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NEW ORLEANS -- Daily injections of low-molecular-weight heparin (LMWH) failed to improve live birth rates for women with a history of recurrent miscarriages and inherited forms of thrombophilia, a randomized trial found.

In the 326-patient study, live birth rates were a similar 71.6% in women who received LMWH versus 70.9% with standard pregnancy care alone (adjusted OR 1.08, 95% CI 0.65-1.78, P=0.77), reported Saskia Middeldorp, MD, PhD, of the University of Amsterdam.

"The conclusions and take-home messages are pretty clear and ... end a debate of decades," Middeldorp said during a press briefing at the American Society of Hematology annual meeting.

But "we should not say this a negative study," she added. "What we can do in our offices, in our practices, is reassure women with a history of recurrent pregnancy loss that they have a 70% chance of having a healthy baby."

Side effects, while mostly minor, were significantly more frequent in the LMWH arm, with 43.9% experiencing one or more adverse events versus 26.5% in the control arm (OR 2.17, 95% CI 1.32-3.55). Common side effects included easy bruising, skin reactions at the injection site, and minor bleeding.

Middeldorp said the findings suggest that women with recurrent miscarriages should no longer be tested for inherited thrombophilia, pointing out that elimination of this testing could save an estimated $4,000, along with the additional $3,500 in savings for LMWH injections over the duration of a pregnancy.

In the U.S., "many women do get thrombophilia testing when they've had recurrent miscarriages, and there can be a lot of pressure of doing something versus doing nothing," said press briefing moderator Cynthia Dunbar, MD, of the National Heart, Lung, and Blood Institute at the NIH.

"I had recurrent miscarriages myself and at the time read the literature and decided I wasn't going to push for that and it didn't make sense, but it was a hard decision," she told MedPage Today. "Luckily, I also had two successful pregnancies after three miscarriages -- so I have some personal experience with this."

Dunbar said she hoped the findings would "settle the issue," and that patients will stop getting very expensive panels that then label them as having a disease even if they have never had a clot.

"It's not necessarily information that is helpful in any way, expect making you very anxious," she said. "I was very happy about this trial -- not happy about the results, I guess, but happy that at least it's clear and it was a very well-performed trial."

Past studies have shown an association between recurrent miscarriages and inherited thrombophilia, while other research has suggested that clots in the developing placenta could be a causal factor in miscarriages.

In a from Middeldorp and colleagues in which anti-thrombotic therapy failed to increase live birth rates for women with unexplained recurrent miscarriages, there was a hint of potential benefit for the very small subgroup of women with inherited thrombophilia, leading to the current trial.

"For inherited thrombophilia, the curtains are closing in terms of aspirin and anticoagulants," said Middeldorp, adding that the only group that benefits from aspirin and LMWH are women with acquired thrombophilia antiphospholipid syndrome.

ALIFE2 was an investigator-initiated trial that from 2012 to 2021 randomized 326 pregnant women with two or more miscarriages and inherited thrombophilia to standard care with or without LMWH (enoxaparin 40 mg, dalteparin 5,000 IU, tinzaparin 4,500 IU, or nadroparin 3,800 IU). Aspirin was also used in 11% of patients.

Participants had to be enrolled at gestational age of 7 weeks or earlier. Overall, more than 10,000 women were screened for inclusion over the 9-year study period at 41 centers in five countries (the Netherlands, U.S., U.K., Slovenia, and Belgium), with most women excluded for not having confirmed inherited thrombophilia.

The primary endpoint was live birth rate, with secondary endpoints including miscarriage and adverse obstetric outcomes. Safety outcomes included bleeding episodes, thrombocytopenia, skin reactions, and neonatal congenital malformations.

Average patient age was 33-34 years, most were white, and 70% of the women in each arm had experienced three or more prior miscarriages. The most common thrombophilia types were heterozygosity for factor V Leiden (55-58%), prothrombin 20210A mutation (24-27%), and protein S deficiency (13-14%), while 3.6% had combined thrombophilia.

The OR for the primary endpoint adjusted for differences in baseline characteristics, including maternal age, number of miscarriages, type of center, and country.

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