Journal of Assisted Reproduction and Genetics

, Volume 14, Issue 10, pp 603–608 | Cite as

Antiphospholipid Antibodies Associated with Implantation Failure After IVF/ET

  • Carolyn B. Coulam
  • Brian D. Kaider
  • Azadeth S. Kaider
  • Patrick Janowicz
  • Roumen G. Roussev


Purpose: Our purpose was to determine the specific anti-phospholipid antibodies (APAs) that should be evaluated to identify individuals at risk for implantation failure associated with reproductive autoimmune failure syndrome (RAFS).

Methods: The prevalence of APAs among 312 women with implantation failure was compared with that of 100 fertile control women. To be included in the implantation failure group, each woman had to have had at least 12 embryos transferred without subsequent positive pregnancy test. Enzyme-linked immunoabsorbant assay was used to measure IgG, IgM, and IgA anticardiolipin, antiphosphatidyl ethanol-amine, antiphosphatidyl inositol, antiphospatidic acid, antiphosphatidyl glycerol, antiphosphatidyl choline, and antiphosphatidyl serine.

Results: When the values for each of the seven APAs in three isotypes were compared between women with implantation failure and the control population, all of the APAs tested had a significantly higher frequency among women with implantation failure. Positive APAs were detected in 69 (22%) of the 312 women with implantation failure compared with 5 (5%) of the 100 control women (P < 0.0001). Anticardiolipin antibodies were found in 13 (4%) of the 312 women with implantation failure and none of the controls. Fifty-six (18%) of the 312 with implantation failure were negative for anticardiolipin antibodies but had positive values of other APAs.

Conclusions: A complete APA panel using seven isotypes is necessary for diagnosing implantation failure associated with RAFS. If only anticardiolipin antibody is measured, 4% (13/312) of the positive APAs are detected, and 81% (56/69) of women with implantation failure associated with RAFS will have the diagnosis missed.

antiphospholipid antibodies implantation failure in vitro fertilization embryo transfer 


