During pregnancy, women have a fivefold increased risk of venous thromboembolism (VTE), compared with nonpregnant women. The absolute risk of symptomatic venous thrombosis during pregnancy is between 0.5 and 3.0 per 1,000 women based on studies using radiographic documentation .Pulmonary embolism (PE) is a leading cause of maternal death in the United States .The prevalence and severity of this condition warrant consideration of anticoagulant therapy in pregnancy for women at risk for VTE. Such therapy includes the treatment of acute thrombotic events, prophylaxis for patients with a history of thrombotic events or identified acquired or congenital thrombophilias, and prevention and treatment of systemic embolization in women with valvular heart disease. The purpose of this document is to review the current literature on the prevention and management of thromboembolism in obstetric patients, discuss the data behind sometimes conflicting guidelines from expert panels, and offer evidence-based recommendations to address the most clinically relevant issues in the management of these patients.
Numerous changes in the coagulation system account for the hypercoagulable state associated with pregnancy .Recently, it has been recognized that up to half of women who have thrombotic events during pregnancy possess an underlying congenital or acquired thrombophilia .The most common thrombophilias in the Caucasian population are the factor V Leiden mutation, which has a prevalence of 5% in this population, and the prothrombin gene mutation G20210A, which has a prevalence of 2% in this population .In approximately 50% of patients with a hereditary thrombophilia, the initial thrombotic event occurs in the presence of an additional risk factor such as pregnancy, oral contraceptive use, orthopedic trauma, immobilization, or surgery .
Pregnancy-Associated Changes in Coagulation
Increases in clotting factors (I, VII, VIII, IX, X)
Decreases in protein S
Decreases in fibrinolytic activity
Increased venous stasis
Vascular injury associated with delivery
Increased activation of platelets
Resistance to activated protein C
Risk of Thromboembolism During Pregnancy
Traditionally, it was believed that the risk of venous thrombosis was greatest in the third trimester and immediately postpartum. More recent studies using objective criteria for diagnosis have found that antepartum deep vein thrombosis (DVT) is at least as common as postpartum thrombosis and occurs with equal frequency in all three trimesters .However, PE is more common postpartum.
Women with a history of thromboembolism have an increased risk of recurrence when they become pregnant; however, the estimates of recurrence are based primarily on two retrospective studies and range from 7.5% to 12% .No studies differentiated the risk of recurrence based on underlying factors such as acquired or congenital thrombophilias, use of oral contraceptives, pregnancy, orthopedic trauma, recent surgery, or the occurrence of the event in the antepartum versus postpartum period. Most of the estimates of recurrence are based on women who had their initial event during oral contraceptive use or pregnancy. Risk factors for thromboembolic disorders are noted in the box.
Risk Factors for Deep Vein Thrombosis and Thromboembolic Disorders
Hereditary Thrombophilia (prevalence in general population) Factor V Leiden mutation (5-9%)* AT-III deficiency (0.02-0.2%) Protein C deficiency (0.2-0.5%) Protein S deficiency (0.08%) Hyperhomocystinemia (1-11%) Prothrombin gene mutation (2-4%) Prior history of deep vein thrombosis Mechanical heart valve Atrial fibrillation Trauma/prolonged immobilization/major surgery Other familialhypercoagulable states Antiphospholipid syndrome
*For African Americans, about 1%; for Caucasians, 6-11%. Data from Lockwood CJ. Heritable coagulopathies in pregnancy. Obstet Gynecol Surv 1999;54:754-765
Anticoagulation Medications in Pregnancy
Although many terms have been used to classify anticoagulant regimens, the following terminology will be used in this document:
Low-dose prophylaxis-a fixed dose of anticoagulant given 1-2 times per day without use of routine monitoring to verify a therapeutic prolongation of the activated partial thromboplastin time (APTT).
Adjusted-dose prophylaxis-anticoagulant administered for prophylaxis to achieve traditional therapeutic effects, given 2-3 times per day with frequent laboratory testing to verify adequate APTT prolongation of at least 1.5 to 2.5.
There is considerable clinical experience with heparin use in pregnancy .Heparin requirements appear to increase during pregnancy because of increases in heparin-binding proteins, plasma volume, renal clearance, and heparin degradation by the placenta, which reduces the bioavailability of heparin .There are no prospective trials that have determined adequate prophylactic doses in pregnancy. The major concerns with heparin use during pregnancy are not fetal but maternal and include heparin-induced osteoporosis and heparin-induced thrombocytopenia (HIT).
Two prospective trials of pregnant women exposed to heparin confirmed a mean bone loss of 5% ,with approximately one third sustaining a 10% or greater decrease in bone density . The complete reversibility of this process has not been clearly established, nor does there appear to be a clear dose-response relationship .In selected patients, such as those who have a strong family history of osteoporosis or are smokers, postpartum evaluation of bone density may have prognostic and therapeutic implications .
There are two types of heparin-induced thrombocytopenia. The more common type is the benign, reversible nonimmune form, which occurs in patients within the first few days of therapy and typically resolves by 5 days. This condition does not require cessation of heparin therapy. The less common but more severe type is the immune form of HIT, which occurs within 5-14 days of full-dose heparin therapy in as many as 3% of patients and may result in widespread thrombosis .The occurrence of autoimmune thrombocytopenia from prophylactic doses of heparin has been reported, but is rare. Deep vein thrombosis and PE are the most frequent clinical presentations of the immune form of HIT. It has been recommended, therefore, that platelet counts be checked on day 5 and then periodically for the first 2 weeks of heparin therapy. If the HIT is severe, heparin therapy must be stopped and alternative anticoagulation therapy initiated; low-molecular-weight heparin (LMWH) may not be a safe alternative because it has a low cross reactivity with heparin. In such situations, consultation with someone with expertise in the field may be needed .
Low-Molecular-Weight HeparinLow-molecular-weight heparin may reduce three of the complications caused by standard heparin: bleeding, osteoporosis, and thrombocytopenia. However, virtually all data on LMWH come from nonpregnant patients. It has been conclusively demonstrated that LMWH does not cross the placenta into the fetal circulation . Although the bioavailability of LMWH should be improved over standard heparin because of the reduction of heparin binding, the increases in renal clearance and volume of distribution of the drug may necessitate dosage increases in pregnancy . Another advantage of LMWH is that dosing can be limited to once or twice daily . If laboratory monitoring is used, monitoring peak antifactor Xa levels every 4-6 weeks should be utilized particularly when twice daily dosing is given. The APTT does not correlate well with the anticoagulant effect of LMWH.
WarfarinWarfarin derivatives cross the placenta and in most cases are relatively contraindicated in pregnancy; therefore, they primarily are used postpartum or in patients with certain types of mechanical heart valves . War-farin use should be restricted to the second or early third trimester in selected patients in whom prolonged high-dose heparin therapy is relatively contraindicated. A skeletal embryopathy resulting in stippled epiphyses and nasal and limb hypoplasia can occur when warfarin is given between 6 and 12 weeks of gestation . Midtrimester exposure may result in optic atrophy, microcephaly, and developmental delay. Bleeding can occur in the fetus at any time, resulting in a high fetal loss rate .