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Clinical Reviews


Anticoagulation in pregnancy: Q&A on low molecular weight heparin

A discussion of the accumulating evidence that low molecular weight heparin may be the safest and most effective anticoagulant for gravidas.

April 2004 · Vol. 16, No. 4

KEY POINTS

  • Low molecular weight heparin appears to be as safe as unfractionated heparin in pregnancy, with longer-lasting effects and reduced need for monitoring. Both the American College pregnancy with appropriate counseling.
  • Although warfarin is the anticoagulant of choice in the nonpregnant state, it crosses the placenta and has been linked to structural birth defects known as “warfarin embryopathy.”
  • A single subcutaneous, prophylactic 40-mg dose of the low molecular weight heparin enoxaparin costs about $30, compared with about $1 for an equivalent dose of unfractionated heparin.

What are the attributes of the ideal anticoagulant in pregnancy? Low molecular weight heparin fills the bill in many ways: It is safe for both mother and fetus, as effective in pregnancy as in the nongravid population, and side effects are minimal. It also has a favorable dosing route and interval, with less need for monitoring than with unfractionated heparin (UH).

In other ways, low molecular weight heparin (LMWH) is distinctly inferior. This article describes its strengths and weaknesses, addressing 10 common clinical questions.

Assessing the heightened risks of pregnancy

Pregnant women have 5 times the risk of venous thromboembolism (VTE) of nongravid patients.1 The increased risk is due to physiologic, mechanical and, sometimes, iatrogenic factors (TABLE 1):

  • Gravidas have greater concentrations of factors I, VII, VIII, IX, and X; decreased fibrinolytic activity; and increased platelet activation. These changes in the coagulation system predispose the gravida to clot formation. Although they may protect against hemorrhage, they also heighten the risk for VTE during pregnancy and the postpartum period.
  • The enlarging uterus can compress venous drainage from the lower extremities, resulting in stasis. Further, prolonged immobilization in the form of bed rest is often prescribed for obstetric complications such as hypertension, preterm labor, hemorrhage, and preterm premature rupture of membranes.
  • Both abdominal and vaginal operative delivery can predispose to vascular endothelial injury.

LMWH deactivates more slowly than UH, exposing patients to fewer periods of subtherapeutic anticoagulation.

These factors—singularly or in combination–can lead to a thrombotic or embolic event.2

TABLE 1

Pregnancy-associated risk factors for venous thromboembolism

RISK FACTOR

CAUSES

Changes in the coagulation system

Increased factors I, VII, VIII, IX, X

Decreased fibrinolytic activity

Increased platelet activation

Venous stasis

Enlarging uterus compresses venous return from lower extremities

Endothelial injury

Vacuum delivery

Forceps delivery

Cesarean delivery

Prolonged immobilization

Preterm labor

Preterm premature rupture of membranes

Obstetric hemorrhage

Hypertensive disorders of pregnancy

Question 1When is anticoagulation warranted in pregnancy?

It is indicated in women who:

  • experience a thromboembolic event,
  • become pregnant while being treated for VTE,
  • have a previous history of unprovoked VTE (unrelated to trauma, immobilization, etc),
  • have a known hereditary thrombophilia such as antithrombin III deficiency, factor V Leiden mutation, or the prothrombin G20210A mutation, with or without a personal history of thrombosis, or
  • have a connective tissue disorder such as antiphospholipid syndrome.

Anticoagulation in pregnancy is common, and usually is given for the duration of pregnancy, into the postpartum period.

Question 2What are the options for anticoagulation?

Heparin is the sole choice for long-term anticoagulation, since warfarin is contraindicated in pregnancy.3 (See “Dangers of warfarin”.)

Unfortunately, heparin has disadvantages that render it a second-line agent in the nonpregnant population. For example, because of enzymatic degradation, heparins cannot be given orally. In addition, because of its large size and strongly positive charge, the parent heparin molecule—known as “unfractionated” heparin—is rapidly deactivated by tissue proteins, making for an unpredictable anticoagulation response. Underdosing and overdosing are typical, and frequent monitoring is necessary.

For these and other reasons, investigators have sought a more predictable, reliable agent for long-term anticoagulation in patients who cannot take warfarin. Interest has focused on a derivative of the parent heparin molecule: LMWH.

