ANTICOAGULATION IS ESSENTIAL in a wide variety of conditions in women of child-bearing age. Some, such as venous thromboembolism, occur more often during pregnancy. Others, such as recurrent fetal loss in the setting of antiphospholipid antibodies, are specific to pregnancy.
While anticoagulants are useful in many circumstances, their use during pregnancy increases the risk of hemorrhage and other adverse effects on the mother and the fetus. Treatment with anticoagulants during pregnancy must therefore be carefully considered, with judicious selection of the agent, and with reflection on the physiologic changes of pregnancy to ensure appropriate dosing. In this article, we review these issues.
WHY IS THROMBOTIC RISK HIGHER DURING PREGNANCY?
Venous thromboembolism is among the leading causes of maternal death in developed countries. 1–3 Modern care has dramatically reduced the risk of maternal death from hemorrhage, infection, and hypertension, but rates of morbidity and death from thrombosis have remained stable or increased in recent years. 4
Pregnancy is a period of increased risk of thrombotic complications (TABLE 1) , owing to hypercoagulability, venous stasis, and vascular damage—the three elements of Virchow’s triad. 5 Several changes to the maternal coagulation system increase clotting risk:
- Much higher levels of fibrinogen and factors VII, VIII, IX, and X
- Lower levels of protein S and increased resistance to activated protein C
- Impaired fibrinolysis, due to inhibitors derived from the placenta.
Acquired antithrombin deficiency may also occur in high-proteinuric states such as nephrotic syndrome or preeclampsia, further increasing thrombotic risk. Pooling of venous blood, caused by progesterone-mediated venous dilation and compounded by compression of the inferior vena cava by the uterus in later pregnancy, also increases thrombotic risk. And endothelial disruption of the pelvic vessels may occur during delivery, particularly during cesarean section.
Additional factors that increase thrombotic risk include immobilization, such as bed rest for pregnancy complications; surgery, including cesarean section; ovarian hyperstimulation during gonadotropin use for in vitro fertilization; trauma; malignancy; and hereditary or acquired hypercoagulable states. 6 These hypercoagulable states include deficiencies of antithrombin or the intrinsic anticoagulant proteins C or S; resistance to activated protein C, usually due to the factor V Leiden mutation; the PT20210A mutation of the prothrombin gene; hyperhomocystinemia due to mutation of the methyltetrahydrofolate reductase (MTHFR) gene; and the sustained presence of antiphospholipid antibodies, including lupus anticoagulant antibodies, sometimes also with moderately high titers of anticardiolipin or beta-2-glycoprotein I antibodies.
Other conditions that increase thrombotic risk include hyperemesis gravidarum, obesity, inflammatory bowel disease, infection, smoking, and indwelling intravenous catheters. 6 Given the multitude of risk factors, pregnant women have a risk of thrombotic complications three to five times higher than nonpregnant women. 7
HEPARIN USE DURING PREGNANCY
Low-molecular-weight heparins (LMWHs) 8 and unfractionated heparin bind to anti-thrombin and thus change the shape of the antithrombin molecule, dramatically increasing its interaction with the clotting factors Xa and prothrombin (factor II). The enhanced clearance of these procoagulant proteins leads to the anticoagulant effect. Unfractionated heparin has roughly equivalent interaction with factors Xa and II and prolongs the activated partial thromboplastin time (aPTT), which is therefore used to monitor the intensity of anticoagulation.
LMWHs, on the other hand, interact relatively little with factor II and do not predictably prolong the aPTT. Monitoring their effect is therefore more difficult and requires direct measurement of anti-factor-Xa activity. This test is widely available, but it is time-consuming (it takes several hours and results may not be available within 24 hours if the test is requested “after hours”), and therefore it is of limited use in the acute clinical setting. While weight-based dosing of LMWHs is reliable and safe in nonpregnant patients, it has not yet been validated for pregnant women.
Unfractionated heparin has been used for decades for many indications during pregnancy. It is a large molecule, so it does not cross the placenta and thus, in contrast to the coumarin derivatives, does not cause teratogene-sis or toxic fetal effects. Its main limitations in pregnancy are its inconvenient dosing (at least twice daily when given subcutaneously) and its potential maternal adverse effects (mainly osteoporosis and heparin-induced thrombocytopenia).
Over the last 10 years LMWHs have become the preferred anticoagulants for treating and preventing thromboembolism in all patients. They are equivalent or superior to unfractionated heparin in efficacy and safety in the initial treatment of acute deep venous thrombosis 9,10 and pulmonary embolism 11,12 outside of pregnancy. While comparative data are much less robust in pregnant patients, several series have confirmed the safety and efficacy of LMWHs in pregnancy. 13–15 LMWHs do not cross the placenta