Thromboembolism in Pregnancy Medication

When a high level of suspicion exists for an acute PE, empiric anticoagulation is recommended (unless contraindicated for other reasons) prior to the diagnostic evaluation. In patients with low or intermediate suspicion for PE or DVT, anticoagulation may await conclusive expeditious diagnostic testing.

Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated in the absence of contraindications. The common classes of anticoagulation drugs are as follows:

1. Indirect thrombin inhibitors: These include unfractionated heparin and low molecular weight heparins (eg, enoxaparin), as well as synthetic heparin pentasaccharides (eg, fondaparinux) and the new orally administered Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban).

2. Direct thrombin inhibitors: These include argatroban, lepirudin, and bivalirudin. This class also includes the oral medication dabigatran.

3. Vitamin K antagonist: This includes warfarin, however this is NOT recommended as initial anticoagulation therapy for VTE.

Heparins (unfractionated and low molecular weight) are the preferred drugs for management of VTE in pregnancy. UFH is listed as a category C drug in pregnancy and LMWH is category B. Both are large molecular weight molecules and neither crosses the placenta.

Low molecular weight heparin: Enoxaparin

Subcutaneous low molecular weight heparin (LMWH) is the preferred treatment for most patients with acute VTE. ^{[12, 34]} A large meta-analyses comparing LMWH to unfractionated heparin (UFH) showed that LMWH decreased the risk of mortality, recurrent VTE, and hemorrhage compared with heparin. ^{[51, 52]} Other advantages of LMWH may include more predictable therapeutic response, ease of administration and monitoring, and less heparin-induced thrombocytopenia. Disadvantages of LMWH include cost and longer half-life compared with heparin.

The most commonly used LMWH is enoxaparin (Lovenox). The recommended dosing of enoxaparin for acute VTE in pregnancy is 1 mg/kg every 12 hours. Some authors have suggested that LMWH dosing should be evaluated by monitoring anti-Xa level in pregnancy because of the effects of increased plasma volume and glomerular filtration rate on pharmacokinetics. ^{[53, 54]}

In a study of 13 pregnancies requiring therapeutic anti-coagulation, Barbour et al monitored the patients’ peak (2-4 hours after dosing) and trough (pre-dose) levels of anti-Xa while on weight based dosing of LMWH.  They found that 85% of patients required dosing adjustments to maintain peak anti-Xa levels in therapeutic range, and noted that trough values were therapeutic only 9% of the time. ^[55]

Nevertheless, monitoring anti-Xa levels is not required according to American College of Chest Physician guidelines. Bates et al cite “the absence of large studies using clinical end points that demonstrate an optimal therapeutic anti-Xa range or that dose adjustments increase the safety or efficacy of therapy, the lack of accuracy and reliability of the measurement, the lack of correlation with risk of bleeding or recurrence, and the cost of the assay” as reasons making routine monitoring of anti-Xa levels difficult to justify. ^[34]

LMWH is excreted by the kidneys and should not be used if the patient’s creatinine clearance is less than 30 mL/min. Weight-based dosing with LMWH is only feasible in patients that weight less than 150kg. For patients, greater than 150 kg, UFH maybe preferred or else closer monitoring of anti-Xa levels should be performed to ensure therapeutic effect. ^[56]

Unfractionated heparin

Unfractionated heparin (UFH) may be preferred if the patient is likely to have immediate surgery because of its shorter half-life and reversibility with protamine compared with LMWH. As noted above, UFH may be preferred if creatinine clearance is less than 30 mL/min or if the patient weights >150kg. ^[56]

In the setting of acute VTE, UFH is administered by IV bolus, followed by IV infusion, with titration of the dose to an aPTT. The target aPTT is laboratory dependent. Many institutions have a normogram available to assist in the initial dose and titration of heparin infusions to therapeutic aPTT. The heparin infusion is typically increased or decreased by 10-30% to titrate to goal aPTT. ^[34]

After achieving a therapeutic and stable aPTT, the heparin can be converted to either subcutaneous UFH or LMWH. Subcutaneous UFH is less predictable for anticoagulation as significant dosing variability exists to maintain therapeutic response compared to LMWH. ^[34] However, due to cost, some patients may have limited access to LMWH.

If subcutaneous heparin is used, one may start at 17,500 every 12 hours, then check aPTT 6 hours after the second dose. The dose may be increased or decreased by 10-30% to titrate to therapeutic range. After aPTT is stable, it may be checked again in 3-4 days, then at least weekly thereafter. ^[34]

Warfarin and direct thrombin inhibitors

Warfarin freely crosses the placenta and is classified as category X by the FDA. Teratogenic effects including chondromalacia punctate, mid-face hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs, and short fingers have been described when warfarin is given in the first trimester. ^[57] Other possible effects are CNS abnormalities or fetal/neonatal hemorrhage and death if given at any gestational age.