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  1. 1.
    Cowchock S, Smith JB, Gocial B: Antibodies to phospholipids and nuclear antigens in patients with repeated abortions. Am J Obstet Gynecol 1986;155:1002–1010Google Scholar
  2. 2.
    Petri M, Golbus M, Anderson R, Whiting-O'Keefe Q, Corash L, Hellmann D: Antinuclear antibody, lupus anticoagulant, and anticardiolipin antibody in women with idiopathic habitual abortion: A controlled prospective study of 44 women. Arth Rheum 1987;30:601–606Google Scholar
  3. 3.
    Triplett DA: Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1989;20:52–67Google Scholar
  4. 4.
    Rote NA, Dostal-Johnson DA, Branch DW: Antiphospholipid antibodies and recurrent pregnancy loss: correlation between the activated partial thromboplastin time and antibodies against phosphatidyl-serine and cardiolipin. Am J Obstet Gynecol 1990;163:575–584Google Scholar
  5. 5.
    Roussev RG, Kaider BD, Price DE, Coulam CB: Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol 1996;35:415–420Google Scholar
  6. 6.
    Yetman DL, Kutteh WH: Antiphospholipid antibody panels and recurrent pregnancy loss: Prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril 1996;66:540–546Google Scholar
  7. 7.
    Matzner W, Chong P, Xu G, Ching W: Characterization of antiphospholipid antibodies in women with recurrent spontaneous abortions. J Reprod Med 1994;39:27–30Google Scholar
  8. 8.
    Gilman-Sachs A, Lubinski J, Beer AE, Brend S, Beaman KD: Patterns of antiphospholipid antibody specificities. J Clin Lab Immunol 1991;35:83–88Google Scholar
  9. 9.
    Branch DW, Silver R, Pierangeli S, Van Leeuwen I, Harris EN: Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls and antiphospholipid syndrome. Obstet Gynecol 1997;89:549–555Google Scholar
  10. 10.
    Hughes GR, Harrison EN, Gharavi AE: The anticardiolipin syndrome. J Rheumatol 1986;13:486–489Google Scholar
  11. 11.
    Bringly PJ, Hoffbrand BI: Antiphospholipid antibody syndrome: A review. J Roy Soc Med 1987;80:445–448Google Scholar
  12. 12.
    Gleicher N, El-Roeiy A, Confino E, Friberg J: Reproductive failure because of autoantibodies: Unexplained infertility and pregnancy wastage. Am J Obstet Gynecol 1989;160:1376–1385Google Scholar
  13. 13.
    Nilsson IM, Astedt B, Hedner U, Berezin D: Intrauterine death and circulating anticoagulant (“antithromboplastin”). Acta Med Scand 1975;197:153–159Google Scholar
  14. 14.
    Gleicher N, El-Roeiy A: The reproductive autoimmune failure syndrome. Am J Obstet Gynecol 1988;159:223–117Google Scholar
  15. 15.
    El Roeiy A, Gleicher N, Confino E, Friberg J, Dudkiewicz AB: Correlation between peripheral blood and follicular fluid: Autoantibodies and impact on in vitro fertilization. Obstet Gynecol 1987;70:163–170Google Scholar
  16. 16.
    Fisch B, Rikover Y, Shohat L, Zurgil N, Tadir Y, Ovadia J, Witz IP, Yron I: The relationship between in vitro fertilization and naturally occurring antibodies: Evidence for increased production of antiphospholipid autoantibodies. Fertil Steril 1991;56:718–724Google Scholar
  17. 17.
    Birkenfield A, Mukaida T, Minichiello L, Jackson M, Kase NG, Yemini M: Incidence of autoimmune antibodies in failed embryo transfer cycles. Am J Reprod Immunol 1994;31:65–68Google Scholar
  18. 18.
    Geva E, Yaron Y, Lessing JB, Yovel I, Vardinon N, Burke M, Amit A: Circulating autoimmune antibodies may be responsible for implantation failure in in vitro fertilization. Fertil Steril 1994;62:802–806Google Scholar
  19. 19.
    Sher G, Feinman M, Zouves C, Kuttner G, Maassarani G, Salem R, Matzner W, Ching W, 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;9:2278–2283Google Scholar
  20. 20.
    Gleicher N, Liu HC, Dudkiewicz A, Rosenwaks Z, Kaberlein G, Pratt D, Karande V: Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet Gynecol 1994;170:1145–1149Google Scholar
  21. 21.
    Nipp MM, Taylor PV, Rutherford AJ, Hancock KW: Autoantibodies and follicular fluids of infertile patients: Relation to reproductive outcome after in vitro fertilization. Hum Reprod 1995;10:2564–2569Google Scholar
  22. 22.
    Fisch B, Fried S, Manor Y, Ovadia J, Witz IP, Yron I: Increased antiphospholipid antibody activity in in vitro fertilization patients is not treatment dependent but rather an inherent characteristic of infertile state. Am J Reprod Immunol 1995;34:370–374Google Scholar
  23. 23.
    Kaider BD, Price BE, Roussev RG, Coulam CB: Antiphospholipid antibody prevalence in patients with IVF failure. Am J Reprod Immunol 1996;35:388–393Google Scholar
  24. 24.
    Birdsall M, Lockwood GM, Ledger WL, Johnson PM, Chamley LW: Antiphospholipid antibodies in women having in vitro fertilization. Hum Reprod 1996;11:1185–1189Google Scholar
  25. 25.
    Schenk LM, Butler, L, Morris JP, et al.: Heparin and aspirin treatment yields higher implantation rates in IVFF patients with antiphospholipid antibody seropositivity compared to untreated seronegative patients. American Society of Reproductive Medicine Meeting, Boston, MA, November 1996, abstract 0-076Google Scholar
