Venous thromboembolism in pregnancy: Prevention

INTRODUCTION — Pregnancy and the puerperium are well-established risk factors for deep vein thrombosis and pulmonary embolism, which are collectively referred to as venous thromboembolic (VTE) disease. The need for thromboprophylaxis should be assessed antepartum, postpartum, and at any time the patient transitions from the outpatient to inpatient setting. When it is determined that thromboprophylaxis is warranted, an appropriate strategy should be selected and prescribed.

Thromboprophylaxis can be pharmacologic (ie, anticoagulation) or mechanical (eg, intermittent pneumatic compression devices or graduated compression stockings). Indications, method, and duration of thromboprophylaxis in pregnant women are the major focuses of this topic. Issues concerning the use of anticoagulants during pregnancy and prevention of VTE in medical, surgical, and gynecologic patients are discussed separately. (See "Use of anticoagulants during pregnancy and postpartum" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

The management set out in this topic is, for the most part, in keeping with the American Society of Hematology [1].

RATIONALE — Pregnancy and the puerperium are risk factors for the development of venous thromboembolism (VTE). This risk is thought to be due to venous stasis of the lower extremities, endothelial injury, and the hypercoagulable state that occurs during pregnancy. The incidence of VTE is increased throughout all trimesters of pregnancy but is highest during the postpartum period. Factors that may further augment the risk include a prior history of VTE, hospitalization for an acute illness or cesarean delivery, and presence of an inherited thrombophilia (eg, factor V Leiden mutation; prothrombin gene mutation; or antithrombin III, protein C, or protein S deficiencies). (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis".)

INDICATIONS — Although pregnancy and the puerperium are risk factors for the development of venous thromboembolism (VTE), the vast majority of pregnant women do not require thromboprophylaxis. However, thromboprophylaxis is typically targeted at those who are considered to be at greatest risk for the development of VTE during the antepartum and postpartum periods. The indications for thromboprophylaxis in this particular population of patients are discussed in this section.

Outpatient thromboprophylaxis — The indications for thromboprophylaxis differ for antepartum and postpartum women.

Antepartum — All antepartum women should be subjected to vigilant clinical surveillance throughout pregnancy for signs and symptoms of VTE. Pharmacologic thromboprophylaxis can be administered to a select population of antepartum women considered at high risk for VTE. Our approach is, in general, consistent with the 2012 American College of Chest Physicians (ACCP) and 2013 American College of Obstetricians and Gynecologists (ACOG) and the American Society of Hematology guidelines on the selection criteria for antepartum pharmacologic thromboprophylaxis during pregnancy [1-3]. In each case, the decision to administer antepartum pharmacologic thromboprophylaxis should carefully weigh the benefits of VTE prevention against the risks of bleeding and fetal complications.

Data are insufficient to support routine outpatient pharmacologic thromboprophylaxis for most pregnant women. Pharmacologic prophylaxis may be considered in patients with a history of a single idiopathic, pregnancy-associated or estrogen-associated VTE, and in those with a history of multiple VTEs, regardless of the cause. Pharmacologic prophylaxis is also considered for patients with a known thrombophilia and in those with persistent risk factors and a prior history of VTE. The use of pharmacologic prophylaxis in pregnant patients with a known thrombophilia is discussed in more detail separately. (See "Inherited thrombophilias in pregnancy" and "Screening for inherited thrombophilia in asymptomatic adults".)

The evidence to support pharmacologic thromboprophylaxis in the indicated populations is mostly indirect and largely based upon small retrospective studies of thromboprophylaxis in high-risk populations, one large randomized trial that compared high with low-dose heparin, and our clinical experience [2-11]. Nonetheless, studies consistently report the highest incidence of VTE in those with high-risk variants of inherited thrombophilia (see "Inherited thrombophilias in pregnancy") and persistent risk factors in those with a prior history of VTE. Pregnant women who have had a prior VTE related to a high estrogen state (eg, prior pregnancy or estrogen-related VTE) are considered candidates for thromboprophylaxis because these risk factors are likely to increase the chances of recurrent VTE during pregnancy. Optimal dosing is discussed separately. (See 'Pharmacologic prophylaxis' below and "Use of anticoagulants during pregnancy and postpartum".)

In contrast, for those women in whom a transient risk factor for prior VTE (eg, trauma, immobility, surgery) is identified, the likelihood of recurrence is presumed to be lower. Thus, clinical surveillance is preferred over pharmacologic thromboprophylaxis for those without persistent risk factors, unless multiple VTEs have occurred. (See "Overview of the causes of venous thrombosis".)