Warfarin is rarely used in pregnancy. One exception is the use of warfarin after the first trimester in women with prosthetic heart valves.

There is insufficient experience to evaluate the risks and benefits of direct thrombin inhibitors in pregnancy.

Direct oral anticoagulants

Because data on the maternal and fetal safety of direct oral anticoagulants (DOACs) are scant, these agents are generally avoided in pregnancy. A meta-analysis by Areia and Mota-Pinto supports the conclusion that DOACs should be avoided 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%. ^[58]

Complications of medical management

After initiation of anticoagulation therapy, patients should be monitored for progressive or refractory VTE (eg, extension of DVT or continued pulmonary emboli), bleeding (major bleeding occurs in 1-3% of patients anticoagulated with UFH), ^[59] and heparin allergies including heparin-induced thrombocytopenia (HIT).

HIT occurs in 1-3% of nonpregnant patients using UFH and even less often in patients using LMWH(estimated at 1/1,000). ^[60] HIT is an immune response due to development of drug-induced IgG antibodies that leads to a hypercoagulable state of the venous system and may also involve the arterial system.

Appropriate monitoring for HIT depends on the clinical circumstance. Patients on therapeutic anticoagulation with UFH should have platelets checked every other day from days 4 to 14 after initiation of therapy. If the patient is on prophylactic dose UFH, platelets should be followed every 2-3 days from days 4-14 after initiation of therapy. Platelet monitoring may stop if heparin therapy is stopped. Routine platelet count monitoring is not required with LMWH. ^[59]

HIT should be considered if platelet count drops 50% or more for baseline (even if above 100 x 10^9/L) or falls below 100 x 10^9/L, if new venous or arterial thrombosis occurs after initiation of heparin, if anaphylactoid reactions occurs after IV UFH infusion, or if skin necrosis occurs even in the absence of thrombocytopenia. Mild thrombocytopenia occurs in approximately 10-20% of patients treated with heparin and is generally benign if serial monitoring documents a return to pretreatment platelet levels.

HIT is a thrombocytopenic state that is paradoxically more likely to produce both arterial and venous thromboembolism. If HIT is suspected, heparin therapy should be discontinued, and consultation with a hematologist should be expeditiously obtained to determine the best of method of anti-coagulation or prevention of embolus (e.g. vena cava filter, direct thrombin inhibitors). Platelet transfusion is typically considered contra-indicated as it increases the risk of thrombosis in HIT.

Labor and delivery

Many patients may present in labor while undergoing therapeutic anticoagulation. Most patients do not have increased delivery-related bleeding. ^[61] Temporary discontinuation of anti-coagulation is for the purpose of availability of regional anesthesia for the patient and to decrease the risk of epidural or spinal hematoma.

The American Society of Regional Anesthesia and Pain Medicine guidelines state that neuraxial regional anesthesia should be withheld for 12 hours following the last prophylactic LMWH dose or 24 hours following the last therapeutic LMWH dose. These guidelines also assert that neuraxial anesthesia in patients using prophylactic UFH up to 5,000 units twice daily is safe, although less is known about higher doses. ^[61]

Several reasonable management options exist for anticoagulation prior to delivery. Patients may be converted from LMWH to subcutaneous UFH at 36 weeks or sooner if delivery is expected earlier to permit access to timely regional anesthesia in labor. If a patient is using UFH and presents in labor, aPTT can be checked before placement of neuraxial anesthesia to ensure clearance. If delivery is planned, subcutaneous LMWH or UFH may be discontinued 24-36 hours prior to anticipated delivery or induction. If prolonged periods without anticoagulation is undesirable, subcutaneous LMWH or UFH can be discontinued and the patient can be anti-coagulated with IV UFH because of its shorter half-life. IV UFH can be discontinued 4-6 hours prior to delivery. ^[34] Prior to neuraxial anesthesia, IV UFH could also be stopped and aPTT checked to ensure clearance.

Postpartum

Anticoagulation may be restarted with UFH or LMWH 4-6 hours following vaginal delivery or 6-12 hours following cesarean delivery. ^[7] If neuraxial blockade was used, prophylactic anti-coagulation should not be restarted any sooner than 2 hours following epidural removal. ^[62] Although the ideal time to restart therapeutic anticoagulation following epidural removal is unclear, waiting 12 hours after removal of the epidural may be a reasonable approach. ^[7]

The total length and intensity of anticoagulation therapy depends on the timing of the VTE, whether or not the VTE occurred in the setting of pregnancy or other transient risk settings, and the presence of and specific type of any thrombophilia.

Pregnant patients with acute VTE are typically treated with therapeutic anticoagulation for a minimum of 6 months, and for at least 6 weeks postpartum. ^[34] Again, note that VTE is most likely to be more common in the postpartum period.

