Anticoagulants and pregnancy: When are they safe?
ABSTRACTPrescribing anticoagulants to pregnant women can be difficult and stressful. Fortunately, low-molecular-weight heparins (LMWHs) and unfractionated heparin are quite safe and efficacious when properly selected, dosed, and monitored. Maternal and fetal concerns must be considered at all times, with a careful assessment of the risks and benefits of anticoagulant therapy in each patient. Further research should help to clarify who should receive thromboprophylaxis, how to prevent adverse pregnancy outcomes in women with various thrombophilias, and how best to treat pregnant women who have a prosthetic heart valve.
KEY POINTS
- Pregnancy is a hypercoagulable state. Thrombotic risk in an individual pregnancy depends on many maternal and situational factors.
- When indicated, careful anticoagulation can proceed with minimal risk to the mother and fetus.
- Heparins, especially LMWHs, are the main anticoagulants used in pregnancy. Dosing depends on the clinical indications and on the agent selected.
- If anticoagulation is absolutely necessary and LMWH is contraindicated, a newer, alternative anticoagulant should be considered.
- Warfarin should not be used in pregnancy in any but the highest-risk situations.
Which heparin to use?
Prophylactic anticoagulation during pregnancy can be with either LMWH or unfractionated heparin. For most women this involves “prophylactic” dosing with the goal of maintaining a mid-interval anti-factor-Xa activity level of approximately 0.05 to 0.2 U/mL. Thromboprophylaxis with LMWH can be with lower, fixed, once-daily doses throughout pregnancy20 (Table 2), although some clinicians still prefer twice-daily dosing. The heparin should be started as soon as pregnancy is confirmed, as the pregnancy-associated increase in thrombotic risk begins by the middle of the first trimester.
To maintain effective prophylactic levels, the dose of unfractionated heparin should be increased sequentially over the trimesters62,63: approximately 5,000 units subcutaneously twice daily in the first trimester, then 7,500 units twice daily in the second trimester, and 10,000 units twice daily in the third trimester for a woman of average size.
When to add low-dose aspirin
Women with antiphospholipid antibodies, particularly those with prior recurrent pregnancy loss or fetal demise, should receive aspirin 81 mg/day in addition to heparin.39 The aspirin may be started prior to conception or when pregnancy is confirmed.
Other measures
Women on anticoagulant therapy who are at risk of recurrent venous thromboembolism should be encouraged to wear elastic compression stockings. Intermittent pneumatic compression of the legs via automated devices may be considered for women hospitalized for any reason or on bedrest.
Whichever measures are used, a high index of suspicion and a low threshold for investigating for recurrent thrombosis should be maintained throughout pregnancy and the puerperium.
PERIPARTUM AND POSTPARTUM MANAGEMENT OF ANTICOAGULATION
Heparin therapy must be interrupted temporarily during the immediate peripartum interval to minimize the risk of hemorrhage and to allow for the option of regional anesthesia. As mentioned earlier, because of the theoretical risk of paraspinal hemorrhage in women receiving heparin who undergo epidural or spinal anesthesia, the American Society of Regional Anesthesia guidelines advise waiting to insert the needle at least 10 to 12 hours after the last prophylactic dose of LMWH, and at least 24 hours after the last therapeutic dose.31
The guidelines state that neuraxial anesthesia is not contraindicated in patients on prophylactic unfractionated heparin.31
To facilitate use of regional anesthesia in these women, therefore, options include:
- Electively stopping LMWH 24 hours before planned induction of labor
- Electively stopping prophylactic-dose LMWH or unfractionated heparin at about 38 weeks of gestation, to await spontaneous labor, or
- Switching therapeutic or prophylactic LMWH to unfractionated heparin at about 36 weeks of gestation, with instructions to discontinue the injections in the earliest stages of spontaneous labor. This aims to shorten the heparin-free period required before neuraxial anesthesia while minimizing maternal thrombotic risk.
Additional advantages to using unfractionated heparin peripartum include the option of obtaining a rapid aPTT measurement to confirm the absence of a significant ongoing heparin effect prior to regional anesthesia or delivery, and the ability to completely reverse the heparin effect with protamine sulfate if major bleeding occurs. LMWHs are only partially reversible.64
Interrupting anticoagulation after an initial thrombotic event
If therapeutic anticoagulation must be interrupted for labor within 1 month of the initial thrombotic event, the risk of recurrent thrombotic complications is high65; these women must be observed very carefully and may benefit from intravenous heparin before and after delivery. They may even merit placement of a temporary vena cava filter (particularly if less than 2 weeks have elapsed since the venous thromboembolic event and in women with a large deep venous clot burden), a procedure that has been used safely but little studied in pregnant women.66
Fluoroscopic guidance may be needed for filter placement. This exposes the fetus to radiation, but the low-level exposure at this late gestational age is unlikely to pose a significant risk. The filter may be removed within 1 to 2 weeks postpartum, assuming there are no ongoing contraindications to anticoagulation.
In the rare woman with antithrombin deficiency and a recent or prior thrombotic event, giving antithrombin concentrate during the peripartum (heparin-free) interval has been described and may be considered under the guidance of a hematologist.67
Ongoing anticoagulation is essential postpartum, as the puerperium is the period of highest day-to-day risk of thromboembolic events: about one-third of pregnancy-associated events occur during these 6 to 12 weeks.2 Heparin should be resumed 6 to 12 hours after delivery, once hemostasis is confirmed.
Options for women requiring ongoing therapeutic anticoagulation include intravenous heparin started without a bolus, to minimize bleeding risk, with aPTT measured 12 hours later, or an initial prophylactic dose of LMWH 6 to 12 hours postpartum, with therapeutic dosing resumed on postpartum day 1. If prophylactic dosing is desired, unfractionated heparin or LMWH may be given subcutaneously starting at about 6 hours postpartum.
Warfarin in the puerperium
Women may subsequently be maintained on either LMWH or unfractionated heparin, or switched to an oral anticoagulant such as warfarin. Although warfarin may appear in minute amounts in breast milk, it has not been associated with adverse events in newborns and is considered compatible with breastfeeding.68 Heparin should be continued during the initial days of warfarin therapy, until the INR is at a therapeutic level for 24 hours. Some physicians prefer to delay warfarin for several days, giving LMWH alone in the immediate postpartum period, to allow wound-healing and to reduce bleeding risk.
Postpartum, anticoagulation should be continued for at least 6 to 12 weeks, at which point the physiologic changes in the coagulation system related to pregnancy will have returned to normal.
