Anticoagulants and pregnancy: When are they safe?

INDICATIONS FOR ANTICOAGULANTS DURING PREGNANCY

Acute deep venous thrombosis and pulmonary embolism

Anticoagulant therapy should begin as full doses of either LMWH or intravenous unfractionated heparin. We prefer starting with LMWH, as it can be started rapidly with less need for nursing care (eg, no need to start and maintain an intravenous line and monitor the aPTT) and has excellent safety. If LMWH is selected, initial dosing should be based on the current weight (Table 2). Subsequent monitoring of the peak anti-factor-Xa activity levels (ie, 4 hours after the dose) is recommended, with the first level drawn in the first few days of treatment, and repeat levels every 1 to 3 months for the rest of treatment. As mentioned earlier, weight-based dosing has not been systematically evaluated in pregnancy.

If unfractionated heparin is the initial agent, it should be given as a bolus followed by a continuous infusion, ideally utilizing a weight-based nomogram to estimate required doses, with adjustment of the infusion rate to maintain the aPTT at 1.5 to 2.5 times the baseline value (obtained during pregnancy). After several days, the heparin may be switched to LMWH in therapeutic doses (Table 2).

Alternatively, in women approaching term or who cannot afford LMWH, anticoagulation may be continued as adjusted-dose subcutaneous unfractionated heparin, ie, two or three large daily doses of subcutaneous heparin to provide therapeutic levels of anticoagulation. The starting dose can be calculated as the total units of heparin required to maintain full anticoagulation intravenously over 24 hours, given as two or three divided doses (Table 2). The aPTT at the mid-dosing interval (eg, 6 hours after the subcutaneous dose during every-12-hour dosing) should be monitored and the dose adjusted to maintain the aPTT at 1.5 to 2.5 times the baseline value.

A therapeutic level of anticoagulation should be maintained for at least 3 months after an acute thrombotic event during pregnancy, though many physicians prefer to continue full anticoagulation for a total of 6 months. Beyond this interval, if the woman is still pregnant, the anticoagulation may be reduced in intensity, perhaps even to a prophylactic level for the duration of the pregnancy (see discussion below on prior venous thromboembolic events) (Table 2). Peripartum and postpartum anticoagulation are discussed further below.

PRIOR VENOUS THROMBOEMBOLIC EVENT

While all pregnant women are at higher risk of venous thrombosis, the overall incidence of thromboembolism is only about one event per 1,000 pregnancies. Routine thromboprophylaxis in all pregnant women is therefore not justified. However, women who have previously had a venous thromboembolic event are at a substantially higher risk of recurrent thrombosis and should be considered for thromboprophylaxis in all subsequent high-risk situations, including pregnancy.

For women on indefinite therapeutic anticoagulation (ie, because of recurrent thrombosis), full therapeutic anticoagulation with LMWH or adjusted-dose unfractionated heparin should be maintained throughout pregnancy, as described above.

Which other women should receive prophylactic anticoagulation is a topic of ongoing debate and controversy.

How great is the risk of recurrent thromboembolism?

A small observational study⁵⁹ examined the risk of recurrent venous thromboembolism during subsequent pregnancies in women with a prior thrombotic event. Anticoagulation was withheld during the antepartum period and restarted briefly after delivery. Among the 125 women enrolled, recurrent venous thromboembolism occurred in 4.8%, with half of the events occurring during the antepartum period. Among those with underlying thrombophilia, the rate of recurrent venous thromboembolism was 13% (95% confidence interval [CI] 1.7%–40.5%) to 20% (95% CI 2.5%–56.5%), and those with a prior idiopathic clot without thrombophilia had an event rate of 7.7% (95% CI 0.01%–25.1%). The subgroup with a prior reversible risk factor (at the time of their initial venous thromboembolic event) and without detectable thrombophilia had no recurrent events.

This study suggests that women with prior venous thromboembolism and thrombophilia or a prior idiopathic thrombotic event are at a substantial risk of recurrent thrombotic events during pregnancy. And other data confirm the high risk of recurrent venous thromboembolism in thrombophilic pregnant women.⁶⁰ These women should all be offered active antepartum and postpartum thromboprophylaxis with LMWH or unfractionated heparin (Tables 2 and 4). Women without thrombophilia but with a history of venous thromboembolism related to pregnancy or oral contraceptive use also have a substantial risk of recurrent venous thrombosis and should be offered antepartum and postpartum thromboprophylaxis.⁶¹ In contrast, women with a prior “secondary” clot, no thrombophilia, and no additional current risk factors (Table 1) appear to be at low risk of recurrent venous thromboembolism.

The risks should be discussed with these women, with an option for close clinical surveillance during pregnancy (Table 4), but with a low threshold to investigate any worrisome symptoms. Such women may also elect to take LMWH or unfractionated heparin during pregnancy.