Women who are already receiving anticoagulant therapy should have the need for ongoing therapeutic anticoagulation reassessed at the beginning of the pregnancy. If it is determined that therapeutic anticoagulation is necessary, women who are receiving oral anticoagulation (a direct thrombin inhibitor, a factor Xa inhibitor, or warfarin) should have their anticoagulant regimen converted to a heparin-based regimen. The timing of this conversion is discussed in more detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Switching from oral anticoagulants to LMW heparin'.)

The choice of regimen and duration of prophylaxis are discussed separately. (See 'Administration' below.)

Postpartum — All postpartum women should be subjected to vigilant clinical surveillance for signs and symptoms of VTE. Pharmacologic thromboprophylaxis can be administered to a select population of postpartum women considered at high risk for VTE. We agree with the 2012 ACCP and 2013 ACOG guidelines on the selection criteria for pharmacologic thromboprophylaxis for postpartum women [2,3]. The decision to administer postpartum pharmacologic thromboprophylaxis should be individualized for each patient, with careful assessment of the benefits and harms.

Data are insufficient to support routine outpatient pharmacologic thromboprophylaxis for most women in the postpartum period. Pharmacologic prophylaxis may be considered in patients with a history of prior VTE (single or multiple) regardless of the provoking factor (transient or persistent, inherited thrombophilia) and in a subset of patients with inherited thrombophilia without a personal or family history of VTE. The use of pharmacologic prophylaxis in patients with a known thrombophilia is discussed in more detail separately. (See "Inherited thrombophilias in pregnancy" and "Screening for inherited thrombophilia in asymptomatic adults".)

The rationale for the use of thromboprophylaxis in the postpartum period is similar to that provided for the antepartum period [2-9,12]. However, the threshold for anticoagulation is lowered in the postpartum setting, largely because the risk of VTE is increased and the potential for the more serious adverse effects of anticoagulation, including placental hemorrhage, spinal hematoma, and fetal hemorrhage, is no longer a consideration. Compared with the antepartum period, VTE, especially pulmonary embolism, is two to five times more common in the puerperium, with some epidemiologic evidence suggesting persistent risk for six weeks beyond delivery [12-17]. (See "Inherited thrombophilias in pregnancy", section on 'Prevention of VTE' and "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis".)

The choice of regimen and duration of prophylaxis are discussed separately. (See 'Administration' below.)

Inpatient thromboprophylaxis — Based on data from the National Inpatient Sample database, the risk of pulmonary embolism is low in women hospitalized for pregnancy-related reasons during pregnancy, labor, or the puerperium (0.02 percent of more than 37 million admissions between 2007 and 2015) [18].

Antepartum admission — There are insufficient data to support the routine use of thromboprophylaxis for every woman hospitalized during pregnancy or postpartum. Women who are candidates for outpatient pharmacologic thromboprophylaxis are also candidates for prophylaxis as an inpatient. Select women who do not meet the criteria for outpatient thromboprophylaxis may benefit from thromboprophylaxis during an acute hospitalization. A decision regarding the use of pharmacologic thromboprophylaxis in this setting must be made on an individual basis, with careful assessment of the risk of VTE and the potential harms of anticoagulation. (See 'Outpatient thromboprophylaxis' above.)

Examples of women who may be considered at moderate to high risk for VTE during hospitalization include those admitted for medical or surgical reasons (eg, pneumonia, sepsis, orthopedic injury), patients on prolonged bedrest (>3 days), and those with additional or multiple accepted risk factors for VTE during pregnancy (eg, obesity, older maternal age, critical illness, malignancy, ovarian hyperstimulation, multiparity) [19].

The risk of bleeding with pharmacologic prophylaxis is increased in patients with serious or severe bleeding unrelated to pregnancy, those at risk of severe bleeding because of imminent vaginal or cesarean delivery, or those at risk of serious or severe bleeding due to antepartum complications (eg, placental abruption, placenta previa, expanding subchorionic hematoma).

The optimal method of thromboprophylaxis in hospitalized women is not known. Options include early ambulation, mechanical methods, and/or pharmacologic agents. The benefits of each form of thromboprophylaxis should be carefully weighed against the risks and individualized to each hospitalized patient.

