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