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Semin Reprod Med 2000; 18(4): 393-400
DOI: 10.1055/s-2000-13729
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Alloimmune Causes of Recurrent Pregnancy Loss

T. Flint Porter, James R. Scott
  • Department of Obstetrics & Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Recurrent pregnancy loss is a vexing problem facing many couples. Some authorities have suggested that idiopathic recurrent pregnancy loss is alloimmune in nature. Suggested mechanisms include the presence of cytotoxic antibodies, absence of maternal blocking antibodies, inappropriate sharing of human leukocyte antigens, and disturbances in natural killer cell function and distribution. Proposed therapies for so-called alloimmune-related pregnancy loss include leukocyte immunization and intravenous immune globulin. Unfortunately, neither has been successful in well-designed trials and both are expensive. Although alloimmune disturbances may be responsible for some idiopathic recurrent pregnancy loss, the pathophysiology is far from certain and there is currently no clinical indication for immunotherapy.

KEYWORD

Alloimmune - recurrent pregnancy loss - intravenous immune globulin

REFERENCES

  • 1 Hill J A. Immunologic factors in spontaneous abortion.  Reprod Immunol . 1996;  16 433-442
    PubMedSearch in Google Scholar
  • 2 Rocklin R F, Kitzmiller J L, Carpenter C B, Garvey M R, David J R. Maternal-fetal relation: absence of an immunologic blocking factor from serum of women with chronic abortions.  N Engl J Med . 1976;  295 1209-1211
    PubMedSearch in Google Scholar
  • 3 Newman M J, Hines H C. Production of fetally stimulated lymphocytotoxic antibodies by primiparous cows.  Anim Blood Groups Biochem Genet . 1979;  10 87
    PubMedSearch in Google Scholar
  • 4 Berke J, Johansen K. The formation of HLA antibodies in pregnancy: the antigenicity of aborted and term fetuses.  J Obstet Gyneacol Br Commonw . 1974;  81 222-228
    PubMedSearch in Google Scholar
  • 5 Bell S C, Billington W D. Major anti-paternal alloantibody induced by murine pregnancy is non-complement fixing IgG1.  Nature . 1980;  288 387-388
    CrossrefPubMedSearch in Google Scholar
  • 6 McIntyre J A, Faulk P, Nichols-Johnson V R, Taylor C G. Immunologic testing and immunotherapy in recurrent spontaneous abortion.  Obstet Gynecol . 1986;  67 169-174
    PubMedSearch in Google Scholar
  • 7 Billington W D, Davies M. Maternal antibody to placental syncytiotrophoblast during pregnancy. In: Wegmann TG, Gill TJ, eds. Immunology of Reproduction New York: Oxford University Press; 1987
    Search in Google Scholar
  • 8 Coulam C B. Immunologic tests in the evaluation of reproductive disorders: a critical review.  Am J Obstet Gynecol . 1992;  167 1844-1851
    PubMedSearch in Google Scholar
  • 9 Cowchock F S, Smith J B. Predictors for live birth after unexplained spontaneous abortions: correlations between immunologic test results, obstetric histories, and outcome of next pregnancy without treatment.  Am J Obstet Gynecol . 1992;  167 1208-1212
    PubMedSearch in Google Scholar
  • 10 Beer A E, Quebbeman J F, Ayers J WI, Haines F-RF. Major histocompatibility complex antigens, maternal and fetal immune responses, and chronic habitual abortion in humans.  Am J Obstet Gynecol . 1981;  141 987-999
    PubMedSearch in Google Scholar
  • 11 Stephenson M D, Wu V, Mackinnon M, Sadoway J, Keown P A. Standardization of flow cytometric crossmatch (FCXM) for investigation of unexplained habitual abortion.  Am J Reprod Immunol . 1995;  33 1-9
    PubMedSearch in Google Scholar
