Heparin unable to prevent miscarriages in women with inherited thrombophilia

Daily shots of low-molecular weight heparin (LMWH) fall short of improving live birth rates for women with a history of at least two pregnancy losses and inherited thrombophilia, according to the results of the open-label trial ALIFE2.

There was no significant difference in live birth rates between the women who received LMWH and those who received standard care (absolute risk difference, 0.7 percent, 95 percent confidence interval [CI], –9.2 percent to 10.6 percent; adjusted odds ratio, 1.08, 95 percent CI, 0.65 to 1.78; p=0.770). [Lancet 2023;doi:10.1016/S0140-6736(23)00693-1]

“Obviously, we all want to find a cure for miscarriage. The positive thing about this is there’s no doubt [that LMWH] made no difference at all. The number of live births in each group was almost identical—71.6 percent in the LMWH group and 70.9 percent in the standard care group,” said lead investigator Prof Siobhan Quenby of Warwick Medical School, University of Warwick, Coventry, UK, who spoke to an audience at RCOG 2023.

“The other interesting thing is the side effects and safety of LMWH. We had no—absolutely zero—heparin-induced thrombocytopenia, which I think is quite reassuring for people who are using LMWH a lot for thromboprophylaxis,” Quenby reported.

Overall, 72 of 164 women (44 percent) in the LMWH group and 43 of 162 women (27 percent) in the standard care group reported adverse events. Quenby noted a difference in adverse events but pointed out that such differences included only minor bleeding, a bit of nose bleeding, and a few bruises around the injection site (absolute difference, 17.4 percent, 95 percent CI, 7.2–27.6; odds ratio, 2.17, 95 percent CI, 1.32–3.55).

Finally, in a subgroup analysis, the results were similar to that of the primary analysis. There was no difference in live birth rates between the LMWH and the standard care treatment arms across subgroups of younger women with thrombophilia, those who had three or more miscarriages, those who had never had a child, and those with different types of thrombophilia.

Psychological support required

In light of the present data, Quenby advised against using LMWH in women with inherited thrombophilia and recurrent miscarriage to prevent another pregnancy loss.

“We also do not recommend … test[ing] people for inherited thrombophilia because we do not have effective treatment and, more controversially, miscarriage is not entirely about excessive coagulation,” she said. “I think we really need to move on with miscarriage and think about other things, particularly how we’re going to support these women psychologically.”

As part of the take-home message, Quenby stressed that women with recurrent miscarriage experience pain and bleeding and go through psychological trauma, given the controversy amongst experts as to how many miscarriages people had to have before they could be referred to a recurrent miscarriage clinic.

If women have been through miscarriage twice, they now then have a 30-percent chance of it happening again, Quenby said. She pointed out that while there isn’t enough resources to refer all of them to an expensive recurrent miscarriage service, these women do need psychological support and should not be told to return only after a third miscarriage for blood tests.

Lower treatment burden

Quenby shared that she and her team were hoping that their study would help lower the burden of treatment and testing. She referred to all those clinical centres who couldn’t join in the trial because the consultant already did screening for inherited thrombophilia and already gave LMWH, explaining that if the screening and treatment did not happen, there would be significant cost savings.

“Enoxaparin costs about GBP 6, so if we give it for 36 weeks, we’re taking about GBP 1,685. And [this drug] is more expensive in North America,” Quenby said.

Study details

ALIFE2 assessed a total of 10,625 women for eligibility, of which 326 conceived and were randomly assigned to receive standard care alone or alongside LMWH. The participants were recruited from hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1).

The eligibility criteria were as follows: two or more pregnancy losses, confirmed inherited thrombophilia, and trying to conceive or were already pregnant (≤7 weeks' gestation). LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy.

“This trial was not blinded because we didn’t think it was ethically acceptable to expect pregnant women to inject themselves with normal saline every day throughout pregnancy,” Quenby noted.

The sample size was also modest, she added, but the rate of loss to follow-up was low.