Postpartum therapeutic anticoagulation may consist of continued use of therapeutic heparin, or the patient may be bridged to warfarin. Discontinuation in heparin early in the transition to warfarin may cause increased short-term risk of VTE. To minimize this risk during conversion to warfarin, the patient should remain on therapeutic anticoagulation with heparin for at least 4-5 days while the warfarin is titrated to a goal INR of 2.0-3.0. Warfarin has a narrow therapeutic window and has significant variability in dosing. It requires close monitoring to ensure therapeutic range anti-coagulation. The annual incidence of major bleeding related to warfarin is 2-5%. ^[56]

Both heparins and warfarin are considered safe in lactation. No evidence exists that either enter the breast milk in quantities that create any anticoagulation effects in the breast-fed infant.

For further detail on the use of thrombolytics and vena cava filters in pregnancy, please refer to the Medscape Reference topic Anticoagulants and Thrombolytics in Pregnancy.

Prophylaxis for VTE

Decisions to provide prophylaxis for VTE in pregnancy must be based on the patient’s history. Pertinent to the decision is if the patient has experienced VTE previously, whether the patient has experienced more than one VTE in the past, whether or not a prior VTE occurred with a transient risk factor (eg, prolonged immobility or surgery), whether or not a prior VTE occurred in association with a pregnancy or estrogen-related state, whether or not a low or high risk thrombophilia is present, and whether or not the patient was receiving long-term anti-coagulation therapy prior to pregnancy.

Patients undergoing cesarean delivery have twice the risk of VTE as patients in the setting of vaginal delivery. Sequential compression devices may be used during cesarean delivery and continued until the patient is ambulatory. Early ambulation is a recommended strategy for thromboprophylaxis in women undergoing cesarean delivery. ^[34] In the absence of other risk factors, medical thromboprophylaxis with heparin or LMWH is not recommended because the overall risk of VTE is low and is comparable to other surgical procedures where prophylaxis is not recommended. ^[34]

Early recognition and widespread implementation of thromboprophylaxis guidelines has shown a significant decrease in VTE related deaths in the UK. According to the United Kingdom Centre for Maternal and Child Inquiries 8^th Report on Confidential Inquiries into Maternal Deaths in the UK, VTE was the leading cause of direct maternal death in the UK for all but the final of the two year eras reported from 1985 to 2008, more common than death from sepsis, preeclampsia, amniotic fluid embolism, or hemorrhage. ^[24] Interestingly, the statistically significant decrease in maternal death due to VTE in 2006-2008 era was noted after the first publication of the Royal College of Obstetricians and Gynecologist Green Top Guideline “Thromboprophylaxis during Pregnancy, Labour and after Vaginal Delivery” in 2004.

Implementation of the American College of Obstetricians and Gynecologists (ACOG) and ACCP guidelines for the prevention of thromboembolism can help reduce the rates of VTE related morbidity and mortality in the US. The following recommendations are based on the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9^th Ed) for venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. The following recommendations are based on the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9^th Ed) for venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. ^[63]

Table 1. Evidence-Based Clinical Practice Guidelines for Venous Thromboembolism, Thrombophilia, Antithrombotic Therapy, and Pregnancy. (Open Table in a new window)

According to recommendations from ACOG, VTE prophylaxis during pregnancy and/or the postpartum period may be required for persons with the following risk factors ^[64] :

• 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

Once the diagnosis of venous thromboembolism (VTE) is made, therapeutic anticoagulation should be initiated in the absence of contraindications. The goals of pharmacotherapy are to prevent or correct thromboembolic disorders, prevent complications, and reduce morbidity.

The National Partnership for Maternal Safety reviewed current guidelines and made the following recommendations for prophylaxis which included the following ^[65] :

• The authors recommend that all pregnant women should undergo risk assessment for VTE throughout pregnancy. In particular, clinicians should assess patients during the first prenatal visit, during any antepartum hospitalizations, immediately postpartum during a hospitalization for childbirth, and after they are discharged home after a delivery.
• Clinicians should use a patient's modified Caprini or Padua score to identify those who are at high risk for VTE and who are therefore candidates for thromboprophylaxis.
• For antepartum outpatient prophylaxis, treatment-dose low-molecular-weight (LMW) heparin or unfractionated heparin (UFH) is recommended for women with a clinical history of multiple VTE episodes, VTE with high-risk thrombophilia, or VTE with acquired thrombophilia.
• For all antepartum patients who are hospitalized for 3 days or longer who are not at high risk for bleeding or imminent childbirth, prophylaxis with daily LMW heparin or twice-daily UFH is recommended.
• Women undergoing cesarean delivery who are not receiving pharmacologic thromboprophylaxis should also receive perioperative mechanical thromboprophylaxis. Depending on their specific risk factors, these women should also receive postoperative pharmacologic thromboprophylaxis with LMW
• Heparin or UFH, based on Royal College of Obstetricians and Gynaecologists (RCOG) criteria or modified Caprini scores.
• Extended postpartum pharmacologic thromboprophylaxis after hospitalization for childbirth is recommended. For example, women with a clinical history of multiple VTE episodes, VTE with high-risk thrombophilia, or VTE with acquired thrombophilia should receive a 6-wk treatment dose of LMW heparin or UFH. 

