Higher dose of thromboprophylaxis in pregnant woman not necessary No higher risk of new thromboembolism at low-dose than at intermediate-dose

Pregnant women who have had venous thrombosis or pulmonary embolism in the past require the anticoagulant drug low-molecular-weight heparin to reduce the risk of new blood clots. During pregnancy, a low dose is enough, whereas after delivery, a higher dose is needed. This was found in large international study led by Saskia Middeldorp of Radboud university medical center. 

Women who have already had venous thromboembolism (VTE) run a 6 to 10 percent risk of a new blood clot in a vein or the lungs during pregnancy and in in the 6 weeks after delivery. Therefore, they have to use preventive medication during this period; consisting of a daily injection of low-molecular-weight heparin. But for a long time, how much heparin was needed remained unclear.

The Highlow study fills this knowledge gap of optimal drug dosing in pregnant women. The international clinical trial was led by Saskia Middeldorp, previously internist and professor at Amsterdam UMC and now head of the department of Internal Medicine at Radboudumc. The researchers followed 1,100 women with a history of venous thromboembolism in nine countries during their pregnancy and the six weeks after delivery. Half of the women received a low dose of low-molecular-weight heparin; the other half received a higher, double dose. The researchers wanted to know how often venous thromboembolism occurred during pregnancy and childbirth. 

No difference during pregnancy

Looking at the entire period from pregnancy to 6 weeks after delivery, there appeared to be no statistical difference between the two groups; the risk of a recurrent venous thromboembolism was found to be 2.0 percent in the intermediate-dose group and 2.9 percent in the low-dose heparin group. 

During pregnancy, the risk of a recurrent venous thromboembolism or pulmonary embolism was the same in both groups: 0.9 percent. This means that the low dose is sufficient to reduce the risk of new blood clots during pregnancy. And that's good news, says Middeldorp: ‘It's not a pleasant drug. Pregnant women have to inject themselves every day with heparin; the only drug we know is safe for the baby. We are now establishing for the first time that a low dose during pregnancy works just as well. We also reliably determined the risk of recurrent venous thromboembolism despite anticoagulation medication. This provides clarity. The low dose gives fewer side effects at the injection sites and makes giving an epidural during delivery easier. In addition, it saves half the cost.’

After delivery

During the six weeks after delivery however, a higher dose appeared more effective than the low amount. During this postpartum period, the risk of recurrent venous thromboembolism is highest. ‘We do not yet know exactly why, but likely causes are the tissue damage caused by childbirth and the changing composition of the blood,’ says Middeldorp. 

This knowledge is useful for the conversation between doctor and patient, Middeldorp says. ‘Women can now make an informed decision about whether or not to consider a new pregnancy after a previous venous thromboembolism. Venous thrombosisand pulmonary embolism are serious diseases and knowledge about the risks and optimal medication to prevent recurrence during pregnancy are very important. We now provide women with much better information.’

Research in pregnant women

Middeldorp wants more high-quality thrombosis research for women, particularly during pregnancies. Middeldorp: ‘For a long time one thought that we know how the female body works during pregnancy and no specific research was conducted. But during pregnancy blood volume increases, drugs distribute differently in the body and heparin is processed faster by the healthy kidneys, all known information. Yet such a large study of anticoagulants in pregnant women has never been done before.’

Until now, the amount of heparin that pregnant women received after a venous thromboembolism varied from hospital to hospital and was based on research in people who had ondergone hip or knee replacement. Middeldorp: ‘These are often older people whose kidneys don't work as well, for example, so a low dose may have a different effect than in pregnant women. I find it unbearable that they had to inject themselves daily with a drug for ten months, without knowing whether this was effective. That's why I'm so pleased with these results. Now we know what’s best.’

About the publication

This article appeared in The Lancet: Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and postpartum women with a history of venous thromboembolism (Highlow Study): an open-label, multicentre, randomised, controlled trial - Ingrid M. Bistervels, Andrea Buchmüller, Hanke M.G. Wiegers, Fionnuala Ní Áinle, Bernard Tardy, Jennifer Donnelly, Peter Verhamme, Anne F. Jacobsen, Anette T. Hansen, Marc A. Rodger, Maria T. DeSancho, Roman G. Shmakov, Nick van Es, Martin H. Prins, Céline Chauleur, Saskia Middeldorp, for the Highlow Investigators.

Photo: baby Vaeda, photographer: milestonesbyrana.

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