Safety and Efficacy of Low-Molecular-Weight Heparin in Pregnant Women at Increased Risk of Venous Thromboembolism: A Prospective Stratified Multicentre Trial.
Authors: Bauersachs Rupert M. , Dudenhausen Joachim , Faridi Andree , Fischer Thorsten , Fung Samson , Geisen Ulrich , Harenberg Job , Herchenhan Eberhard , Keller Franz , Kemkes-Matthes Bettina , Schinzel Helmut , Spannagl Michael , Thaler Christian J. ,   for the EThIG Investigators
Published: October 2019

Abstract
Women with a history of VTE, thrombophilia or both are at increased risk for VTE during pregnancy, but the optimal management strategy, and the need for thromboprophylaxis is not well defined in clinical guidelines because of limited trial data. The EThIG (Efficacy of Thromboprophylaxis as an Intervention during Gravidity) is a multicenter trial that prospectively enrolled 810 pregnant women at risk of VTE. Women were assigned to one of 3 management strategies: Low risk group I (including women with prior secondary VTE, or asymptomatic thrombophilia) with “watchful waiting” management, and dalteparin prophylaxis postpartum (50–100 IU/kg), or earlier if additional risk factors occurred; high risk group II (e.g. idiopathic VTE or symptomatic thrombophilia) receiving 50–100 IU/kg dalteparin; and very high-risk group III (e.g. acute VTE, prior long-term OAC, symptomatic AT-deficiency or antiphospholipid syndrome), receiving 100–200 IU/kg dalteparin. Primary efficacy outcome measure was symptomatic VTE, main safety outcome measures were haemorrhages, osteoporosis, thromboctopenia and pregnancy outcome.
Results (mean ± SD / 95% CI): 810 women (age 30.8±5.4 years, weight 73.6±16.1kg) were enrolled, 28 % in group I, 58 % in II and 14% in III, including 66 women with acute VTE. 60.1% had prior VTE, 75.4% had thrombophilia (42.1 % FV-Leiden, 2.1 % homozygous, 9.5 % FII G20210A, 4.1% PC-, 1 % AT-deficiency; 17.4 % APS). 35.8 % had previous miscarriage, still birth or physical malformation. Comorbid conditions included lupus erythematosus, liver transplantation, ventricular septum defect, paraplegia, hepatitis C, nephrotic syndrome, asthma, chronic haemolytic anaemia, thalassaemia, osteoporosis and thrombocytopaenia. Median treatment initiation was at 17.0 weeks, at 24.0 weeks in group I, 14.5 weeks in group II and 16.0 weeks for group III. Mean daily dose was 66.2 ± 22.5 IU per kg (group I), 76.8 ± 24.1 IU per kg (group II) and 120.0 ± 49.1 IU per kg (group III). Objectively confirmed, symptomatic VTE occurred in 5 of 810 women (0.6%;0.2–1.5%). The rate of serious bleeding was 3.0% (1.9–4.4%), 0.9% (0.3–1.8%) occurred in the antepartum period, 2.1% (1.3–3.4%) peri-partum;1.1% (0.5–2.2%) was possibly heparin-related. There was no evidence of heparin-induced thrombocytopenia, and one case of osteoporosis (fracture of the saccygous bone during delivery). There were 94.4% successful pregnancies, 40 foetuses (4.9%; 3.6–6.7%) were lost due to miscarriage, 7 due to elective termination. Risk-stratified heparin prophylaxis was associated with a low incidence of symptomatic venous thromboembolism and few clinically important adverse events. Antepartum heparin prophylaxis is warranted in pregnant women with prior idiopathic thrombosis or symptomatic thrombophilia.