Indirect support for the use of thromboprophylaxis in hospitalized pregnant women is provided by the known increased risk of VTE during pregnancy, together with the established risk of VTE during hospitalization for nonpregnant patients [20]. The risk of VTE in pregnant women hospitalized for non-delivery reasons was examined in an analysis of a national database of over 200,000 women aged 15 to 44 years who had one or more pregnancies from 1997 to 2010 [21]. Admission to the hospital for non-delivery reasons was associated with a risk of VTE that was 18-fold higher during hospitalization (absolute rate 1752 per 100,000 person years) and sixfold higher for the 28 days after discharge (676 per 100,000 person years) when compared with other times spent outside of the hospital. The highest rates were observed in those pregnant with a body mass index >30 kg/m², maternal age >35 years, an admission during the third trimester, and a hospital stay >3 days. This study suggests that the risk of VTE in hospitalized pregnant women is similar to that of high-risk hospitalized patients in the general population in whom thromboprophylaxis is frequently prescribed. Further study is needed to elucidate the efficacy and safety of mechanical or pharmacologic thromboprophylaxis in antepartum hospitalized patients. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

The duration of prophylaxis is discussed separately. (See 'Administration' below.)

Cesarean section — Cesarean section (CS) is associated with an increased risk of VTE, especially when performed emergently. Despite an increase in relative risk, the absolute increase in VTE incidence is thought to be low. Observational data suggest that the risk for clinically important events is similar to that seen in low-risk surgical patients for whom no routine thromboprophylaxis other than early ambulation is recommended [22]. As such, we and others prefer early ambulation and/or mechanical devices (eg, intermittent pneumatic compression) in those patients who undergo a CS who do not have any additional risk factors for VTE [2,3]. The addition of pharmacologic prophylaxis after CS is frequently considered for women with additional or multiple risk factors [2,3]. Guideline recommendations from the ACCP and the ACOG for VTE prevention in the patient who undergoes a CS are discussed in detail separately. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Thromboembolism prophylaxis'.)

ADMINISTRATION

Pharmacologic prophylaxis — In contrast with anticoagulation of nonpregnant women, the choice of anticoagulant during pregnancy needs to take into account fetal safety and maternal peripartum issues (eg, unpredictable onset of labor, use of neuraxial anesthesia for management of labor pain). Heparins are used for most pregnant women because they do not cross the placenta and do not anticoagulate the fetus. Low molecular weight (LMW) heparin-based regimens are generally preferred. Unfractionated heparin is preferred over LMW heparin in patients with severe renal insufficiency (eg, creatinine clearance <30 mL/min) because LMW heparin metabolism is exclusively renal, while metabolism of unfractionated heparin is renal and hepatic.

Heparins can be administered during pregnancy at different doses depending on the risk of thromboembolism and desired degree of anticoagulation (table 1). In general, the following terms apply (see "Use of anticoagulants during pregnancy and postpartum"):

●Prophylactic-dose anticoagulation refers to the use of low doses of anticoagulants (eg, enoxaparin 40 mg subcutaneously once daily in patients with weight <100 kg), which aims to reduce the risk of thromboembolism while minimizing bleeding complications.

●Intermediate-dose anticoagulation refers to the adjustment of prophylactic-dose anticoagulation with weight gain during pregnancy. While we prefer enoxaparin 40 mg twice daily as recommended by the American College of Physicians [2] and American College of Gynecologists [3], some experts start at 40 mg once daily and slowly increase the dose over the course of the pregnancy to enoxaparin at 1 mg/kg.

●Therapeutic-dose anticoagulation refers to the use of anticoagulants at doses typically reserved for treatment of thromboembolic disease (eg, enoxaparin 1 mg/kg subcutaneously twice daily). Despite the nomenclature, therapeutic dosing may be used prophylactically (ie, to prevent thromboembolism).

When LMW heparin is administered for venous thromboembolism prophylaxis in a patient without a thrombophilia, prophylactic or intermediate doses are used. Therapeutic dosing is used when prophylactic or intermediate dosing is thought to be insufficient for thromboembolism prophylaxis in some patients at very high risk of thromboembolism.

The administration of prophylactic, intermediate, and therapeutic heparin during pregnancy is discussed in more detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Dosing and laboratory monitoring'.)

Mechanical prophylaxis — The efficacy of mechanical thromboprophylaxis (eg, frequent left-lateral decubitus positioning during late pregnancy, graduated elastic compression stockings, and pneumatic compression devices) during pregnancy or the puerperium is unknown because there is a paucity of evidence. In a study of 10 pregnant women, venous Doppler ultrasound demonstrated that graduated compression stockings increased femoral vein flow velocity during late pregnancy [23]. Nonetheless, the use of mechanical prophylaxis following cesarean section and for hospitalized women during pregnancy is considered safe and is discussed above. (See 'Inpatient thromboprophylaxis' above.)

