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

Background: Pregnancy-related venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and postpartum women with a history of VTE.The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the postpartum period is uncertain.Methods: In this international, open-label, randomised trial, pregnant women with a history of venous thromboembolism were randomised before 14 weeks of gestational age to weight-adjusted intermediatedose or fixed low-dose low-molecular-weight heparin until 6 weeks postpartum.The primary efficacy outcome was objectively confirmed venous thromboembolism.The primary safety outcome was major bleeding.Findings: A total of 1,110 pregnant women were randomised and included in the intention-to-treat population.Venous thromboembolism occurred in 11 of 555 (2•0%) women assigned to weight-adjusted intermediate-dose low-molecular-weight heparin and in 16 of 555 (2•9%) assigned to fixed low-dose lowmolecular-weight heparin (relative risk, 0•69; 95% confidence interval [CI], 0•32-1•47; P=0•33).Venous thromboembolism occurred antepartum in five (0•9%) and five (0•9%) women, and postpartum in six (1•1%) and 11 women (2•0%) in the intermediate-dose and low-dose groups, respectively.On-treatment venous thromboembolism in the per-protocol population (N=972) occurred in 1•0% and 2•4% (relative risk, 0•43; 95% CI, 0•15-1•20).On-treatment major bleeding in the safety population (N=1,045) occurred in 4•4% and in 3•8% receiving intermediate-dose or low-dose low-molecular-weight heparin, respectively (relative risk, 1•16; 95% CI, 0•65-2•09).Interpretation: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and postpartum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin.These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose.Postpartum, intermediate-dose low-molecular-weight heparin may be more effective than low dose low-molecular-weight heparin.(ClinicalTrials.govnumber, NCT01828697)