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Cited by 352Reproductive System and PregnancySystemic Lupus Erythematosus ResearchBlood Coagulation and Thrombosis Mechanisms

Low Molecular Weight Heparin and Aspirin for Recurrent Pregnancy Loss: Results from the Randomized, Controlled HepASA Trial

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LASKIN, CARL A., SPITZER, KAREN A., CLARK, CHRISTINE A., CROWTHER, MARK R., GINSBERG, JEFF S., HAWKER, GILLIAN A., KINGDOM, JOHN C., BARRETT, JON +1 more·2009·The Journal of Rheumatology
DOI 10.3899/jrheum.080763
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Abstract

Objective.: To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts. Methods.: The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT. Results.: Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA. Conclusion.: LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.

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  • Pooled data from one RCT in women with first-trimester losses and eight observational studies not exclusively early losses indicated higher likelihood of live births with LDA plus prophylactic heparin versus LDA alone.

    “Pooled data from one RCT including only patients with a history of first trimester losses46 and eight supporting observational studies47–54 that did not exclusively study women with early pregnancy losses indicated a higher likelihood of live births with combination treatment with LDA and heparin at prophylactic dosage versus LDA alone.”

    From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [54]

    The Objectives section says the HepASA trial included women with losses before 32 weeks, and Table 1 (Discussion) records participants with histories of losses after 14 weeks. It was therefore not restricted to first-trimester losses. The Abstract reports no live-birth advantage for heparin plus aspirin over aspirin alone in this trial; the eight observational studies are cited separately in the claiming sentence. (LLM, conf=0.92)

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Research works printed but not linked: 4

  1. Carson SA, Branch DW. ACOG Practice Bulletin 24. Management of recurrent early pregnancy loss. 2002 Compendium of Selected Publications. Washington, DC: American College of Obstetricians and Gynecologists; 2001:372-83.
  2. Ramsay Goldman R. Pregnancy in systemic lupus erythematosus. Rheum Dis Clin North Am 1988;14:169-85.
  3. Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipids antibodies. BMJ 1997;314:253-7.
  4. Erkan D, Merrill JT, Yazici Y, et al. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum 2001;44:1466-7.

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Authors
LASKIN, C. A., SPITZER, K. A., CLARK, C. A., CROWTHER, M. R., GINSBERG, J. S., HAWKER, G. A., KINGDOM, J. C., BARRETT, J., & GENT, M.
Affiliations
  • University of Toronto (CA)
  • Mount Sinai Hospital (CA)
ORCID
Venue
The Journal of Rheumatology
Publisher
The Journal of Rheumatology
Published
2009-02
Volume
36
Issue
2
Pages
279-287
ISSN
  • 0315-162X (ISSN-L)
  • 1499-2752
DOI
10.3899/jrheum.080763
OpenAlex
W2022226231
Cited by
352
References
43
Citations by year
2026: 8 · 2025: 5 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 11 · 2020: 18 · 2019: 19 · 2018: 16 · 2017: 33 · 2016: 11 · 2015: 28 · 2014: 33 · 2013: 22 · 2012: 19
FWCI
15.96
Type
journal article
Language
en
Open access
Locations
  • The Journal of Rheumatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • Pfizer Canada
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
recurrent pregnancy loss, low molecular weight heparin, aspirin, antiphospholipid antibodies, antithrombotic therapy, live birth rate, bone mineral density, inherited thrombophilia, antinuclear antibodies, pregnancy loss prevention, adverse events, bone loss
MeSH terms
Abortion, Habitual, Adult, Anticoagulants, Antibodies, Antinuclear, Aspirin, Autoimmune Diseases, Blood Coagulation Disorders, Female, Heparin, Low-Molecular-Weight, Humans, Platelet Aggregation Inhibitors, Pregnancy, Pregnancy Complications, Hematologic, Cohort Studies, Bone Density, Antiphospholipid Syndrome, Treatment Outcome, Thrombophilia

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