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
Further Information

Publication History

Publication Date:
31 December 2000 (online)

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.

REFERENCES

  • 1 Hill J A. Immunologic factors in spontaneous abortion.  Reprod Immunol . 1996;  16 433-442
  • 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
  • 3 Newman M J, Hines H C. Production of fetally stimulated lymphocytotoxic antibodies by primiparous cows.  Anim Blood Groups Biochem Genet . 1979;  10 87
  • 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
  • 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
  • 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
  • 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
  • 8 Coulam C B. Immunologic tests in the evaluation of reproductive disorders: a critical review.  Am J Obstet Gynecol . 1992;  167 1844-1851
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 17 Komlos L, Zamir R, Joshua H, Albrecht I. Common HLA antigens in couples with repeated abortion.  Clin Immunol Immunopathol . 1977;  7 330-335
  • 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
  • 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
  • 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
  • 21 Gill T J. Immunogenetics of spontaneous abortions in humans.  Transplantation . 1983;  35 1-6
  • 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
  • 23 Gerencer M, Singer Z, Pfeifer S. HLA and red blood group antigens in pregnancy disorders.  Tissue Antigens . 1988;  32 130-138
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 30 Cauchi M N, Tait B, Wilshire M I. Histocompatibility antigens and habitual abortion.  Am J Reprod Immunol Micriobiol . 1988;  18 28-31
  • 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
  • 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
  • 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
  • 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
  • 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
  • 36 Takamizawa M, Juji T, Tsuneyoshi H. Recurrent spontaneous abortion and human leukocyte antigen Drw8.  Am J Obstet Gynecol . 1987;  157 514-515
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 52 Aoki K, Kajiura S, Matsumoto Y. Preconceptual natural killer cell activity as a predictor of miscarriage.  Lanced . 1995;  345 1340-1342
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 61 Ober C, Karrison T, Odem R R. Mononuclear cell immunisation in prevention of recurrent miscarriages: a randomised trial.  Lancet . 1999;  354 365-369
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 69 Dwyer J M. Intravenous therapy with gamma globulin.  Adv Intern Med . 1987;  32 111-135
  • 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
  • 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
  • 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
  • 73 Mueller-Eckhardt G, Heine O, Polten B. IVIG to prevent recurrent spontaneous abortion.  Lancet . 1991;  337 424-425
  • 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
  • 75 The German RSA/IVIG Group. Intravenous immune globulin in the prevention of recurrent miscarriage.  Br J Obstet Gynaecol . 1994;  101 1072-1077
  • 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
  • 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
  • 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
  • 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
  • 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
    >