Snapshot of LMWH. This agent is produced by the controlled enzymatic degradation of unfractionated heparin (molecular weight of approximately 10,000 to 15,000 daltons) into approximately 5,000-dalton molecules. Although they are much smaller than the parent molecule, these polymers still carry a strong positive charge.

This polarity is probably why LMWH does not cross the placenta—a major advantage over warfarin for anticoagulation during pregnancy.5

In addition, accumulating evidence6,7 suggests that LMWH is at least as safe and effective as UH in pregnancy, although more research is needed. As with UH, there appears to be no transplacental passage.8

Pregnancy category. According to the manufacturer, the LMWH enoxaparin falls into pregnancy category B.9 Another LMWH, dalteparin, also falls into pregnancy category B. Both the American College of Obstetricians and Gynecologists2 and the Society for Maternal-Fetal Medicine10 endorse the use of LMWH in pregnancy with appropriate counseling.8

Dangers of warfarin

Although it is the drug of choice in the nonpregnant population, warfarin is contraindicated in pregnancy because it can cross the placenta and has been linked to adverse pregnancy outcomes.

Several studies have demonstrated an association between first-trimester warfarin exposure and a constellation of structural birth defects, termed “warfarin embryopathy,” which includes craniofacial and skeletal defects. Exposure in any trimester is associated with fetal and neonatal intracranial hemorrhage.3

For these reasons, warfarin is contraindicated in pregnancy with the rare exception of women with mechanical prosthetic heart valves.4

Question 3How does LMWH differ from unfractionated heparin?

LMWH is more efficient. Both UH and LMWH contain an essential pentasaccharide within their polymer structure that binds to and enhances antithrombin III, which in turn inhibits thrombin and activated factor X (Xa). Because of its smaller size, LMWH preferentially inhibits Xa, which is higher in the coagulation cascade. Inhibition of a single molecule of Xa prevents the formation of many molecules of thrombin. Molecule for molecule, LMWH is a more efficient anticoagulant than UH (FIGURE).11

The second way that LMWH differs from UH also relates to the molecule’s size. Smaller heparin molecules are less likely to be deactivated by tissue proteins. This results in improved bioavailability of the administered dose. Greater bioavailability translates to a more predictable dose-response relationship, a long half-life, and better anticoagulation.12

FIGURE Simplified schematic of the coagulation cascade



Question 4What are the clinical advantages of LMWH?

LMWH has longer-lasting effects and subcutaneous dosing. It also has fewer side effects than UH.

Because of its large size and positive charge, UH has an unfavorable pharmacokinetic profile. Tissue proteins interfere with and deactivate it, and many of these proteins increase in pregnancy and with advancing gestation. Heparin tissue levels are therefore erratic and unpredictable and often lead to periods of subtherapeutic coverage. This is true even with intravenous (IV) dosing.

Rapid absorption, no intravenous dosing. In contrast, because of its smaller size, LMWH is rapidly and predictably absorbed from a subcutaneous injection. Intravenous dosing is not necessary to obtain adequate tissue levels. Once in tissue, it is deactivated more slowly and therefore maintains its anticoagulation effect longer. Consequently, patients are exposed to fewer periods of subtherapeutic anticoagulation. A longer half-life also translates to more favorable dosing routes (subcutaneous rather than IV) and regimens (daily versus twice daily). Similarly, since the dose-response is predictable and tissue levels are more constant, frequent monitoring of treatment response is not routinely necessary.

Fewer side effects. Another advantage of LMWH over UH is the improved side-effect profile. Patients on LMWH have decreased risk of hemorrhage, osteoporosis, and antibody-mediated thrombocytopenia.11 Although most data regarding these advantages come from the nonpregnant population, it is plausible to speculate that these traits also are present in pregnant women (TABLE 2).

TABLE 2

Advantages and disadvantages of LMWH in pregnancy

ADVANTAGES

  More effective anticoagulation

  Better dose-response

  Longer half-life

  Better dosing route

  Decreased need for monitoring

  Fewer side effects

DISADVANTAGES

  Longer half-life

  Risk of hematoma with epidural anesthesia

  Not fully reversible with protamine sulfate

  Anticoagulation effect difficult to monitor

  Higher cost

Question 5What are the disadvantages?

