New Data on the Use of Heparin in Recurrent IVF Failure
July 4, 2009
An increased occurrence of anti-phospholipid antibodies (APA) has been observed in nearly 22% of infertile women, and 30% of those with recurrent implantation failure (RIF). In order to overcome the abnormalities in implantation or placentation associated with repeated IVF failure, interventions such as immunoglobulin and antithrombotic therapy (heparin/aspirin) have been suggested. In a recent open-label randomized trial, researchers provided further evidence that administration of luteal phase empirical low molecular weight heparin (LMWH) improves live birth rates in women with recurrent implantation failure (RIF) following ICSI-ET cycles. The findings have been published in the recent issue of the journal, Human Reproduction.
Bulent Urman and coworkers from the Assisted Reproduction Unit of the American Hospital of Istanbul, Turkey, conducted the pilot study on 150 women who had ≥2 failed ART cycles to assess if supplementation of LMWH has any beneficial effect on embryo implantation. After employing the long protocol for controlled ovarian stimulation, the participants were randomly divided to receive either 1 mg/kg/day of LMWH or no treatment, apart from the luteal phase support (LPS) on the day following oocyte retrieval. In the subjects who conceived, the administration of LPS and LMWH was continued till 12 weeks of gestation. The study results are listed in the table below.
| Outcomes | LMWH group | Control group | P value |
| Live birth rate (%) | 34.7 | 26.7 | 0.29 |
| Clinical pregnancy rate (%) | 45.3 | 38.7 | 0.41 |
| Implantation rate (%) | 24.5 | 19.8 | 0.33 |
The researchers suggested that a 30% relative increase in live birth rates in the LMWH group could be considered as a clinically significant trend, supporting further research on the beneficial effect of LMWH in RIF patients as well as in all the subjects opting for ART.
Qublan et al (Human Fertility [Cambridge, England], 2008), in an earlier study, evaluated the safety and efficacy of LMWH for thromboprophylaxis in patients with history of IVF failures and thrombophilia. The researchers reported that LMWH is safe and considerably increases the implantation, pregnancy, and live birth rates in these patients.
Several studies have been conducted to assess the proposed association of APA with RIF after IVF. In one such study, Halbmayer et al (Hamostaseologie, 2005) evaluated 56 patients with mean age of 34.7 ± 4.3 years, who had a previous history of recurrent IVF failures and/or early pregnancy loss. The subjects were screened for resistance against activated protein C (APC), antibodies against annexin V, and APA such as lupus anticoagulant, and antibodies against cardiolipin, or beta2 -glycoprotein-1. Among the participants, 42 of them underwent another IVF cycle after supplementation with LMWH and/or acetylsalicylic acid in those who reported positive resistance against APC, anti-annexin-V antibodies, or APA.
The researchers found that 34% had successful pregnancies following the IVF attempt. It was noted that women with recurrent IVF failures had a higher prevalence of resistance against APC and APA as compared to anti-annexin V antibody positivity. The results also showed that LMWH positively influences the IVF outcomes in such patients.
In a randomized, double-blind, placebo-controlled trial, Stern et al (Fertility and Sterility, 2003) administered heparin (5,000 IU twice daily) and aspirin (100 mg daily) or placebo to IVF implantation failure patients. Contrary to the earlier findings, the investigators did not find any improvement in pregnancy or implantation rates in APA-positive or anti-nuclear antibody-positive RIF patients by administering heparin or aspirin.
Although several studies have identified possible causative factors for implantation failure following ART, only few of them have indicated effective therapeutic solutions. A recent review by Nelson and Greer (Human Re production Update, 2008) suggested that heparin has the potential to improve ART outcomes as it is a structural analogue of heparan sulphates, which play an important role in conception and early pregnancy events. Heparin administration in ART could enhance the success rate by:
• Changing the hemostatic response to controlled ovarian stimulation and altering thrombosis risk
• Modulating the fundamental physiological processes needed for blastocyst apposition, adherence and implantation; and also trophoblast differentiation and invasion.
References
1. Urman B, Ata B, Yakin K, 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 Jul;24(7):1640-7. Epub 2009 Apr 8.
2. Qublan H, Amarin Z, Dabbas M, et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil (Camb). 2008 Dec;11(4):246-53.
3. Halbmayer WM, Feichtinger W, Kindermann C, Prendinger B, Böhm M. Recurrent miscarriage or failed in-vitro fertilization: antibodies against annexin V, cardiolipin, beta-2-glycoprotein-1 and APC-resistance. Hamostaseologie. 2005 Nov;25(4):391-3.
4. Stern C, Chamley L, Norris H, Hale L, Baker HW. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil Steril. 2003 Aug;80(2):376-83.
5. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update. 2008 Nov-Dec;14(6):623-45.
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