Deep vein thrombosis (DVT) and pulmonary embolism (PE) are collectively referred to as venous thromboembolic events. Approximately 75–80% of cases of pregnancy- associated venous thromboembolism are caused by DVT, and 20–25% of cases are caused by PE. One half of these events occur during pregnancy and one half occur during the postpartum period.
Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women. Approximately 80% of thromboembolic events in pregnancy are venous, with a prevalence of 0.5–2.0 per 1,000 pregnant women. Pregnancy and the puerperium put women at increased risk of venous thromboembolism (VTE) due to both baseline maternal risk factors and the development of pregnancy-related prothrombotic anatomic and physiologic changes.
Pregnant women are at an approximately 5-fold increased risk of VTE compared with nonpregnant women, and the risk of VTE increases further (to ≥ 20-fold) in puerperium; risk remains increased until approximately 12 weeks postpartum. In Western nations, venous thromboembolism is an important cause of morbidity and the most common cause of maternal death during pregnancy and the puerperium. Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries, or 9 % of all maternal deaths in the United States. In the developing world, the leading cause of maternal death is hemorrhage; however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death. The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy.
Pregnancy is associated with physiologic and anatomic changes that increase the risk of thromboembolism, including hypercoagulability, increased venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the enlarging uterus, and decreased mobility. Pregnancy alters the levels of coagulation factors normally responsible for hemostasis. The overall effect of these changes is an increased thrombogenic state. When DVT occurs during pregnancy, it is more likely to involve the left lower extremity.
The risk of venous thromboembolism may be higher in the third trimester compared with the first and second trimesters, but the increased risk of venous thromboembolism is present from the first trimester, often before many anatomic changes of pregnancy occur. The risk of venous thromboembolism is higher during the postpartum period than it is during pregnancy, especially during the first week postpartum.
The most important individual risk factor for venous thromboembolism in pregnancy is a personal history of thrombosis. The risk of recurrent venous thromboembolism during pregnancy is increased threefold to fourfold (relative risk, 3.5; 95% confidence interval, 1.6–7.8), and 15–25% of all cases of venous thromboembolism in pregnancy are recurrent events. The next most important individual risk factor for venous thromboembolism in pregnancy is the presence of a thrombophilia. Thrombophilia is present in 20–50% of women who experience venous thromboembolism during pregnancy and the postpartum period. Both acquired and inherited thrombophilias increase the risk of venous thromboembolism.
Besides a personal history of thrombosis, other risk factors for the development of pregnancy-associated venous thromboembolism include the physiologic changes that accompany pregnancy and childbirth, medical factors (such as obesity, hemoglobinopathies, hypertension, and smoking), and pregnancy complications (including operative delivery).
The use of anticoagulation therapy in women during pregnancy warrants special consideration for both mother and fetus. Most women who require anticoagulation therapy before conception will need to continue this therapy during pregnancy and the postpartum period. Common anticoagulation medications include unfractionated heparin, low molecular weight heparin (LMWH), and warfarin.
The preferred anticoagulants in pregnancy are heparin compounds.
Neither unfractionated heparin nor LMWH crosses the placenta and both are considered safe in pregnancy. Unique considerations regarding the use of anticoagulation therapy in pregnancy include a 40–50% increase in maternal blood volume; an increase in glomerular filtration, which results in increased renal excretion of heparin compounds; and an increase in protein binding of heparin. During pregnancy, both unfractionated heparin and LMWH have shorter half-lives and lower peak plasma concentrations, usually necessitating higher doses and more frequent administration in order to maintain effective concentrations.
There are few comparative studies of LMWH use in pregnancy, but in nonpregnant patients, LMWH has been associated with fewer adverse effects than unfractionated heparin. Potential advantages of LMWH include fewer bleeding episodes, a more predictable therapeutic response, a lower risk of heparin-induced thrombocytopenia, a longer half-life, and less bone mineral density loss
Importantly, neither LMWH nor unfractionated heparin is associated with significant bone loss when used in prophylactic doses during pregnancy. Unfractionated heparin, which is associated with increased bruising at the injection sites, also has been associated with other skin reactions and serious allergic reactions. Moreover, unfractionated heparin is dispensed in multiple-dose vials, which are potentially vulnerable to contamination. Besides its greater cost, a relative disadvantage of LMWH at the time of delivery is its longer half-life, which is an important consideration for both neuraxial anesthesia and peripartum bleeding risk.
Warfarin, a common agent for long-term anticoagulation therapy outside of pregnancy, has been associated with potentially harmful fetal effects, especially with first trimester exposure. Warfarin embryopathy has been linked with exposure at 6–12 weeks of gestation, highlighting the importance of early pregnancy care in such patients. Therefore, for most women receiving prolonged anticoagulation therapy who become pregnant, it is recommended that unfractionated heparin or LMWH be used in place of warfarin.
Although rarely prescribed in pregnancy, warfarin is still considered in pregnancy for women with mechanical heart valves because of their high risk of thrombosis even with heparin or LMWH anticoagulation therapy. The management of such women requires a multidisciplinary care approach, and the decision regarding optimal anticoagulation therapy merits a detailed discussion with the patient and her health care providers regarding the risks and benefits of the various treatment options.
Note: Clinical Considerations and Recommendations for managing the Thromboembolism in pregnancy shall be discussed in the subsequent article.