Adjunct low-molecular-weight heparin to improve live birth rate after recurrent implantation failure: A systematic review and meta-analysis

Human Reproduction Update

Volumn 19, Issue 6, 2013, Pages 674-684

  Potdar, Neelam ^a   Gelbaya, Tarek A ^a   Konje, Justin C ^b   Nardo, Luciano G ^c  

^a UNIVERSITY HOSPITALS OF LEICESTER NHS TRUST   (United Kingdom)

^b UNIVERSITY OF LEICESTER   (United Kingdom)

^c Reproductive Medicine and Surgery Unit   (United Kingdom)

Author keywords

Heparin; IVF; Low molecular weight heparin; Recurrent implantation failure; Thrombophilia

Indexed keywords

ACETYLSALICYLIC ACID; DALTEPARIN; ENOXAPARIN; HEPARIN; LOW MOLECULAR WEIGHT HEPARIN; PLACEBO;

ALLERGIC REACTION; ARTICLE; BIRTH RATE; BLEEDING; CONGENITAL DISORDER; FERTILIZATION IN VITRO; HUMAN; LIVE BIRTH; META ANALYSIS; NIDATION; OUTCOME ASSESSMENT; PREGNANCY OUTCOME; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECURRENT IMPLANTATION FAILURE; RISK ASSESSMENT; SKIN BRUISING; SPONTANEOUS ABORTION; SYSTEMATIC REVIEW; THROMBOCYTOPENIA; THROMBOPHILIA; TREATMENT FAILURE;

HEPARIN; IVF; LOW-MOLECULAR-WEIGHT HEPARIN; RECURRENT IMPLANTATION FAILURE; THROMBOPHILIA;

ABORTION, HABITUAL; ANTICOAGULANTS; BIRTH RATE; EMBRYO IMPLANTATION; FEMALE; HEPARIN, LOW-MOLECULAR-WEIGHT; HUMANS; LIVE BIRTH; PREGNANCY; RANDOMIZED CONTROLLED TRIALS AS TOPIC; THROMBOPHILIA;

EID: 84886305110     PISSN: 13554786     EISSN: 14602369     Source Type: Journal    
DOI: 10.1093/humupd/dmt032     Document Type: Article

References (59)