A systematic review by Croles et al that included 36 studies reported that women with antithrombin, protein C, or protein S deficiency or with homozygous factor V Leiden should be considered for antepartum or postpartum thrombosis prophylaxis, or both. Women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutation, or compound heterozygous factor V Leiden and prothrombin G20210A mutation should generally not be prescribed thrombosis prophylaxis on the basis of thrombophilia and family history alone. ^[66] ​

Class Summary

Once the diagnosis of VTE is made, therapeutic anticoagulation should be initiated in the absence of contraindications. Anticoagulants prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation. In patients with heparin-induced thrombocytopenia, LVAD implantation has been performed successfully, albeit with additional risk, by using alternative anticoagulants.

Heparin

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Heparin may be used if thrombocytopenia is not present. Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents the recurrence of a clot after spontaneous fibrinolysis. Heparin does not cross the placenta.

Warfarin (Coumadin, Jantoven)

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Warfarin, which is administered orally, is used if long-term anticoagulation is needed. The international normalized ratio (INR) is followed, with a target range of 2-3. Warfarin crosses the placenta and is teratogenic, causing a constellation of anomalies known as warfarin embryopathy, with greatest risk between the sixth and twelfth week of gestation.  Warfarin is still often recommended in pregnant patients with mechanical heart valves.

Enoxaparin (Lovenox)

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Enoxaparin is produced by the partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa.

Enoxaparin binds to antithrombin III, enhancing its therapeutic effect. The heparin-antithrombin III complex binds to and inactivates activated factor X (Xa) and factor II (thrombin). It does not actively lyse but is able to inhibit further thrombogenesis, preventing clot reaccumulation after spontaneous fibrinolysis.

The advantages of enoxaparin include intermittent dosing and a decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing. The drug has a wide therapeutic window, and aPTT does not correlate with the anticoagulant effect. The maximum antifactor Xa and antithrombin activities occur 3-5 hours after administration. Enoxaparin does not appear to cross the placenta. 

Dalteparin (Fragmin)

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LMW heparin with antithrombotic properties; it enhances inhibition of factor Xa and thrombin by antithrombin, with minimal effect on aPTT.

Tinzaparin

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Tinzaparin is an LMW heparin with antithrombotic properties; it enhances inhibition of factor Xa and thrombin by antithrombin, with minimal effect on aPTT. Does not cross placenta in human studies.

Argatroban

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Argatroban is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. It inhibits thrombin-induced platelet aggregation.

Dabigatran etexilate (Pradaxa)

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Dabigatran etexilate is a selective thrombin inhibitor that inhibits thrombin formation by binding to the active thrombin site of free and fibrin-bound thrombin. A study by Bapat et al has concluded that dabigatran crosses the human placenta. It inhibits thrombin-induced platelet aggregation.

Bivalirudin (Angiomax)

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Bivalirudin inhibits coagulant effects by preventing thrombin-mediated cleavage of fibrinogen to fibrin.

Fondaparinux (Arixtra)

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Fondaparinux is a synthetic heparin pentasaccharide that causes an antithrombin lll mediated selective inhibition of factor Xa. This interrupts the blood coagulation cascade, which in turn inhibits thrombin formation and thrombus development.

Rivaroxaban (Xarelto)

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Rivaroxaban is a selective and reversible inhibition factor of Xa (FXa) in the intrinsic and extrinsic coagulation pathways. This interrupts the blood coagulation cascade, which in turn inhibits thrombin formation and thrombus development. A study by Bapat et al concluded that rivaroxaban crosses the human placenta.

Apixaban (Eliquis)

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Inhibits platelet activation and fibrin clot formation via direct, selective, and reversible inhibition of free and clot-bound factor Xa. Factor Xa, as part of the prothrombinase complex, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.

Edoxaban (Savaysa)

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Selective Xa inhibitor, inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation.

Class Summary

These agents can be considered to help prevent future ischemic strokes.

Aspirin (Ecotrin, Ascriptin Maximum Strength, Ascriptin Regular Strength, Bayer Aspirin)

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Aspirin's efficacy in preventing stroke relies on the inhibitory effect of aspirin on platelet function. This presumably helps to prevent thrombus formation and propagation.