  • 12 Rocklin R F, Kitzmiller J L, Garvey M R. Maternal-fetal relations: further characterization of an immunologic blocking factor that develops during pregnancy.  Clin Immunol Immunopathol . 1982;  22 305-315
    CrossrefPubMedSearch in Google Scholar
  • 13 Sargent I L, Wilkins T, Redman C WG. Maternal immune responses to the fetus in early pregnancy and recurrent miscarriage.  Lance . 1988;  2 1099-1104
    PubMedSearch in Google Scholar
  • 14 Duc H T, Masse A, Bobe P. Deviation of humoral and cellular alloimmune reactions by placental extracts.  J Reprod Immunol . 1985;  7 27-39
    PubMedSearch in Google Scholar
  • 15 Rodger J C. Lack of a requirement for a maternal humoral immune response to establish and maintain successful allogeneic pregnancy.  Transplantation . 1985;  40 372-375
    PubMedSearch in Google Scholar
  • 16 Power D A, Catto G RD, Mason R J, Macload A M, Stewart G M, Stewart K M. The fetus as an allograft: evidence for a role of antibodies to HLA linked paternal antigens.  Lancet . 1983;  2 701-704
    PubMedSearch in Google Scholar
  • 17 Komlos L, Zamir R, Joshua H, Albrecht I. Common HLA antigens in couples with repeated abortion.  Clin Immunol Immunopathol . 1977;  7 330-335
    CrossrefPubMedSearch in Google Scholar
  • 18 Unander A M, Olding L B. Habitual abortion: paternal sharing of HLA antigens, absence of maternal blocking antibodies and suppression of maternal lymphocytes.  Am J Reprod Immunol . 1983;  4 171-178
    PubMedSearch in Google Scholar
  • 19 Coulam C B, Moore S B, O'Fallon W M. Association between major histocompatibility antigen and reproductive performance.  Am J Reprod Immunol Microbiol . 1987;  14 54-58
    PubMedSearch in Google Scholar
  • 20 Ober C, Hyslop T, Elias S, Weitkamp L R, Hauck W W. Human leukocyte antigen matching and fetal loss: results of a 10 year prospective study.  Hum Reprod . 1998;  13 33-38
    CrossrefPubMedSearch in Google Scholar
  • 21 Gill T J. Immunogenetics of spontaneous abortions in humans.  Transplantation . 1983;  35 1-6
    PubMedSearch in Google Scholar
  • 22 Reznikoff-Etievant M F, Edelman P, Muller J Y, Pinon F, Sureau C. HLA-DR locus and maternal-fetal relation.  Tissue Antigens . 1984;  24 30-34
    PubMedSearch in Google Scholar
  • 23 Gerencer M, Singer Z, Pfeifer S. HLA and red blood group antigens in pregnancy disorders.  Tissue Antigens . 1988;  32 130-138
    PubMedSearch in Google Scholar
  • 24 Johnson P M, Chia K V, Risk J M, Barnes R MR, Woodrow J C. Immunological and immunogenetic investigation of recurrent spontaneous abortion.  Dis Markers . 1988;  6 163-171
    PubMedSearch in Google Scholar
  • 25 Ober C, Elias S, Kostyu D D, Hauck W W. Decreased fecundability in Hutterite couples sharing HLA-DR.  Am J Hum Genet . 1992;  50 6-14
    PubMedSearch in Google Scholar
  • 26 Jin K, Ho H-N, Speed T P, Gill T J. Reproductive failure and the major histocompatibility complex.  Am J Hum Genet . 1995;  56 1456-1467
    PubMedSearch in Google Scholar
  • 27 Sbracia M, Mastrone M, Scarpellini F, Grasso J A. Influence of histocompatibility antigens in recurrent spontaneous abortion couples and on their reproductive performance.  Am J Reprod Immunol . 1996;  35 85-92
    PubMedSearch in Google Scholar
  • 28 Caudle M R, Rote N S, Scott J R, Dewitt C, Barney M F. Histocompatibility in couples with recurrent spontaneous abortion and normal fertility.  Fertil Steril . 1983;  39 793-798
    PubMedSearch in Google Scholar
  • 29 Oksenberg J R, Persitz E, Amar A, Brautbar C. Maternal-paternal histocompatibility: lack of an association with habitual abortion.  Fertil Steril . 1984;  42 389-395
    PubMedSearch in Google Scholar
  • 30 Cauchi M N, Tait B, Wilshire M I. Histocompatibility antigens and habitual abortion.  Am J Reprod Immunol Micriobiol . 1988;  18 28-31
