Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy

Abstract

To assess the safety and efficacy of lowmolecular-weight heparins (LMWHs) for thromboprophylaxis and treatment of venous thromboembolism (VTE) in pregnancy, a systematic review of studies to the end of 2003 was undertaken. Data on VTE recurrence and side effects were extracted and cumulative incidences of VTE and adverse effects calculated. Of 81 reports identified, 64 reporting 2777 pregnancies were included. In 15 studies (174 patients) the indication for LMWH was treatment of acute VTE, and in 61 studies (2603 pregnancies) it was thromboprophylaxis or adverse pregnancy outcome. There were no maternal deaths. VTE and arterial thrombosis (associated with antiphospholipid syndrome) were reported in 0.86% (95% confidence interval [CI], 0.55%-1.28%) and 0.50% (95% CI, 0.28%-0.84%) of pregnancies, respectively. Significant bleeding, generally associated with primary obstetric causes, occurred in 1.98% (95% CI, 1.50%-2.57%), allergic skin reactions in 1.80% (95% CI, 1.34%-2.37%), heparin-induced thrombocytopenia in 0%, thrombocytopenia (unrelated to LMWH) in 0.11% (95% CI, 0.02%-0.32%), and osteoporotic fracture in 0.04% (95% CI, < 0.01%-0.20%) of pregnancies. Overall, live births were reported in 94.7% of pregnancies, including 85.4% in those receiving LMWH for recurrent pregnancy loss. LMWH is both safe and effective to prevent or treat VTE in pregnancy. IntroductionPulmonary embolism (PE) remains the leading cause of direct maternal death in the United Kingdom 1 and venous thromboembolism (VTE) in pregnancy is an important cause of morbidity, not only in pregnancy but also in the long term. 2 Effective primary prevention and acute management of VTE in pregnancy are therefore important to reduce maternal mortality and morbidity. Coumarins cross the placenta and their use in pregnancy is associated with significant fetal and maternal risks, related particularly to teratogenesis and hemorrhage. 3 For many years, unfractionated heparin (UFH) was the standard anticoagulant used in pregnancy. 4 Low-molecular-weight heparins (LMWHs) have replaced UFH for the prevention and management of acute VTE without pregnancy. 5,6 In the United Kingdom, Europe, and Australasia, LMWHs are now also widely used for the prevention and treatment of VTE in pregnancy. 7,8 The advantages of LMWHs over UFH include an enhanced ratio of anti-Xa (antithrombotic) to anti-IIa (anticoagulant), resulting in a reduced risk of bleeding; stable and predictable pharmacokinetics with increased bioavailability and half-life, allowing less frequent fixed or weight-based dosing without the need for monitoring; subcutaneous administration 8 ; and less activation of platelets, with less binding to platelet factor 4 substantially reducing the risk of heparin-induced thrombocytopenia (HIT). 9,10 A major concern with the widespread use of UFH in pregnancy has been the 2% risk of symptomatic heparininduced osteoporotic fracture in pregnancy. 9 LMWHs are associated with a lower risk of this devastating complication. [11][12][13] Peer-reviewed international guid...

Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence‐based lens

“…A significant absolute risk increase (ARI) in haemorrhage >1000 ml was found (ARI = 4.4%; P  < 0.001), which would likely be lower for women only receiving LMWH postpartum. Other observational studies estimate the risk of significant haemorrhage to be 0.3–1.1% 5, 50, 51…”

“…Large studies of obstetric and non‐obstetric patients receiving prophylactic LMWH have demonstrated minimal risk 4, 17, 50, 52…”

Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis

“…31 To our knowledge, three reviews systematically evaluated bone complications of long-term LMWH treatment in pregnant participants prone to VTE. [29][30][31] Ensom et al 29 reviewed 40 studies associated with long-term LMWH use in over 700 pregnant women and found two cases of osteoporotic vertebral fractures. Greer et al 30 identified 64 eligible studies in 2777 pregnancies comparing long-term LMWH against control treatments and found one study reporting one vertebral fracture (rate: 0.04 %) in a woman treated with high-dose LMWH (15,000 IU/day) for 9 months.…”

“…[29][30][31] Ensom et al 29 reviewed 40 studies associated with long-term LMWH use in over 700 pregnant women and found two cases of osteoporotic vertebral fractures. Greer et al 30 identified 64 eligible studies in 2777 pregnancies comparing long-term LMWH against control treatments and found one study reporting one vertebral fracture (rate: 0.04 %) in a woman treated with high-dose LMWH (15,000 IU/day) for 9 months. The authors warned about other cases of osteoporotic fractures in this population and urged further research concerning LMWH-induced osteoporosis.…”

“…The effects of LMWH on bone were mainly studied in the pregnant population. Some research has suggested that long-term LMWH prophylaxis in pregnancy for at least 3 months was associated with bone loss and fractures, [29][30][31] although others have argued that the absolute risk of fracture in this population was small (1-2 %) 32 and that decreases in mean bone mineral density (BMD) of 2-4 % caused by the prophylactic doses of LMWH or unfractionated heparin (UFH) were similar to the bone loss that occurs physiologically during pregnancy. 33,34 Nevertheless, a decrease in BMD of 2-4 % or a small increase in the risk of fracture of up to 2 % would be clinically important for other adult populations such as cancer patients or the elderly who may require long-term LMWH and whose baseline risk of fractures is increased owing to aging or underlying comorbidities.…”