Intermediate-Dose Versus Low-Dose Low-Molecular-Weight Heparin in Pregnant and Post-Partum Women with a History of Venous Thromboembolism (Highlow Study): An Open-Label, Multicentre, Randomised, Controlled Trial

Abstract

ABSTRACT Venous thromboembolism (VTE) in pregnancy is a major cause of maternal morbidity and mortality, but its prevention, medical thromboprophylaxis, can cause bleeding complications. Without thromboprophylaxis, up to 10% of women with a history of VTE are at risk of pregnancy-related recurrence. For those women with a history of VTE who are not on long-term anticoagulation medication, guidelines recommend subcutaneous low-molecular-weight heparin (LMWH) in all women in the postpartum stage. For those with moderate or high risk of recurrent VTE, antepartum thromboprophylaxis is recommended. In both cases, the optimal dose of heparin is unknown, and professional societies do not provide clear specific guidance often recommending multiple different dosing approaches without clear evidence to guide recommendations. The aim of this study was to assess the efficacy and safety of low- versus intermediate-dose LMWH in pregnant women with a history of VTE. This was an open-label, randomized controlled study conducted at 70 hospitals in the Netherlands, France, Belgium, Norway, Demark, Canada, the United States, and Russia. Included were adult pregnant women with a history of objectively confirmed VTE, either unprovoked or provoked by hormonal or minor risk factors, and a gestational age ≤14 weeks. Excluded were women with previous VTE related to a major risk factor, indication for therapeutic-dose anticoagulants, or contraindication to LMWH. Eligible women were randomly assigned to receive either weight-adjusted intermediate-dose heparin or fixed, low-dose heparin. Participants self-administered their allocated dose of heparin once daily and participated in in-person or telephone contacts 2 weeks after randomization; at 20 and 30 weeks of gestation; and 1 week, 6 weeks, and 3 months postpartum. The primary efficacy outcome was symptomatic VTE, and the primary safety outcome was major bleeding. A total of 1110 women were included in the analysis—555 were randomized to the intermediate-dose group and 555 to the low-dose group. Approximately 81% of women had a history of VTE related to hormone use, pregnancy, or the postpartum period. From randomization to 6 weeks postpartum, VTE occurred in 2% of women in the intermediate-dose group and 3% in the low-dose group (relative risk, 0.69; 95% confidence interval, 0.32–1.47; P = 0.33). Antepartum VTE occurred in 1% of women in each treatment group; postpartum VTE occurred in 1% in the intermediate-dose group and 2% in the low-dose group. These findings remained consistent up to 3 months postpartum. From randomization to 6 weeks postpartum, major bleeding occurred in 4% of women in the intermediate-dose group and 4% in the low-dose group (relative risk, 1.16; 95% confidence interval, 0.65–2.09; p = 0.63). Antepartum major bleeding occurred in <1% of women in each treatment group. Early postpartum bleeding occurred in 4% in the intermediate-dose group and 3% in the low-dose group. Last postpartum bleeding occurred in <1% in the intermediate-dose group and none in the low-dose group. In comparing weight-adjusted, intermediate-dose LMWH with fixed, low-dose LMWH, the risk of VTE was similar in pregnant women with a history of VTE in the antepartum and postpartum periods. Moreover, no differences were observed in the occurrence of major bleeding between the 2 treatment groups. These findings provide evidence-based guidance that low-dose heparin is appropriate for preventing pregnancy-related recurrent VTE.