Anticoagulants and Thrombolytics in Pregnancy

Updated: Dec 17, 2014
  • Author: Teresa Marino, MD; Chief Editor: Richard A Lange, MD, MBA  more...
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Overview

Practice Essentials

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]

The image below illustrates the diagnosis of deep vein thrombosis during pregnancy.

Diagnosis of deep vein thrombosis during pregnancy Diagnosis of deep vein thrombosis during pregnancy.

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 possibly 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 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.

Maternal complications

  • Major bleeding in patients treated with UFH therapy (2%) [13]
  • Heparin-induced thrombocytopenia (3%)
  • 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 [14, 15, 16]
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Overview

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, [17, 18] 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.

Diagnosis of deep vein thrombosis during pregnancy Diagnosis of deep vein thrombosis during pregnancy.
Diagnosis of pulmonary embolism during pregnancy. Diagnosis of pulmonary embolism 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). 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. However, warfarin has been used extensively in pregnancy, while the 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. [19]

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).

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Indications for Antithrombotic Agents

Indications for antithrombotic use include the following [20] :

  • Acute and chronic VTE (including pulmonary embolism )
  • Valvular and structural heart disease
  • Acute coronary syndromes [21]
  • 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]

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Etiology of Thrombosis in Pregnancy

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. [22]

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.

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Prevention and Treatment of Venous Thromboembolism

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)

Risk Factor Recommendations
Pregnant women LMWH instead of unfractionated heparin (UFH), to prevent and treat VTE (grade 1B)
Women who become pregnant while receiving anticoagulant therapy for VTE LMWH instead of vitamin K antagonists during the first trimester (grade 1A) and during the second and third trimesters (grade 1B), as well as during late pregnancy when birth is imminent (grade 1A)
Women attempting to become pregnant who need long-term vitamin K antagonists and are candidates for LMWH substitution Frequent pregnancy tests and the substitution of LMWH for vitamin K when the patient becomes pregnant (grade 2C)
Pregnant women Restrict fondaparinux and parenteral direct thrombin inhibitors to patients who not only have severe allergic reactions to heparin but who also cannot take danaparoid (grade 2C)
Pregnant women No oral direct thrombin (eg, dabigatran) or anti-Xa (eg, rivaroxaban, apixaban) inhibitors (grade 1C)
Lactating women who wish to breastfeed but who are taking warfarin, acenocoumarol, or UFH Continue the medication (grade 1A)
Lactating women who wish to breastfeed but who are taking LMWH, danaparoid, or r-hirudin Continue the medication (grade 1B)
Women who are breastfeeding Anticoagulants other than fondaparinux (grade 2C)
Women who are breastfeeding Anticoagulants other than oral direct thrombin (eg, dabigatran) and factor Xa inhibitors (eg, rivaroxaban, apixaban) (grade 1C).
Lactating women who wish to breastfeed but who are taking low-dose aspirin for vascular indications Continue the medication (grade 2C)
Women undergoing assisted reproduction No routine thrombosis prophylaxis (grade 1B)
Women undergoing assisted reproduction who develop severe ovarian hyperstimulation syndrome Prophylactic LMWH for 3 months after the syndrome has resolved (grade 2C)
Women who are undergoing cesarean section and have no additional risk factors for thrombosis No thrombosis prophylaxis aside from early mobilization (grade 1B)
Women with 1 major or at least 2 minor risk factors that increase their chance of VTE following cesarean section While still in the hospital following delivery, prophylactic LMWH or, in patients with contraindications to anticoagulants, mechanical prophylaxis (elastic stockings or intermittent pneumatic compression) (grade 2B)
Women undergoing cesarean section who have a very high VTE risk and multiple additional thromboembolic risk factors that persist in the puerperium Prophylactic LMWH in combination with elastic stockings and/or intermittent pneumatic compression (grade 2C)
Selected high-risk patients who still have significant risk factors postdelivery Extended prophylaxis (for as long as 6 weeks postdelivery) after hospital discharge (grade 2C)
Pregnant women with acute VTE Adjusted-dose subcutaneous LMWH rather than adjusted-dose UFH (grade 1B)
Pregnant women with acute VTE Prenatal treatment with LMWH rather than a vitamin K antagonist (grade 1A)
Pregnant women with acute VTE Continuation of anticoagulant therapy for at least 6 weeks postpartum, so that the total duration of therapy is at least 3 months (grade 2C)
Pregnant women being treated with adjusted-dose LMWH and where delivery is planned Discontinuation of LMWH at least 24 hours before labor is induced, a cesarean section is performed, or neuraxial anesthesia is administered (grade 1B)
All pregnant women with prior VTE 6 weeks of postpartum prophylaxis with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted to achieve an INR of 2.0 to 3.0 (grade 2B)
Pregnant women with a low risk of recurrent VTE (ie, those whose single VTE episode was linked to a transient risk factor unassociated with pregnancy or estrogen use) Clinical vigilance, rather than prophylaxis, antepartum (grade 2C)
Pregnant women with a moderate to high risk of recurrent VTE (ie, those who have had a single episode of unprovoked VTE, have had pregnancy- or estrogen-related VTE, or have had multiple unprovoked episodes of VTE, who are not undergoing long-term anticoagulation therapy) Antepartum prophylaxis with prophylactic- or intermediate-dose LMWH (grade 2C)
Pregnant women on long-term vitamin K antagonists Adjusted-dose LMWH or 75% of a therapeutic dose of LMWH throughout pregnancy, with long-term anticoagulants resumed postpartum (grade 2C)
Pregnant women who are homozygous for factor V Leiden or the prothrombin 20210A mutation, who have a family history of VTE but no history of it themselves Antepartum: Prophylaxis with prophylactic- or intermediate-dose LMWH



