Thrombosis in Pregnancy
TREATMENT
ANTICOAGULATION THERAPY
The treatment of VTE can be lifesaving. In a study comparing 35 patients with PE randomly assigned to treatment with anticoagulants versus no treatment, 5 of 19 patients in the untreated group died from PE and an additional 5 had nonfatal recurrences, as compared with none in the treated group.24 Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are both safe and effective anticoagulants during pregnancy as neither crosses the placenta. In a review of 186 reports of fetal and infant outcomes following anticoagulant therapy during pregnancy in 1325 pregnancies, outcomes in UFH-treated patients were similar to those in the normal population after excluding pregnancies with comorbid conditions independently associated with adverse outcomes.34 A 2005 systematic review of LMWH for prophylaxis and treatment of VTE during pregnancy included 64 studies of 277 pregnancies. There were no maternal deaths, live births resulted from 94.7% of the pregnancies, VTE or arterial thrombosis occurred in 0.86%, and significant bleeding occurred in 1.98%.35
The standard UFH regimen is an initial bolus of 5000 units subcutaneously and 17,500 units every 12 hours, with dose adjustment made based on a mid-interval activated partial thromboplastin time (aPTT).36 Although still controversial, it has been suggested that the anti-Xa assay with a mid-dosing interval target of 0.3 to 0.7 U/mL is a more reliable measure of therapeutic UFH activity than the aPTT, as the aPTT response is suppressed due to a pregnancy-related increase in factor VIII. LMWH is dosed based on weight; regimens are enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg subcutaneously once daily, and dalteparin 100 units/kg every 12 hours or 150 units/kg daily.
A 2017 Cochrane review of the effect of LMWH compared with UFH for the treatment of VTE in the nonpregnant setting included 23 studies with 9587 patients. Thrombotic complications (odds ratio [OR] 0.70 [CI 0.57 to 0.85]) and major hemorrhage (OR 0.58 [CI 0.40 to 0.83]) were lower in patients receiving LMWH, with a trend toward lower mortality.37 In addition, the incidence of bleeding complications in patients treated with subcutaneous LMWH versus intravenous heparin was compared in a 2012 systematic review of 27 randomized controlled trials with a total of 28,637 patients. In patients treated with LMWH, there was a nonstatistically significant lower incidence of major bleeding events (OR 0.79 [95% CI 0.60 to 1.04]) and a statistically significant reduction in bleeding risk (OR 0.68 [95% CI 0.47 to 1.00]) compared to patients treated with UFH.38 Additionally, a trial comparing the use of standard UFH versus LMWH found a significantly lower incidence of thrombocytopenia in patients treated with LMWH.39,40 Overall, LMWH is more effective at decreasing both thrombotic and bleeding complications, and the risk for osteoporosis is lower with LMWH. Based on these results, the American College of Chest Physicians (ACCP) recommends LMWH as the first-line treatment for VTE in pregnancy.41
,In specific clinical situations, such as patients with renal dysfunction with creatinine clearance (CrCl) less than 30 mL/min, UFH is indicated. In a study of 103 pregnancies in 93 women given anti-coagulation during pregnancy, 89.3% received UFH. There were no maternal deaths, and fetal demise occurred in 8 pregnancies (7.8%) at a median of 14 weeks’ gestation. There were 2 episodes of PE (1.9%) and 2 major bleeding events requiring transfusion (1.9%).42 UFH costs much less than LMWH, and therefore UFH remains an important, inexpensive, and efficacious anticoagulant option for pregnant women who require anticoagulation and cannot afford LMWH.43
Due to the physiologic changes associated with pregnancy, LMWH and UFH dosages may need to be adjusted. An observational study of 20 pregnant women with acute VTE found no recurrent VTE or major bleeding after treatment with dalteparin. Dalteparin doses approximately 10% to 20% higher than those recommended in nonpregnant women were required to reach therapeutic target anti-Xa activity.44
Caution Regarding Oral Anticoagulants
Due to its teratogenicity, warfarin is not a first-line anticoagulation option. It is strictly contraindicated during the first trimester during organogenesis, and its use during pregnancy is restricted to women with mechanical heart valves. Warfarin crosses the placenta and has been associated with nasal hypoplasia, stippled epiphyses, and growth restriction, particularly between 6 to 9 weeks’ gestation. Every effort should be made to substitute UFH or LMWH for warfarin between 6 and 12 weeks of gestation. The bridging process should begin as early in the gestational age as possible due to the long half-life of warfarin.45 When used later in gestation, warfarin has been associated with fetal hemorrhage and central nervous system abnormalities. Other complications from use during the second and third trimesters include microcephaly, blindness, deafness, and fetal growth restriction.46,47 Its use also increases the risk for abortion and fetal death in utero.48–50
The direct oral anticoagulants (DOACs) are not approved for use in pregnancy. Although there are limited anecdotal reports of DOAC use in pregnancy,51 there is preclinical evidence of placental transfer with the DOACs rivaroxaban and apixaban (direct Xa inhibitors) and the oral thrombin inhibitor dabigatran, thus increasing the risk to the fetus.52–54 Edoxaban, another direct Xa inhibitor, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should be discontinued in nursing mothers.55