    PubMedSearch in Google Scholar
  • 31 Christiansen O B, Riison K, Lauritsen J G, Grunnet N. No increased histocompatibility antigen sharing in couples with idopathic habitual abortion.  Hum Reprod . 1989;  4 160-162
    PubMedSearch in Google Scholar
  • 32 Takakuwa K, Higashino M, Ueda H. Significant compatibility does not exist at the HLA-DQB gene locus in couples with unexplained recurrent abortions.  Am J Obstet Reprod Immunol . 1992;  28 12-16
    PubMedSearch in Google Scholar
  • 33 Dizon-Townson D, Nelson L, Scott J R, Branch D W, Ward K. Human leukocyte antigen DQ alpha sharing is not increased in couples with recurrent miscarriage.  Am J Reprod Immunol . 1995;  34 209-212
    PubMedSearch in Google Scholar
  • 34 Wagenknecht D R, Green K M, McIntyre J A. Analyses of HLA-DQ alleles in recurrent spontaneous abortion (RSA) couples.  Am J Reprod Immunol . 1997;  37 1-6
    PubMedSearch in Google Scholar
  • 35 Gerencer M, Drazancic A, Kuvacic I, Tomaskovic Z, Kastelan A. HLA antigen studies in women with recurrent gestational disorders.  Fertil Steril . 1979;  31 401-404
    PubMedSearch in Google Scholar
  • 36 Takamizawa M, Juji T, Tsuneyoshi H. Recurrent spontaneous abortion and human leukocyte antigen Drw8.  Am J Obstet Gynecol . 1987;  157 514-515
    PubMedSearch in Google Scholar
  • 37 Smith J B, Cowchock F S, Hankinson B, Iftekhar A. Association of HLA-DR5 with recurrent spontaneous abortion in women treated with paternal leukocytes.  Arthritis Rheum . 1989;  32 1572-1576
    PubMedSearch in Google Scholar
  • 38 Laitenen T. A set of MHC haplotypes found among Finnish couples suffering from recurrent spontaneous abortions.  Am J Reprod Immunol . 1993;  29 148-154
    PubMedSearch in Google Scholar
  • 39 Christiansen O B, Andersen H H, Hojbjerre M, Kruse T A, Lauritzen S L, Grunnet N. Maternal HLA class II allogenotypes are markers for the predisposition to fetal losses in families of women with unexplained recurrent fetal loss.  Eur J Immunogenet . 1995;  22 323-334
    PubMedSearch in Google Scholar
  • 40 Sasaki T, Yamada H, Kato E H. Increased frequency of HLA-DR4 allele in women with unexplained recurrent spontaneous abortions, detected by the method of PCR-SSP.  J Reprod Immunol . 1997;  32 273-279
    PubMedSearch in Google Scholar
  • 41 Ho H N, Gill T J, Nsieh R P, Hsieh H J, Lee T Y. Sharing of human leukocyte antigens (HLA) in primary and secondary recurrent spontaneous abortions.  Am J Obstet Gynecol . 1990;  163 178-188
    PubMedSearch in Google Scholar
  • 42 Ober C, Steck T, van der Ven K. MHC compatibility in aborted fetuses and term infants of couples with recurrent spontaneous abortion.  J Reprod Immunol . 1993;  25 195-207
    PubMedSearch in Google Scholar
  • 43 Clark D A, Vince G, Flanders K C, Hirte H, Starkey P. CD56+ lymphoid cells in human trimester pregnancy decidua as a source of novel transforming growth factor-beta 2-related immunosuppressive factors.  Hum Reprod . 1994;  9 2270-2277
    PubMedSearch in Google Scholar
  • 44 Kodama T K, Hara T, Okamolo E, Kusunoki Y,Ohama K. Characteristic changes of large granular lymphocytes that strongly express CD 56 in endometrium during the menstrual cycle and early pregnancy.  Hum Reprod . 1998;  13 1035-1043
    PubMedSearch in Google Scholar
  • 45 Bulmer J N, Johnson P M, Bulmer D. Leukocyte populations in human decidua and endometrium. In: Gill TJ, Wegmann TG, Nisbet-Brown E, eds. Immunoregulation and Fetal Survival New York: Oxford University Press; 1987
    Search in Google Scholar
  • 46 Starkey P M, Sargent L L, Redman C GW. Cell populations in human early pregnancy decidua: characterization and isolation of large granular lymphocytes by flow cytometry.  Immunology . 1988;  65 129-134
