is common.

Chronic underlying venous disease predisposes all patients, pregnant or not, to thromboembolic events. Unfortunately, clinical studies of thromboembolism in pregnancy have not consistently stratified patients according to the presence and severity of chronic venous disease and thrombodiathesis before pregnancy [4]. Venous thromboembolic events occur throughout gestation and are evenly distributed among all trimesters [5]. Delivery, especially that done by cesarean section, precipitates a substantial increase in the occurrence of thromboembolic events. For epidemiologic purposes, it is useful to assign pregnancy-related thromboembolic events to either the gestational or the puerperal category on the basis of their patterns of occurrence [6]. The incidence of pulmonary embolism is proportional to the incidence of venous thrombosis and thrombophlebitis during gestation and the puerperium.

We can now also identify some groups of women with a genetic predisposition to thromboembolism for whom pregnancy is an additional risk factor. This genetic predisposition may be clinically silent in an individual patient before pregnancy, but it is not necessarily silent in her family. This means that the results of almost all of the previous studies of thromboembolism in pregnancy in which patients were not stratified according to the propensity for thromboembolic events must be interpreted with caution. Friederich and colleagues, in this issue [7], therefore provide important clinical data about the natural history of thromboembolism during pregnancy in women with clinically silent deficiency of antithrombin, protein C, and protein S. As expected, their study showed that the risk for deep venous thromboembolic events was increased and that a higher incidence was seen during the puerperium, but the risk was not as high as other estimates have been.

Friederich and colleagues [7] studied 69 families with antithrombin, protein C, or protein S deficiency. Among these families, 129 women had each had at least one pregnancy and a total of 367 pregnancies had occurred before a thromboembolic event occurred. Of the 129 women studied, 69 were nondeficient and 60 were deficient. Among the 198 pregnancies that had occurred in the nondeficient group, one had been complicated by venous thromboembolism. Among the 169 pregnancies that had occurred in the deficient group, seven episodes of venous thromboembolism had been seen-two during the third trimester of gestation and 5 in the immediate postpartum period.

One difference between the study by Friederich and colleagues and other studies of thrombophilic conditions and pregnancy is the focus by the former on "asymptomatic" women, excluding women who had already presented with a thromboembolic event in relation to pregnancy. Similar data need to be gathered from women with other thrombophilic conditions, such as the lupus anticoagulant syndrome and the factor V Leiden mutation.

Despite progress in our understanding of coagulation and vascular physiology in pregnancy, the clinician's conundrums about the management of risk for thromboembolic events in pregnant women have not been fully resolved. Among the more important questions still to be answered are the following.

1. Should all women entering reproductive life be screened for congenital or acquired thrombophilic conditions?

The relatively low overall incidence of thromboembolic events during pregnancy makes it extravagant to use laboratory testing to screen all women or even all newly pregnant women for antiphospholipid antibodies, antithrombin III, protein S, protein C, and the factor V Leiden mutation. A careful family and personal medical history with an emphasis on thromboembolic events seems to be a more cost-effective and clinically useful screening method. Laboratory evaluation should be reserved for women suspected of having thrombophilia.

2. What are the risk factors for thromboembolic events during pregnancy? Are these risk factors identical in terms of management?

Patients who have an active thrombogenic diathesis, such as the lupus anticoagulant syndrome or the postphlebitic syndrome, are managed with anticoagulative therapy throughout gestation and the puerperium. Most internists and obstetricians would administer anticoagulative prophylaxis to women who had previously had thromboembolic events and who have an identifiable risk factor for thromboembolic events throughout pregnancy. There is room for debate about the need for anticoagulative prophylaxis throughout gestation in women who are at risk for but have not previously had a thromboembolic event. Differences in practice reflect, among other things, differences between practices in Europe and North America. Even a modest increase in risk for thromboembolism would provoke the use of anticoagulative prophylaxis throughout pregnancy in the litigious United States, whereas Friederich and colleagues recommend beginning anticoagulative therapy in the third trimester. No one would contest the need to give anticoagulative prophylaxis to at-risk patients during the puerperium.

3. Which anticoagulants should be used, and at what dose?

It is widely agreed that heparin and the newer low-molecular-weight heparin preparations are preferable during gestation and the puerperium. Information about heparin dosing during gestation is sparse. The situation during the postpartum period is dramatically different, and laboratory confirmation of adequate anticoagulation is needed for women during this period, just as it is for patients who are not pregnant. Some centers [8] adjust heparin dosing during gestation according to the results of assays for the inhibition of factor Xa by heparin-activated antithrombin III or protamine sulfate neutralization, aiming for 0.2 to 0.4 U/mL to treat established thromboembolism and for 0.05 to 0.25 U/mL for prophylaxis, at mid-interval or trough timing. There is, however, justifiable concern about treating patients according to laboratory test results rather than clinical outcomes, and no large studies correlating the clinical outcome of prophylaxis with heparin assay results have yet been done. The natural history of coagulation during gestation suggests that even a small amount of coagulation inhibition could provide effective prophylaxis.

Among women who have deficiencies of various thrombopreventive factors or who have other thrombophilic conditions, gestational thromboembolic events are unusual but are clearly more common than in normal women. In the study by Friederich and colleagues [7], only 4.1% of pregnancies in asymptomatic women who were deficient in protein S, protein C, or antithrombin were complicated by deep venous thromboembolism. Unexplained thrombopreventive and vasoprotective effects of gestation seem to override thrombogenic diathesis in most women.

In short, we know enough to make reasonable decisions about the management of thromboembolic risk associated with pregnancy. But much remains to be learned about both the risk factors and procoagulant mechanisms for thrombosis and the natural anticoagulant state induced by pregnancy.