Antithrombotic Therapy Does Not Improve Outcomes in Recurrent Miscarriage

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 In women with 2 or more unexplained miscarriages, aspirin therapy alone or in combination with the low-molecular-weight heparin derivative nadroparin does not increase the live-birth rate, relative to placebo, despite its widespread use for this purpose.

That is according to the randomized placebo-controlled Anticoagulants for Living Fetuses (ALIFE) study, published online March 24 in the New England Journal of Medicine.

Antithrombotic Therapy Should Not Be Encouraged

The findings in this study "provide good evidence that antithrombotic intervention should not be advocated for unexplained recurrent miscarriage, although further data are needed in women with thrombophilia or with three or more miscarriages," writes I. A. Greer, MD, of Hull York Medical School, University of York, in Heslington, United Kingdom, in an accompanying editorial.

"The widespread use of antithrombotic interventions for women with two or more miscarriages," Dr. Greer contends, "appears to be no more than another false start in the race to identify an effective intervention for this distressing condition that affects so many women."

The study enrolled 364 women aged 18 to 42 years (mean age, 34 years) with a history of 2 or more unexplained miscarriages who were attempting to conceive or who were less than 6 weeks pregnant. The women were randomly assigned to low-dose aspirin alone (80 mg/day; n = 120) or in combination with subcutaneous administration of nadroparin (2850 IU, starting as soon as a viable pregnancy was demonstrated; n = 123), or placebo (n = 121). The primary outcome measure was the live-birth rate.

According to Stef P. Kaandorp, MD, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues, the live-birth rate (the primary outcome measure) did not differ significantly among the 3 study groups, and at a planned second interim analysis, the trial was halted on the basis of futility.

Of the 364 women, 299 became pregnant. The live-birth rates in these women were 61.6% in the aspirin-only group, 69.1% in the combination-therapy group, and 67.0% in the placebo group (absolute difference in live-birth rate: aspirin alone vs placebo –5.4 percentage points; 95% confidence interval [CI], –18.6 to 7.8; combination therapy vs placebo, 2.1 percentage points; 95% CI, –10.8 to 15.0).

"We also found no significant benefit of combination therapy or aspirin alone in subgroup analyses that were stratified according to the number of miscarriages," Dr. Kaandorp and colleagues report. "Likewise, we found no significant benefits in other subgroups, including women with inherited thrombophilia (who might be most likely to benefit from treatment with heparin or aspirin), although our study was not powered to assess subgroup effects."

Consistent with previous research, no major safety issues emerged regarding antithrombotic treatment during pregnancy. Adverse effects, most notably an increased tendency to bruise and swelling or itching at the injection site, occurred in almost half the women in the combination-therapy group.

These findings, the investigators conclude, "do not support the hypothesis that either combination therapy with aspirin and nadroparin or aspirin alone improves the change of a live birth for women with unexplained recurrent miscarriage."

Study Results Consistent With Other Research

"This study and another one that is coming out relatively soon have similar findings and indicate that the use of heparin and aspirin in the treatment of otherwise unexplained miscarriage is not indicated," said D. Ware Branch, MD, who was not involved in the study, in a telephone interview with Medscape Obstetrics & Gynecology when asked for independent comment.

Dr. Branch holds the H.A. and Edna Benning Presidential Chair in Obstetrics and Gynecology at the University of Utah in Salt Lake City.

"I would have expected this result and I think a goodly proportion of the community of experts in recurrent miscarriage would have expected the same thing," added Dr. Branch.

The study was supported in part by a grant from GlaxoSmithKline. Study author Harry R. Büller, MD, PhD, has received consulting and lecture fees from GlaxoSmithKline and Pfizer. Study author Saskia Middeldorp, MD, PhD, has received consulting and lecture fees from GlaxoSmithKline. The other study authors have disclosed no relevant financial relationships.

Dr. Greer has disclosed that his institution received a grant for the SPIN trial relating to antithrombotic treatment of recurrent miscarriage from a government agency. At the behest of the funding source, Sanofi-Aventis UK supplied enoxaparin to a small number of participating centers. Also, Dr. Greer has received honoraria for speaking and advisory group attendance for Sanofi and Leo Pharma.

Dr. Branch has disclosed no relevant financial relationships.

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