    PubMedSearch in Google Scholar
  • 47 Lachapelle M H, Miron P, Hemmings R, Roy D C. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion.  J Immunol . 1996;  156 4027-4034
    PubMedSearch in Google Scholar
  • 48 Gendron R L, Baines M G. Infiltrating decidual natural killer cells are associated with spontaneous abortion in mice.  Cell Immunol . 1988;  113 261-267
    CrossrefPubMedSearch in Google Scholar
  • 49 Fougerolles A R, Baines M G. Modulatin of the natural killer cell activity in pregnant mice alters the spontaneous abortion rate.  J Reprod Immunol . 1987;  11 147-153
    PubMedSearch in Google Scholar
  • 50 Coulam C B, Goodman C, Roussev R G, Thomason E J, Beaman K D. Systemic CD56+ cells can predict pregnancy outcome.  Am J Reprod Immunol . 1995;  33 40-46
    PubMedSearch in Google Scholar
  • 51 Beer A E, Kwak J YH, Ruiz J E. Immunophenotypic profiles of peripheral blood lymphocytes in women with recurrent pregnancy losses and in infertile women with multiple failed in vitro fertilization cycles.  Am J Reprod Immunol . 1996;  35 376-382
    PubMedSearch in Google Scholar
  • 52 Aoki K, Kajiura S, Matsumoto Y. Preconceptual natural killer cell activity as a predictor of miscarriage.  Lanced . 1995;  345 1340-1342
    CrossrefPubMedSearch in Google Scholar
  • 53 Fukui K, Yoshimoto I, Matsubara K, Hori R, Ochi H, Ito M. Leukocyte function-associated antigen-1 expression on natural killer cells in patients with early pregnancy loss.  Mol Hum Reprod . 1999;  5 1083-1088
    CrossrefPubMedSearch in Google Scholar
  • 54 Yamamoto T, Takahashi Y, Kase N, Mori H. Role of decidual natural killer cells in patients with missed abortion: differences between cases with normal and abnormal chromosome.  Clin Exp Immunol . 1999;  116 449-452
    CrossrefPubMedSearch in Google Scholar
  • 55 Gilman-Sachs A, DuChateau B K, Aslakson C J. Natural (NK) cell subsets and NK cell cytotoicity in women with histories of recurrent spontaneous abortions.  Am J Reprod Immunol . 1999;  41 99-105
    PubMedSearch in Google Scholar
  • 56 Kwak J Y, Gilman Sachs A, Moretti M, Beaman K D, Beer A E. Natural killer cell cytoxicity and paternal lymphocyte immunization in women with recurrent spontaneous abortions.  Am J Reprod Immunol . 1998;  40 352-358
    PubMedSearch in Google Scholar
  • 57 Mowbray S F, Gibbons C, Liddell H. Controlled trial of treatment of recurrent spontaneous abortion by immunization with paternal cells.  Lancet . 1985;  1 941-943
    PubMedSearch in Google Scholar
  • 58 Gatenby P A, Cameron K, Simes R J. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial.  Am J Reprod Immunol . 1993;  29 88-94
    PubMedSearch in Google Scholar
  • 59 Ho H N, Gill T H, Hsieh H J, Jiang J J, Lee T Y, Hsieh C Y. Immunotherapy for recurrent spontaneous abortions in a Chinese population.  Am J Reprod Immunol . 1991;  25 10-15
    PubMedSearch in Google Scholar
  • 60 Cauchi M N, Lim D, Young D E, Kloss M, Pepperell R J. Treatment of recurrent aborters by immunization with paternal cells: controlled trial.  Am J Reprod Immunol . 1991;  25 16-17
    PubMedSearch in Google Scholar
  • 61 Ober C, Karrison T, Odem R R. Mononuclear cell immunisation in prevention of recurrent miscarriages: a randomised trial.  Lancet . 1999;  354 365-369
    CrossrefPubMedSearch in Google Scholar
  • 62 Coulam C B, Clark D A, Collins J A, et al (The Recurrent Miscarriage Immunotherapy Trialist Group). Worldwide collaborative observational study and meta-analysis on allogeneic leukocyte immunotherapy for recurrent spontaneous abortion.  Am J Reprod Immunol . 1994;  35 55-72
    PubMedSearch in Google Scholar