They include the long half-life, risk of hematoma with epidural anesthesia, lower efficacy of the antidote, monitoring difficulty, and higher cost.

The long half-life of LMWH is both an advantage and disadvantage. For example, when UH is administered intravenously, it has a half-life of 30 to 60 minutes. When it is given subcutaneously, the half-life is 1 to 2 hours. This means that a patient can undergo vaginal delivery or even surgery within hours of her last subcutaneous UH injection.

In contrast, LMWH has a half-life of approximately 4 hours. A recent dose may increase the risk of operative morbidity in the form of overt or delayed hemorrhage, hematoma, or wound dehiscence.

Not for use with epidural anesthesia. Case reports of epidural hematomas after regional anesthesia during orthopedic procedures have caused considerable concern about the use of LMWH and the placement of a neuraxial block such as a spinal or epidural.13 Many anesthesiologists will not place an epidural or spinal within 24 hours of a LMWH dose.14 However, as experience with these agents in the nonpregnant population expands, a more evidence-based approach is likely to develop.

Antidote less effective. Protamine sulfate is a strong base that binds with the positively charged UH molecule, thereby serving as an antidote through competitive inhibition. Because of its smaller size, LMWH is reversed by protamine to a lesser degree (approximately 60% effective).14 Therefore, hemorrhage associated with LMWH may require replacement of blood components, which carries the risks of infection and transfusion reactions.

Difficult to monitor. The anticoagulation effect of UH can be reliably monitored by the activated partial thromboplastin time (aPTT), which is a widely available test with a rapid turnaround. However, the anticoagulation effect of LMWH is not reflected by the aPTT. Assessment of LMWH activity requires assessment of the antifactor Xa level, a test that is not universally available and has a longer turnaround.

Higher cost. Another limitation of LMWH is its cost. A single, subcutaneous, prophylactic 40-mg dose of enoxaparin costs about $30, compared with about $1 for an equivalent dose of unfractionated heparin (5,000 U subcutaneously twice a day). Because of its increased cost, many insurance companies do not authorize the use of LMWH for prolonged periods such as pregnancy and the postpartum period. However, studies in the nonpregnant population have demonstrated overall decreased cost over UH due to the reduced need for monitoring, shorter length of hospital stay, and diminished treatment failure.

Question 6What is the dose for prophylaxis and treatment?

The standard dose of enoxaparin for prophylaxis in pregnancy and the postpartum period is 40 mg administered subcutaneously every 24 hours (TABLE 3). Therapeutic anticoagulation (sometimes referred to as a “weightadjusted” dose) is usually achieved with 1 mg/kg every 12 hours.

Dalteparin can be given in a prophylactic dose of 5,000 U subcutaneously every 24 hours and a therapeutic dose of 200 U/kg every 24 hours.15 Dosing may need to be adjusted with advancing gestation as plasma volume, renal clearance, and tissue proteins increase.

The various LMWH preparations are not equivalent in their pharmacokinetics. Generally, clinicians familiarize themselves with a single agent. It also is important to note that dosing regimens in pregnancy are not evidence-based but largely “borrowed” from nonpregnant regimens. They also vary widely in the available literature.

TABLE 3

Common low molecular weight heparins

BRAND NAME

GENERIC NAME

PROPHYLACTIC DOSE

THERAPEUTIC DOSE

Lovenox

Enoxaparin

40 mg every 24 hours

1 mg/kg every 12 hours

Fragmin

Dalteparin

5,000 U every 24 hours

200 U/kg every 24 hours

Note: All doses are subcutaneous

Question 7Under what conditions can LMWH be given?

Generally, LMWH can replace UH in any condition that warrants prophylactic or therapeutic anticoagulation in pregnancy, except the acute management of pulmonary embolism and in women with mechanical heart valves.

Prophylactic dosing can be offered to women with a previous thromboembolic event such as deep vein thrombosis (DVT) or pulmonary embolism that was not associated with a reversible and temporary predisposing risk factor such as immobilization or trauma. (In general, pregnancy is not seen as a reversible or temporary risk factor.)

Prophylactic or therapeutic dosing is sometimes offered to women with a hereditary thrombophilia, antiphospholipid syndrome, or other vasculopathies and connective-tissue diseases. In addition, LMWH is an accepted first-line therapeutic anticoagulant for acute DVT in pregnancy.

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