Thrombosis in Pregnancy
For women with a history of estrogen-related VTE, single unprovoked VTE, or recurrent unprovoked VTE not on chronic anticoagulation, antepartum and postpartum pharmacologic thromboprophylaxis with either prophylactic or intermediate-dose LMWH is recommended (grade 2C). In patients with prior history of provoked VTE (non-estrogen related), antepartum clinical vigilance and postpartum pharmacologic thromboprophylaxis is recommended (grade 2C, 2B).
In asymptomatic pregnant women who are homozygote carriers for factor V Leiden or prothrombin G20210A variants and have a positive family history of thrombosis, antepartum and postpartum pharmacologic thromboprophylaxis is recommended (grade 2B). In asymptomatic homozygote carriers of factor V Leiden or prothrombin G20210A variants with no family history of thrombosis and women with all other thrombophilias with a positive family history of thrombosis, postpartum pharmacologic thromboprophylaxis is indicated (grade 2B and 2C, respectively). For women with confirmed APS and clinical criteria of obstetric APS with recurrent pregnancy loss, antepartum thromboprophylaxis with LMWH and low-dose aspirin is recommended (grade 1B). For pregnant women with all other thrombophilias with no personal or family history of thrombosis, clinical vigilance is suggested (grade 2 C).78
As an alternative to LMWH, vitamin K antagonists (VKA) such as warfarin can be used for postpartum thromboprophylaxis; in patients with protein C or S deficiency, due to the risk of warfarin-induced skin necrosis, a rapid-onset anticoagulant must be concomitantly administered. Warfarin and LMWH are safe anticoagulants during lactation, but there are no clinical data on the effects of the DOACs on infants during lactation. Data from animal studies indicate that DOACs are secreted into breast milk.85
,What risks are associated with anticoagulant therapy in pregnancy?
VKAs cross the placenta and can cause teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits. Therefore, discontinuation of VKAs prior to the sixth week of gestation is necessary to avoid warfarin embryopathy. DOACs have been shown to readily cross the placenta but with unknown human reproductive risks. Fondaparinux, a synthetic pentasaccharide, crosses the placenta in small quantities. Though there are reports of the successful use of fondaparinux in pregnancy, there is limited reported experience of its use in the first trimester.86
The risk for bleeding with anticoagulation is notably acceptable. In a case-control study of 88 pregnant women receiving therapeutic-dose anticoagulation, the risk of postpartum hemorrhage (PPH) after vaginal delivery was 30% in those who received LMWH anticoagulation versus 18% in those who did not (OR 1.9 [95% CI 1.1 to 3.5]).87 However, the risk for severe PPH (≥ 500 mL) was similar (5.6% versus 5.0%; OR 1.1 [95% CI 0.4 to 3.6]). The risk for PPH after cesarean section was 12% in LMWH users versus 4% in LMWH non-users (OR 2.9 [95% CI 0.5 to 19.4]). The risk for PPH associated with delivery within 24 hours after the last dose of LMWH was 1.2 times higher (95% CI 0.4 to 3.6) compared to a longer interval. Therefore, therapeutic LMWH increases the risk for blood loss after vaginal delivery, but not the risk for severe PPH. The risk for PPH is influenced by the interval between the last dose of LMWH and delivery. Of note in this study, per the institution’s protocol, the anticoagulation was stopped with signs of labor or determination of need for delivery. The risk for blood loss may be mitigated in more planned delivery scenarios.87
CASE 4 CONTINUED
The patient is placed on prophylactic-dose LMWH with good tolerance and delivers at 39 weeks' gestation via caesarian section due to nonprogression of labor. Postpartum she is restarted on prophylactic-dose anticoagulation with LMWH. Two weeks after discharge from the hospital, she presents with right calf pain and mild shortness of breath. On physical exam, her leg circumferences are equal. A D-dimer assay is 3375 ng/mL (normal 0–229). CUS of the right leg shows a complete occlusive DVT of the mid-distal superficial femoral and popliteal veins and partially occlusive acute DVT of the right posterior tibial and peroneal veins. CTPA reveals a right lower lobe PE. Because she had developed VTE despite prophylactic LMWH, her anticoagulation is changed to therapeutic dose. She is treated with anticoagulation with LMWH for a total of 3 months, after which a repeat CUS shows no residual thrombosis.
What is the recommended dosing of heparin and LMWH during pregnancy?
A prospective study of 14 pregnant women receiving UFH prophylaxis found that a prophylactic dose of 5000 units twice a day was inadequate to achieve prophylactic heparin levels in any patient in the second or third trimester.88 Similar to treatment dosage, there is no consensus evidence for prophylactic dosing, and dosage recommendations are based on expert opinion. In a retrospective study of 25 pregnant women on intermediate-dose UFH, the mean UFH dose required to achieve a target anti-factor Xa level of 0.1 to 0.3 units/mL was 236.9 units/kg/day.89 However, the use of anti-factor Xa levels for monitoring is controversial as there is no data to support a difference in outcomes with its use in prophylactic or therapeutic dosing.