  • 63 Fraser E J, Grimes D A, Schulz K F. Immunization as therapy for recurrent spontaneous abortion: a review anbd meta-analysis.  Obstet Gynecol . 1993;  82 854-859
    PubMedSearch in Google Scholar
  • 64 Daya S, Gunby J. The effectiveness of allogeneic leukocyte immunization in unexplained primary recurrent spontaneous abortion. Recurrent Miscarriage Immunotherapy Trialists Group.  Am J Reprod Immunol . 1994;  32 294-302
    PubMedSearch in Google Scholar
  • 65 Carp H J, Toder V, Torchinsky A. Allogenic leukocyte immunization after five or more miscarriages. Recurrent Miscarriage Immunotherapy Trialists Group.  Hum Reprod . 1997;  12 250-255
    CrossrefPubMedSearch in Google Scholar
  • 66 The Recurrent Miscarriage Immunotherapy Trialist Group. Worldwide collaborative observational study and meta-analysis on allogeneic leukocyte immunotherapy for recurrent spontaneous abortion.  Am J Reprod Immunol . 1994;  35 55-72
    PubMedSearch in Google Scholar
  • 67 Jeng G T, Scott J R, Burmeister L F. A comparison of meta-analytic results using literature vs individual patient data.  JAMA . 1995;  274 830-836
    CrossrefPubMedSearch in Google Scholar
  • 68 Brand A, Witvliet M, Claas F HJ, Eernisse J G. Beneficial effect of intravenous gammaglobulin in a patients with complement-mediated autoimmune thrombocytopenia due to IgM antiplatelet antibodies.  Br J Haematol . 1988;  69 507-511
    PubMedSearch in Google Scholar
  • 69 Dwyer J M. Intravenous therapy with gamma globulin.  Adv Intern Med . 1987;  32 111-135
    PubMedSearch in Google Scholar
  • 70 Ruiz J E, Kwak J Y, Baum L. Intravenous immunoglobulin inhibits natural killer cell activity in vivo in women with recurrent spontaneous abortion.  Am J Reprod Immunol . 1996;  35 370-375
    PubMedSearch in Google Scholar
  • 71 Kwak J Y, Kwak F M, Ainbinder S W, Ruiz A M, Beer A E. Elevated peripheral blood natual killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions.  Am J Reprod Immunol . 1996;  35 363-369
    PubMedSearch in Google Scholar
  • 72 Mueller-Eckhardt G, Heine O, Neppert J, Kunzel W, Mueller-Eckhardt C. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin.  Vox Sang . 1989;  56 151-154
    PubMedSearch in Google Scholar
  • 73 Mueller-Eckhardt G, Heine O, Polten B. IVIG to prevent recurrent spontaneous abortion.  Lancet . 1991;  337 424-425
    PubMedSearch in Google Scholar
  • 74 Coulam B C, Krysa L, Stern J J, Bustillo M. Intravenous immunoglobulin for the treatment of recurrent pregnancy loss.  Am J Reprod Immunol . 1995;  34 333-338
    PubMedSearch in Google Scholar
  • 75 The German RSA/IVIG Group. Intravenous immune globulin in the prevention of recurrent miscarriage.  Br J Obstet Gynaecol . 1994;  101 1072-1077
    PubMedSearch in Google Scholar
  • 76 Chrisitansen O B, Mathiesen O, Husth M. Placebo- controlled trial for treatment of unexplained secondary recurrent abortions and recurrent late spontaneous abortions with IV immunoglobulin.  Hum Reprod . 1995;  10 2690-2694
    PubMedSearch in Google Scholar
  • 77 Stephenson M D, Dreher K, Houlihan E, WuV. Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial.  Am J Reprod Immunol . 1998;  39 82-88
    CrossrefPubMedSearch in Google Scholar
  • 78 Perino A, Vassiliadis A, Vucetich A. Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.  Hum Reprod . 1997;  12 2388-2392
    CrossrefPubMedSearch in Google Scholar
  • 79 Jablonowska B, Selbing A, Palfi M, Ernerudh J, Kjellberg S, Lindton B. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study.  Hum Reprod . 1999;  14 838-841
    CrossrefPubMedSearch in Google Scholar
  • 80 Daya S, Gunby J, Clark D A. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis.  Am J Reprod Immunol . 1998;  39 69-76
    PubMedSearch in Google Scholar