Postpartum: 6 weeks of prophylaxis with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted to achieve an INR of 2.0 to 3.0 (grade 2B)



Pregnant women with all other thrombophilias, who have a family history of VTE but no history of it themselves Antepartum: Clinical vigilance



Postpartum: Prophylaxis with prophylactic- or intermediate-dose LMWH or, in women with no protein C or S deficiency, vitamin K antagonists targeted to achieve an INR of 2.0 to 3.0 (grade 2C)



Pregnant women who are homozygous for factor V Leiden or the prothrombin 20210A mutation but with no personal or family history of VTE Antepartum: Clinical vigilance



Postpartum: Six weeks of prophylaxis with prophylactic- or intermediate-dose LMWH or vitamin K antagonists targeted to achieve an INR of 2.0 to 3.0 (grade 2B)



Pregnant women with all other thrombophilias, who have no personal or family history of VTE Clinical vigilance antepartum and postpartum (grade 2C)
Women who have had 3 or more miscarriages prior to 10 weeks' gestation Screening for antiphospholipid antibodies (APLAs) (grade 1B)
Women with a history of pregnancy complications No screening for inherited thrombophilia (grade 2C)
Women who match the laboratory criteria for APLA syndrome and, based on a history of 3 or more pregnancy losses, fulfill the clinical APLA criteria Antepartum administration of prophylactic- or intermediate-dose UFH or prophylactic LMWH combined with 75-100 mg/day of low-dose aspirin (grade 1B)
Women with inherited thrombophilia and a history of pregnancy complications No antithrombotic prophylaxis (grade 2C)
Women at risk for preeclampsia Low-dose aspirin beginning the second trimester and continuing for the rest of the pregnancy (grade 1B)
Women without APLA or thrombophilia but who have had 2 or more miscarriages No antithrombotic prophylaxis (grade 1B)
Pregnant women with mechanical heart valves One of the following anticoagulant regimens (all of which are grade 1A):



(a) Adjusted-dose LMWH twice a day throughout pregnancy



(b) Adjusted-dose UFH throughout pregnancy, with subcutaneous administration every 12 hours; adjust doses to keep the midinterval activated partial thromboplastin time (aPTT) at least twice control or reach an anti-Xa heparin level of 0.35-0.70 units/mL



(c) Administer UFH or LMWH as detailed above until the 13th week, with vitamin K antagonists then substituted for heparin and with UFH or LMWH administration resumed close to delivery



Women considered to have a very high risk of thromboembolism in whom the efficacy and safety of UFH or LMWH in the above-detailed doses are a matter of concern (eg, women with an older-generation prosthesis in the mitral position or who have a history of thromboembolism) Vitamin K antagonists administered throughout the pregnancy but replaced with UFH or LMWH close to delivery (grade 2C)
Pregnant women with prosthetic valves and a high thromboembolic risk Addition of 75-100 mg/day of low-dose aspirin (grade 2C)
*Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 suppl):e691S-736S.

 

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Anticoagulation in Pregnant Patients With Valvular Heart Disease

Women with valvular heart disease who are pregnant or planning to conceive require careful evaluation and management. Physiologic changes associated with pregnancy, including the following, 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, 23]

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. [22] 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]

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Maternal and Fetal Complications Secondary to Anticoagulation

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. [14, 15, 16]

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