Anticoagulants and Thrombolytics in Pregnancy

The use of anticoagulants and thrombolytics in pregnancy is an important consideration; pregnancy is associated with a 5-fold increase in the risk of venous thromboembolism (VTE), with the risk rising to 20-fold or more during puerperium. ^[1] The risk further increases if an underlying thrombophilia is present. The risk of VTE persists until nearly 12 weeks postpartum. ^[1]

Indications for antithrombotic agents

Anticoagulant therapy is indicated in pregnancy for the treatment of acute VTE and valvular heart disease, as well as for the prevention of pregnancy-related complications in women with antithrombin deficiency, antiphospholipid antibody (APLA) syndrome, ^[2] or other thrombophilias who have had a prior VTE. ^{[3, 4, 5, 6]} Low molecular weight heparins (LMWHs) are the preferred agents in women with confirmed VTE; alternative agents that may be considered are unfractionated heparin (UFH) and possibly fondaparinux. ^[1] In women at high risk for pregnancy-related VTE, LMWHs and UFH may be considered. ^[1]

Etiology of thrombosis in pregnancy

Normal pregnancy is associated with a hypercoagulable state, which arises from the following:

• Increased serum levels of procoagulants: Including fibrinogen and factors II, VII, VIII, X, and XII

• Decreased protein S levels ^[7]

• Increased resistance to activated protein C: Observed in the second and third trimesters of pregnancy

• Increased serum plasminogen activator inhibitor-1 (PAI-1) and placental PAI-2 levels: Lead to a decreased fibrinolytic state ^{[8, 9]}

• Venous stasis: Resulting from pressure of the gravid uterus on the inferior vena cava and decreased venous tone

The risk of pregnancy-related VTE is particularly high in heterozygous carriers of factor V Leiden (4-fold to 16-fold increase) ^[10] or the prothrombin mutation (15-fold increase), ^[11] as well as in women with APLAs (5% incidence). ^[12]

Anticoagulation in pregnant patients with valvular heart disease

Warfarin is more efficacious than unfractionated heparin (UFH) for thromboembolic prophylaxis of pregnant women with mechanical valves. ^[9] Unfortunately, warfarin therapy in the first trimester of pregnancy is associated with a substantial increase in fetal anomalies, and anticoagulation with any agent is associated with an increased incidence of fetal wastage (approximately 30%), prematurity (approximately 45%), and low birth weight (approximately 50%). ^{[7, 10, 11]}

Complications secondary to anticoagulation during pregnancy

Fetal complications

Warfarin crosses the placenta and can cause fetal bleeding (including intracranial hemorrhage) and teratogenicity, with the latter occurring mainly during the first trimester. ^[13] Neither UFH nor low ̶ molecular weight heparin (LMWH) cross the placenta; therefore, these agents do not cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction and fetal wastage are possible.

As there is little information on maternal and fetal safety of direct oral anticoagulants (DOACs), these are avoided in pregnancy. A meta-analysis by Areia and Mota-Pinto supports the conclusion that DOACs should not be used during pregnancy. Their analysis showed a miscarriage rate of 22.2% and an elective termination of pregnancy in 21.8% of 339 cases; fetal anomalies linked to the use of DOACs occurred in 3.6%. ^[14]

Maternal complications

• Major bleeding in patients treated with UFH therapy (2%) ^[13]

• Heparin-induced thrombocytopenia (3%) (HIT)

• Vertebral fracture from heparin-induced osteoporosis (2-3%)

• Significant reduction in bone density from long-term UFH therapy (about 30%); LMWH causes less osteoporosis, including less heparin-induced osteoporosis, than does UFH ^{[15, 16, 17]}

The use of anticoagulants and thrombolytics in pregnancy is an important consideration, because pregnancy is associated with a 4-fold increase in the risk of venous thromboembolism (VTE), with the risk rising to 14-fold during puerperium. The risk further increases if an underlying thrombophilia is present.

Pulmonary embolism (PE) remains a leading cause of maternal mortality in the Western world, ^{[18, 19]} the risk in pregnant women being 5 times higher than in nonpregnant women of the same age. Deep venous thrombosis (DVT), stroke, and myocardial infarction (MI) can also result from pathologic thromboses. The images below show an overview of the process for diagnosing DVT and PE, respectively, during pregnancy.

Antithrombotic agents (ie, anticoagulants and thrombolytic agents) are first-line therapy for pathologic thromboses. Anticoagulants, which are available in oral and parenteral forms, interrupt the coagulation cascade to prevent thrombus formation and extension while endogenous thrombus lysis occurs; thrombolytic agents, which are administered parenterally, promote thrombus lysis.

Anticoagulants

Warfarin is an oral anticoagulant that interferes with the liver's synthesis of vitamin K–dependent clotting factors, which leads to the depletion of factors II (prothrombin), VII, IX, and X and to the prolongation of clotting times (ie, international normalized ratio [INR]).