  26. 26.
    Kutteh WH, Yetman DL, Chantiles SJ, Cr1ain J: Effect of antiphospholipid antibodies in women undergoing in vitro fertilization: Role of heparin and aspirin. Hum Reprod 1997;12:1171–1175Google Scholar
  27. 27.
    Denis AL, Guido M, Adler RD, Bergh PA, Brenner C, Scott RT: Antiphospholipid antibodies and pregnancy rates and outcome in in vitro fertilization patients. Fertil Steril 1997;67:1084–1090Google Scholar
  28. 28.
    Kowalik A, Vichin M, Lui HC, Branch W, Berkeley AS: Midfollicular anticardiolipin and antiphosphatidyl serine antibody titers do not correlate with in vitro fertilization outcome. Fertil Steril 1997;68:298–304Google Scholar
  29. 29.
    Theofilopolous AN: Autoimmunity in basic and clinical immunology. In Basic and Clinical Immunology, DE Stites, ID Stobo, HH Fudenberg, JV Wells (eds). Los Altos, CA: Lange Medical, 1985, pp 153–156Google Scholar
  30. 30.
    Coulam CB, Krysa LLW, Bustillo M: Intravenous immunoglobulin for in vitro fertilization failure. Hum Reprod 1995;9:2265–2269Google Scholar
  31. 31.
    Lockwood CJ, Romero R, Feinberg RF, Clyne LP, Coster B, Hobbins JC: The prevalence and biological significance of lupus anticoagulant and cardiolipin antibodies in general obstetric population. Am J Obstet Gynecol 1989;161:369–373Google Scholar
  32. 32.
    El-Roeiy A, Gleicher N: Definition of normal autoantibody levels in an apparently healthy population. Obstet Gynecol 1996;174:1584–1589Google Scholar
  33. 33.
    Kutteh WH: 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;174:1584–1589Google Scholar
  34. 34.
    Shoenfeld Y, Schwartz RS: Genetic and immunologic factors in autoimmune diseases. N Engl J Med 1984;311:101Google Scholar
  35. 35.
    Chamely LW, McKay EJ, Rattison NS: Inhibition of heparin/antithrombin III cofactor activity by anticardiolipin antibodies: A mechanism for thrombosis. Thromb Res 1993;71:103–111Google Scholar
  36. 36.
    Rote NS: Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1996;35:394–401Google Scholar
  37. 37.
    Gleicher N, Harlow L, Zilberstein M: Regulatory effect of antiphospholipid antibodies on signal transduction: A possible model for antibody induced reproductive failure. Am J Obstet Gynecol 1992;167:637–642Google Scholar
  38. 38.
    Rote NS, Vogt E, Se Vere G, Obringer AR, Ng AK: The role of placental trophoblast in the pathophysiology of the antiphospholipid antibody syndrome. Am J Reprod Immunol 1997 (in press)Google Scholar
  39. 39.
    Tartakovsky B, Bermas BL, Sthoeger Z, Shearer GM, Mozes E: Defective maternal-fetal interaction in a murine autoimmune model. Hum Reprod 1996;11:2408–2411Google Scholar
  40. 40.
    Schick PK, Kurica KB, Chacko GK: Localization of phosphatidyl ethanolamine and phosphatidyl serine in the human platelet plasma membrane. J Clin Invest 1976;57:1221–1226Google Scholar
  41. 41.
    Op den Kamp JAF: Lipid asymmetry in membranes. Annu Rev Biochem 1979;48:47–71Google Scholar
  42. 42.
    Nakashima S, Suganuma A, Matsui A, Nozawa Y: Thormobin induces a biphasic 1,2-diacyl glycerol production in human platelets. Biochem J 275:355–361Google Scholar
  43. 43.
    Dale MP, Robinson NC: Synthesis of cardiolipin derivatives with protection of the free hydroxyl: Its application to the study of cardiolipin stimulation of cytochrome c oxidase. Biochemistry 1988;27:8270–8275Google Scholar
  44. 44.
    Rand JH, WU XX, Guller S, Gil J, Guha A, Scher J, Lockwood CJ: Reduction of annexin V (placental anticoagulant protein-I) on placental villi of women with antiphospholipid antibodies and recurrent spontaneous abortion. Am J Obstet Gynecol 1994;171:1566–1572Google Scholar
  45. 45.
    Kirkun G, Lockwood CJ, Wu XX, Zhou XD, Guller S, Calandri C, Guha A, Nemerson Y, Rand JH: The expression of the placental anticoagulant protein, annexin V, by villous trophoblasts: Immunolocalization and in vitro regulation. Placenta 1994;15:601–612Google Scholar
  46. 46.
    Romisch J, Schorlemmer V, Fickenscher K, Paques EP, Heimburger N: Anticoagulant properties of placental protein 4 (annexin V). Thromb Res 1990;60:355–366Google Scholar
  47. 47.
    Rimarchin JA, Zaninovic N, Vuck LL, Posenwaks Z: Programmed cell death (apoptosis) in human gametes and preembryos in vitro. Hum Reprod 1997;12:39Google Scholar
  48. 48.
    Kaider BD, Purvis MT, Kovacs L, Coulam CB, Roussev RG: In vitro effect of antiphospholipid, antinuclear and antithyroid antibodies upon murine cultured embryos. Am J Reprod Immunol 1996;35:459Google Scholar
  49. 49.
    Coulam CB: Implantation failure and immunotherapy. Hum Reprod 1995;10:1338–1340Google Scholar
  50. 50.
    Tan EM, Cohen AS, Fries JE, et al.: The 1982 revised criteria for classification of systemic lupus erythematosis. Arth Rheum 1982;25:127–132Google Scholar

Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • Carolyn B. Coulam
    • 1
  • Brian D. Kaider
    • 1
  • Azadeth S. Kaider
    • 1
  • Patrick Janowicz
    • 1
  • Roumen G. Roussev
    • 1
  1. 1.The Center for Human ReproductionChicago

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