1. Altmae S, Martinez-Conejero JA, Salumets A, Simon C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod 2010; 16:178-187.
2. Azem F, Many A, Ben Ami I, Yovel I, Amit A, Lessing JB, Kupferminc MJ. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod 2004; 19:368-370.
3. Bellver J, Soares SR, Alvarez C, Munoz E, Ramirez A, Rubio C, Serra V, Remohi J, Pellicer A. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008;23:278-284.
4. 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. Fertil Steril 2011;95:2499-2502.
5. Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M, Whyte S, Greer IA. Scottish Pregnancy Intervention Study SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood 2010;115:4162-4167.
6. Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C et al. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature 2002;417:945-948.
7. Coulam CB, Jeyendran RS, Fishel LA, Roussev R. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod Biomed Online 2006; 12:322-327.
8. Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992;166:1318-1323.
9. Di Simone N, Caliandro D, Castellani R, Ferrazzani S, De Carolis S, Caruso A. Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Hum Reprod 1999;14:489-495.
10. Di Simone N, Di Nicuolo F, Sanguinetti M, Ferrazzani S, D'Alessio MC, Castellani R, Bompiani A, Caruso A. Low-molecular weight heparin induces in vitro trophoblast invasiveness: role of matrix metalloproteinases and tissue inhibitors. Placenta 2007;28:298-304.
11. Dobson AT, Davis RM, Rosen MP, Shen S, Rinaudo PF, Chan J, Cedars MI. Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF. Hum Reprod 2007;22:450-456.
12. Erden O, Imir A, Guvenal T, Muslehiddinoglu A, Arici S, Cetin M, Cetin A. Investigation of the effects of heparin and low molecular weight heparin on E-cadherin and laminin expression in rat pregnancy by immunohistochemistry. Hum Reprod 2006; 21:3014-3018.
13. Fareed J, Walenga JM. Why differentiate low molecular weight heparins for venous thromboembolism? Thromb J 2007;5:8.
14. Fluhr H, Krenzer S, Stein GM, Stork B, Deperschmidt M,Wallwiener D,Wesselborg S, Zygmunt M, Licht P. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis. J Cell Sci 2007;120:4126-4133.
15. Fluhr H, Carli S, Deperschmidt M, Wallwiener D, Zygmunt M, Licht P. Differential effects of human chorionic gonadotropin and decidualization on insulin-like growth factors-I and -II in human endometrial stromal cells. Fertil Steril 2008; 90:1384-1389.
16. Fluhr H, Spratte J, Ehrhardt J, Steinmuller F, Licht P, Zygmunt M. Heparin and low-molecular-weight heparins modulate the decidualization of human endometrial stromal cells. Fertil Steril 2010;93:2581-2587.
17. Garrido-GomezT, Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Vilella F, Simon C. Profiling the gene signature of endometrial receptivity: clinical results. Fertil Steril 2013; 99:1078-1085.
18. Geva E, Amit A, Lerner-Geva L, Azem F, Yovel I, Lessing JB. Autoimmune disorders: another possible cause for in-vitro fertilization and embryo transfer failure. Hum Reprod 1995;10:2560-2563.
19. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004;10:1222-1226.
20. Grandone E, Colaizzo D, Lo Bue A, Checola MG, Cittadini E, Margaglione M. Inherited thrombophilia and in vitro fertilization implantation failure. Fertil Steril 2001; 76:201-202.
21. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
22. Hills FA, Abrahams VM, Gonzalez-Timon B, Francis J, Cloke B, Hinkson L, Rai R, Mor G, Regan L, Sullivan M et al. Heparin prevents programmed cell death in human trophoblast. Mol Hum Reprod 2006;12:237-243.
23. Isaka K, Usuda S, Ito H, Sagawa Y, Nakamura H, Nishi H, Suzuki Y, Li YF, Takayama M. Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts. Placenta 2003;24:53-64.
24. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN et al. (2010) Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med 2010; 362:1586-1596.
25. Klai S, Fekih-Mrissa N, El Housaini S, Kaabechi N,Nsiri B, Rachdi R, Gritli N. Association of MTHFR A1298C polymorphism (but not of MTHFR C677T) with elevated homocysteine levels and placental vasculopathies. Blood Coagul Fibrinolysis 2011; 22:374-378.
26. Kutteh WH. (1996) Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996;174:1584-1589.
27. Kutteh WH. Report from the Society for Gynecologic Investigation, Atlanta, Georgia. J Reprod Immunol 1998;40:175-182.
28. Kutteh WH, Yetman DL, Chantilis SJ, Crain J. Effect of antiphospholipid antibodies in women undergoing in-vitro fertilization: role of heparin and aspirin. Hum Reprod 1997;2:1171-1175.
29. Linhardt RJ,Wang HM, Ampofo SA. New methodologies in heparin structure analysis and the generation of LMW heparins. Adv Exp Med Biol 1992;313:37-47.
30. Lodigiani C, Di Micco P, Ferrazzi P, Libre L, Arfuso V, Polatti F, Benigna M, Rossini R, Morenghi E, Rota L et al. Low-molecular-weight heparin in women with repeated implantation failure. Womens Health (Lond Engl) 2011;7:425-431.
31. Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T. Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod 2006;21:3036-3043.
32. Miyakis S, Lockshin MD, Atsumi T, BranchDW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.
33. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. Open Med 2009;3:123-130.
34. Nair RR, Khanna A, Singh R, Singh K. Association of maternal and fetalMTHFR A1298C polymorphism with the risk of pregnancy loss: a study on an Indian population and a meta-analysis. Fertil Steril 2013;99:1311-1318.
35. Nardo LG, Granne I, Stewart J., Policy and Practice Committee of the British Fertility Society. Medical adjuncts in IVF: evidence for clinical practice. Hum Fertil 2009; 12:1-13.
36. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update 2008;14:623-645.
37. Noci I, Milanini MN, Ruggiero M, Papini F, Fuzzi B, Artini PG. Effect of dalteparin sodium administration on IVF outcome in non-thrombophilic young women: a pilot study. Reprod Biomed Online 2011;22:615-620.
38. Perminova SG YK, Okhtyrskaya T, Shurshalina AV. The role of thrombophilia in IVF implantation failure. J Reprod Med Endocrinol 2010;7:240-383.
39. Qublan HS, Eid SS, Ababneh HA, Amarin ZO, Smadi AZ, Al-Khafaji FF, Khader YS. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 2006;21:2694-2698.
40. Qublan H, Amarin Z, Dabbas M, Farraj AE, Beni-Merei Z, Al-Akash H, Bdoor AN, Nawasreh M, Malkawi S, Diab F et al. Low-molecular-weight heparin in the treatment of recurrent IVF-ET failure and thrombophilia: a prospective randomized placebo-controlled trial. Hum Fertil 2008;11:246-253.
41. Rai R, CohenH,DaveM, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnantwomen with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253-257.
42. Review Manager 5.1. The Cochrane Collaboration. Copenhagen: The Nordic Cochrane Centre, 2011.,
43. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361:901-908.
44. Ricci G, Giolo E, Simeone R. Heparin's 'potential to improve pregnancy rates and outcomes' is not evidence-based. Hum Reprod Update 2010;16:225-227; author reply 27-28.
45. Rinehart J. Recurrent implantation failure: definition. J Assist Reprod Genet 2007; 24:284-287.
46. Schenk LM BL, Morris JP, Cox B, Lecte J, Abuhamed A, Ochninger S, Toner JP, Muasher S. Heparin and aspirin treatment yields higher implantation rates in IVF patients with antiphospholipid antibodies seropositivity compared to untreated seronegative patients (abstract), Boston, USA, In: Proceedings of the Annual Meeting of the American Society of Reproductive Medicine, 1996.
47. Seremak-Mrozikiewicz A, Drews K, Kurzawinska G, Bogacz A, Grzeskowiak E, Mrozikiewicz PM. The significance of 1793G.A polymorphism in MTHFR gene in women with first trimester recurrent miscarriages. Neuro Endocrinol Lett 2010; 31:717-723.
48. Seshadri S, Sunkara SK, Khalaf Y, El-Toukhy T, Hamoda H. Effect of heparin on the outcome of IVF treatment: a systematic review and meta-analysis. Reprod Biomed Online 2012;25:572-584.
49. Sher G, Feinman M, Zouves C, Kuttner G, Maassarani G, Salem R, Matzner W, ChingW, Chong P. High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod 1994;9:2278-2283.
50. Sher G, Matzner W, Feinman M, Maassarani G, Zouves C, Chong P, Ching W. The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am J Reprod Immunol 1998a;40:74-82.
51. Sher G, Zouves C, Feinman M, Maassarani G, MatznerW, Chong P, ChingW.Arational basis for the use of combined heparin/aspirin and IVIG immunotherapy in the treatment of recurrent IVF failure associated with antiphospholipid antibodies. Am J Reprod Immunol 1998b;39:391-394.
52. Simon A, Laufer N. Repeated implantation failure: clinical approach. Fertil Steril 2012; 97:1039-1043.
53. 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;80:376-383.
54. Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins-correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005;11:7003-7011.
55. Tamada H, Higashiyama C, Takano H, Kawate N, Inaba T, Sawada T. The effects of heparin-binding epidermal growth factor-like growth factor on preimplantationembryo development and implantation in the rat. Life Sci 1999;64:1967-1973.
56. Tan WK, Lim SK, Tan LK, Bauptista D. Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. Singapore Med J 2012;53:659-663.
57. Thornhill AR, deDie-Smulders CE, Geraedts JP, Harper JC, Harton GL, Lavery SA, Moutou C, Robinson MD, Schmutzler AG, Scriven PN et al. ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'. Hum Reprod 2005; 20:35-48.
58. Urman B, Ata B, Yakin K, Alatas C, Aksoy S, Mercan R, BalabanB. 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; 24:1640-1647.
59. Wilcox AJ, Baird DD,Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999;340:1796-1799.