Rivaroxaban is an orally active factor Xa inhibitor that prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT) and Dabigatran is an orally administered direct thrombin inhibitor that also results in prolongation of the aPTT.  Unlike warfarin, the pharmacokinetics of rivaroxaban and dabigatran are predictable; thus, routine monitoring of coagulation parameters is not required when one of these agents is used. Warfarin however, has been used extensively in pregnancy, while the fetal safety and efficacy of rivaroxaban or dabigatran in pregnancy have not been established.

The most commonly used parenteral anticoagulants inactivate thrombin and/or factor Xa without depleting circulating levels of clotting factors. Unfractionated heparin (UFH), low–molecular weight heparin (LMWH), heparinoids, synthetic pentasaccharide inhibitors (eg, fondaparinux), and direct thrombin inhibitors (ie, hirudin and argatroban) belong to this category.

LMWH is preferred over UFH for the prevention and treatment of VTE owing to its ease of use, as well as it greater efficacy and safety profile. ^{[20, 21]}

Thrombolytic agents

Thrombolytic agents mediate the dissolution of fibrin clots by promoting the conversion of plasminogen to plasmin, which causes decomposition of fibrin to fibrin degradation products. Traditional thrombolytic agents include streptokinase, anisoylated plasminogen streptokinase activator complex, urokinase, and recombinant tissue plasminogen activator (t-PA).

Indications for antithrombotic use include the following ^[22] :

• Acute and chronic VTE (including pulmonary embolism )

• Atrial fibrillation

• Valvular and structural heart disease

• Ischemic stroke

• Acute coronary syndromes ^[23]

• Peripheral artery occlusive disease

Indications in pregnancy

Anticoagulant therapy is indicated in pregnancy for the treatment of acute VTE and valvular heart disease, as well as for the prevention of pregnancy-related complications in women with antithrombin deficiency, antiphospholipid antibody (APLA) syndrome, or other thrombophilias, who have had a prior VTE. ^{[3, 4, 5]}

VTE and DVT

Normal pregnancy is associated with a hypercoagulable state, which is at least partly due to increased serum levels of procoagulants, such as fibrinogen and factors II, VII, VIII, X, and XII. In addition, protein S levels decrease during pregnancy, ^[7] and increased resistance to activated protein C is observed in the second and third trimesters of pregnancy.

Concomitantly, serum plasminogen activator inhibitor-1 (PAI-1) and placental PAI-2 increase with pregnancy, which leads to a decreased fibrinolytic state. ^{[8, 9]} Venous stasis resulting from pressure of the gravid uterus on the inferior vena cava and decreased venous tone are additional predisposing factors for VTE.

The risk of pregnancy-related VTE is particularly high in heterozygous carriers of factor V Leiden (4-fold to 16-fold increase) ^[10] or the prothrombin mutation (15-fold increase), ^[11] as well as in women with APLAs (5% incidence). ^[12]

In approximately 85% of cases, DVT of the lower extremity occurs on the left side during pregnancy. This is attributed to the more tortuous course of the venous drainage of the left leg through the pelvis and compression of the left common iliac vein by the overlying right iliac artery. ^[24]

Uteroplacental thrombosis and pregnancy loss

A study by Patil et al suggested that an increase in tissue factor – expressing and phosphatidylserine-expressing microparticles, as well as in endothelial microparticles, is associated with uteroplacental thrombosis and recurrent pregnancy loss. According to the investigators, who conducted the study on 115 women with multiple pregnancy losses, if these procoagulant particles remain elevated for at least 3 months after pregnancy loss, the patient may be experiencing continued chronic endothelial damage/activation, a problem that may worsen at the start of a new pregnancy.

Variations in risk factors

A report by Philipp et al indicated that risk factors for thrombosis in women who have had adverse pregnancy outcomes differ significantly between White and Black women. In the study, involving 409 patients (343 White and 66 Black) who had adverse outcomes in pregnancy, the investigators determined the following:

• The prevalence of protein S and antithrombin deficiencies were more prevalent in Black patients

• Diagnosed thrombophilia was more prevalent in White women

• The frequency of a family history of thrombophilia, VTE, and stroke or MI was greater in White patients

• The body mass index was higher in Black women

• Hypertension was more prevalent in Black women

The investigators, however, also found no significant difference between White and Black patients with regard to personal history of VTE. The prevalence of sickle cell disease among Black women in the study was about 27-fold higher than that in the overall Black population of the United States.