DURATION — Outpatient antepartum pharmacologic thromboprophylaxis should be continued through the pregnancy [2,24]. Management of anticoagulation in the final weeks of pregnancy and discontinuation for labor are discussed in more detail separately. (See "Use of anticoagulants during pregnancy and postpartum".)

The optimal duration of outpatient postpartum thromboprophylaxis is unknown. On the basis of clinical experience and estimated risk, we agree with the 2012 American College of Chest Physicians clinical practice guidelines that suggest at least six weeks postpartum, with consideration for a longer duration of up to three months, particularly in those at greatest risk (eg, persistent risk factors for thrombosis) [2].

When thromboprophylaxis is administered during hospitalization (eg, acute illness or cesarean section [CS]), it should continue until the patient is ambulatory, provided that there is no indication for outpatient thromboprophylaxis. Extended prophylaxis (ie, after discharge) is considered by some clinicians to be beneficial in select circumstances (eg, patient with a CS who is assessed to be at very high risk or who has multiple persistent additional risk factors for venous thromboembolism) [2]. (See "Cesarean birth: Preoperative planning and patient preparation", section on 'Thromboembolism prophylaxis'.)

The initiation, timing, and transition of thromboprophylaxis during pregnancy, labor, and delivery as well as during lactation are discussed separately. (See "Use of anticoagulants during pregnancy and postpartum".)

COMPLICATIONS — Heparin has several side effects, including bleeding, thrombocytopenia (with or without associated thrombosis), and osteoporosis. These adverse effects can occur even at prophylactic doses and are more likely with long-term use. Complications of anticoagulants are discussed elsewhere. (See "Venous thromboembolism in pregnancy and postpartum: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism" and "Society guideline links: Anticoagulation in pregnancy".)

SUMMARY AND RECOMMENDATIONS

●Rationale – The risk of venous thromboembolism (VTE) is increased in all trimesters of pregnancy, especially the postpartum period. Although most women do not require thromboprophylaxis, those who are considered to be at greatest risk are generally targeted for VTE prevention. (See 'Rationale' above.)

●Outpatient antepartum – For most non-hospitalized pregnant women, we suggest observation rather than pharmacologic prophylaxis for VTE (Grade 2C). We suggest antepartum pharmacologic prophylaxis for patients with a history of a single idiopathic, pregnancy-associated or estrogen-associated VTE, and in those with a history of multiple VTEs, regardless of the cause (Grade 2C). Pharmacologic prophylaxis is also considered for patients with a known thrombophilia and a history of VTE and for patients with certain "high-risk" thrombophilias plus a family history of VTE. (See 'Antepartum' above.)

●Outpatient postpartum – For most postpartum women, we suggest observation rather than pharmacologic prophylaxis for VTE (Grade 2C). We suggest postpartum pharmacologic prophylaxis in patients with a history of prior VTE (single or multiple) regardless of the provoking factor (transient or persistent, inherited thrombophilia) and in a subset of patients with inherited thrombophilia without a personal history of VTE (Grade 2C). (See 'Postpartum' above.)

●Inpatient antepartum – For most pregnant women who are hospitalized antenatally for non-delivery reasons, we use the same criteria for pharmacologic thromboprophylaxis as we do in the outpatient setting. Select women who do not meet the criteria for outpatient thromboprophylaxis may benefit from thromboprophylaxis during an acute hospitalization. (See 'Antepartum admission' above.)

●Cesarean section (CS) – For women who undergo a CS and have no additional risk factors for VTE, we suggest early ambulation or the use of mechanical devices rather than pharmacologic thromboprophylaxis (Grade 2C). For women who undergo a CS and have additional risk factors for VTE, we suggest the use of both pharmacologic and mechanical thromboprophylaxis (Grade 2C). (See 'Cesarean section' above.)

●Administration – For women in whom the decision is made to administer pharmacologic prophylaxis, heparin-based regimens are safer than oral anticoagulants. We suggest low molecular weight heparin rather than unfractionated heparin, provided that the patient does not have renal insufficiency (eg, creatinine clearance <30 mL/min) (Grade 2C). Heparin regimens are typically administered during pregnancy at different doses depending upon the risk of thromboembolism and desired degree of anticoagulation (prophylactic, intermediate, therapeutic) (table 1). (See 'Administration' above.)

●Duration – Antepartum pharmacologic thromboprophylaxis should be continued until delivery. We suggest that postpartum pharmacologic thromboprophylaxis be continued for six weeks to three months. Following CS, thromboprophylaxis is continued until the patient is ambulatory. (See 'Duration' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David R Schwartz, MD, who contributed to earlier versions of this topic review.