Letter regarding “The role of low molecular weight heparin in recurrent implantation failure.”

9 03 2011

To the Editor:

We read with interest the article titled “The role of low molecular weight heparin in recurrent implantation failure: A prospective quasi-randomised, controlled study” by Berker et al. (1). This study addresses the important clinical question of the role of heparin in women with recurrent implantation failure following IVF treatment. This is the second study to evaluate the role of heparin in recurrent implantation failure in the absence of coagulation disorders.

The first study was published by Urman et al in 2009 (2). This was also a single center study on the empirical use of enoxaparin (1 mg/kg daily) in patients with two or more implantation failures and without coagulation disorders that demonstrated an improvement in clinical pregnancy rates, 34.7% (n = 75) versus 26.7% (n = 75), although the low number of patients precluded statistical significance in the results.

The observed relative increase of approximately 30% in live birth rate (LBR) with low molecular weight heparin (LMWH) was proposed by the investigators as a clinically significant trend, necessitating further research on the use of empirical LMWH in assisted reproduction. Although a sample size calculation of 700 participants was made, this trial was concluded early with 150 participants.

Similarly, the study by Berker et al. (1) was a single center study that recruited only 219 participants and evaluated the use of 40 mg of enoxaparin in patients with recurrent implantation failure (RIF). This study showed no significant difference in the live birth rate, clinical pregnancy rate or implantation rate between the study and control groups. Their sample size calculation used with 80% power and an α value of 0.05 for an approximate difference of 8% in the live birth rate giving a sample size of 520 in each arm.. The authors have done a subgroup analysis quoting a nonsignificant increase in the clinical pregnancy rate, live birth rate and implantation rate in patients with >3 implantation failures, although the numbers in this group were small (n=48).

In conclusion, we agree with the authors that a large multicenter randomized controlled trial is needed to evaluate the role of adjuvant heparin in patients with recurrent implantation failure.

Srividya Seshadri, MBBS, MRCOG
S.K. Sunkara, MRCOG
Assisted Conception Unit
Guy’s Hospital
London, United Kingdom

References
1. Berker B, Taskin S, Kahraman K, Taskin EA, Atabekoglu C, Sonmezer M. The role of low-molecular-weight heparin in recurrent implantation failure: a prospective, quasi-randomized, controlled study. Fertility and Sterility In Press, Corrected Proof.

2. Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R et al. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labeled pilot trial. Hum Reprod 2009 July;24(7):1640-7.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.025

The Authors Respond:

We thank Drs. Seshadri and Sunkara for their interest in our paper.

Despite the lack of evidence-based information, empirical low molecular weight heparin (LMWH) is widely used in recurrent implantation failures. This clinical practice mostly depends on the data obtained from preclinical studies indicating probable beneficial effects of heparin on implantation independent from anticoagulant effect.

We have investigated possible benefits of LMWH in women with recurrent implantation failure who do not have coagulation disorders. Even if the design of the study does not recompense a precise randomization, statistical significance of the beneficial effects of LMWH was not demonstrated. However, if patients with 3 or more implantation failures were analyzed as a separate group, studies with larger patient populations may show some beneficial effects.

Definitely, routine administration of LMWH in patients with recurrent implantation failures should not be suggested at this stage. As emphasized by the authors, wide empirical administration of LMWH should be based upon evidence. Further studies with larger patient populations need to be conducted to prove whether the administration of LMWH is beneficial, and if not, to ensure that we no longer recommend its administration. Results of the two available studies that its use be limited to research purposes only.

Bülent Berker, M.D.
Salih Taşkın, M.D.
Department of Obstetrics and Gynecology
Medical School of Ankara University
Ankara, Turkey

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.024

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