The evidence-based recommendations in table 1, below, are from the American College of Chest Physicians (ACCP). ^[7]

Table 1. ACCP Recommendations for Anticoagulants Before, During, and After Pregnancy* (Open Table in a new window)

According to recommendations from the American College of Obstetricians and Gynecologists (ACOG), VTE prophylaxis during pregnancy and/or the postpartum period may be required for persons with the following risk factors ^[25] :

• A diagnosis of VTE during a previous pregnancy
• A history of VTE, including during pregnancy or with the use of hormonal contraceptives
• A history of thrombophilia with or without a personal or family history of VTE

Women with valvular heart disease who are pregnant or planning to conceive require careful evaluation and management. Physiologic changes associated with pregnancy are poorly tolerated in some cases of valvular heart disease:

• Aortic stenosis

• Mitral regurgitation

• Aortic regurgitation with New York Heart Association (NYHA) class 3-4 symptoms

• Mitral stenosis with NYHA class 2-4 symptoms

• Valvular heart disease that results in severe pulmonary hypertension

• Left ventricular (LV) dysfunction with an ejection fraction (EF) less than 40%

Prosthetic heart valves and anticoagulation

Anticoagulation is recommended in most pregnant patients with a mechanical prosthetic heart valve (but is not required in those with a bioprosthetic valve). However, patients with a mechanical prosthetic valve who require anticoagulation are exposed to special risks during pregnancy. Therefore, whenever possible, symptomatic or severe valvular lesions should be addressed before conception. ^{[5, 26]}

Warfarin is more efficacious than UFH for thromboembolic prophylaxis of pregnant women with mechanical valves. ^[9] Unfortunately, warfarin therapy in the first trimester of pregnancy is associated with a substantial increase in fetal anomalies, and anticoagulation with any agent is associated with an increased incidence of fetal wastage (approximately 30%), prematurity (approximately 45%), and low birth weight (approximately 50%). ^{[7, 10, 11]}

In a systematic review of fetal and maternal outcome of pregnancy in patients with mechanical heart valves, the regimen associated with the lowest risk of valve thrombosis (3.9%) was warfarin throughout pregnancy. Using it through an entire pregnancy, however, was associated with warfarin embryopathy in 6.4% of live births. This risk was eliminated when heparin was substituted for warfarin at or prior to 6 weeks and continued until 12 weeks, although using heparin only from 6-12 weeks' gestation was associated with an increased risk of valve thrombosis (9.2%). ^[9]

Low–molecular weight heparin

In 2002, the US Food and Drug Administration (FDA) issued a warning that LMWH was not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. However, a consensus panel concluded that this recommendation was based on studies in which underdosing or inadequate monitoring of LMWH occurred. ^[12] Consequently, the panel supported the use of LMWH as a treatment option, with monitoring of anti-Xa levels.

Seshadhri et al reviewed 120 articles and concluded that LMWH, compared with UFH, may be a safe and effective agent in patients with mechanical prosthetic heart valves. ^[24] However, large-scale, randomized trials are warranted.

ACCP recommendations

The recommendations below for anticoagulation therapy in pregnant women with prosthetic heart valves are based on the ACCP's 2012 evidence-based clinical practice guidelines. They include the following ^[7] :

• Adjusted-dose, twice-daily (bid) LMWH throughout pregnancy, adjusted to reach the manufacturer's peak anti-Xa LMWH level 4 hours after subcutaneous (SC) injection, OR

• Adjusted-dose bid SC UFH every 12 hours (q12h) throughout pregnancy, adjusted so the midinterval aPTT remains at least twice control or to achieve an anti-Xa heparin level of 0.35-0.70 U/mL, OR

• UFH or LMWH (as above) until 13 weeks' gestation, THEN change to vitamin K antagonists until the patient is close to delivery, and THEN restart UFH or LMWH

Long-term anticoagulants should be resumed postpartum with all regimens. In high-risk women with prosthetic heart valves, such as women with LV dysfunction and those with prior thromboembolic episodes, low-dose aspirin (at 75-100 mg/day) should be added. ^[5]

Use of anticoagulants in the breastfeeding mother

Heparin and LMWHs are not secreted into breast milk, and 2 reports have shown that maternal administration of warfarin does not induce an anticoagulant effect in the breastfed infant. Thus, women using these agents can safely breastfeed.

Fetal complications of anticoagulants during pregnancy

Warfarin crosses the placenta and can cause fetal bleeding and teratogenicity, with the latter occurring mainly during the first trimester. ^[13]

Neither UFH nor LMWH cross the placenta; therefore, these agents do not cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction and fetal wastage are possible.

Maternal complications of anticoagulants during pregnancy

The rate of major bleeding in patients treated with UFH therapy is 2%. ^[13] Approximately 3% of patients receiving UFH develop immune thrombocytopenia (so-called heparin-induced thrombocytopenia [HIT]), which predisposes them to venous and arterial thrombosis.

Heparin-induced osteoporosis causes vertebral fracture in 2-3% of patients, and significant reduction in bone density is seen in about 30% of patients receiving long-term UFH. LMWH causes less osteoporosis and HIT than UFH. ^{[15, 16, 17]}