Low-dose low-molecular-weight heparin proves efficacious for thromboprophylaxis during pregnancy: The Lancet

EUROPE: For thromboprophylaxis during pregnancy, low-dosage, low-molecular-weight heparin is the recommended dose to avoid recurrent venous thromboembolism linked to pregnancy, states a study which was reported in The Lancet.

The primary cause of maternal morbidity and mortality during pregnancy is venous thromboembolism, and pregnant and postpartum women with a history of this condition should get thromboprophylaxis. It is unclear what low-molecular-weight heparin dosage is best for preventing recurrent venous thromboembolism during pregnancy and after delivery.

Therefore, the purpose of this study was to examine the effectiveness of intermediate-dose and low-dose low-molecular-weight heparin in pregnant and postpartum women who had previously experienced venous thromboembolism.

Pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia) for this open-label, randomized, controlled trial (Highlow) . Women who were at least 18 years old, had a history of objectively verified venous thromboembolism, and were at least 14 weeks pregnant were eligible. Prior to the 14th week of pregnancy, eligible women were randomly assigned in a 1:1 ratio, using a web-based system and permuted block randomization (block size of six), stratified by center, to receive either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until the 6th week after delivery.

1339 expectant women were screened between April 24, 2013, and October 31, 2020, and 1110 were randomly assigned to receive weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population).

Deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis, as judged by an independent central adjudication committee, was the primary efficacy outcome in the intention-to-treat (ITT) group (ie, all women randomly assigned to treatment). All women who got at least one dosage of the prescribed treatment and had a known end of treatment date were evaluated for major bleeding, which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post-partum).

Key findings of the study:

  • 11 (2%) of the 555 women in the weight-adjusted intermediate-dose group and 16 (3%) of the 555 women in the fixed low-dose group experienced venous thromboembolism (relative risk [RR] 069 [95% CI 032-147; p=033).
  • 5 (1%) of the women in the intermediate-dose group, 5 (1%) of the women in the low-dose group, and 6 (1%) of the women in the postpartum group experienced venous thromboembolism.
  • In the safety population (N=1045), on-treatment severe bleeding happened in 20 (4%) of the 525 women in the low-dose group and 23 (4%) of the 520 women in the intermediate-dose group (RR 116 [95% CI 065-209]).

The researchers concluded that weight-adjusted intermediate-dose low-molecular-weight heparin did not reduce the incidence of relapse in women with a history of venous thromboembolism compared to fixed low-dose low-molecular-weight heparin during the combined antepartum and postpartum periods.


Bistervels, Ingrid & Buchmüller, Andrea & Wiegers, Hanke & Áinle, Fionnuala & Tardy, Bernard & Donnelly, Jennifer & Verhamme, Peter & Jacobsen, Anne & Hansen, Anette & Rodger, Marc & Desancho, Maria & Shmakov, Roman & Van Es, Nick & Prins, Martin & Chauleur, Céline & Middeldorp, Saskia & Akker, Eline & Bekker, Mireille & Bemmel, Thomas & Zelis, Maartje. (2022). 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. The Lancet. 10.1016/S0140-6736(22)02128-6


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