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An update in recurrent spontaneous abortion

Archives of Gynecology and Obstetrics volume 272, pages 95–108 (2005)Cite this article

Abstract

Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses prior to the 20th week of gestation. The etiology of recurrent spontaneous abortion is often unclear and may be multifactorial, with much controversy regarding diagnosis and treatment. Reasonably accepted etiologic causes include, genetics, anatomical, endocrine, placental anomalies, hormonal problems, infection, smoking and alcohol consumption, exposure to environmental factors, psychological trauma and stressful life event, certain coagulation and immunoregulatory protein defects. Detection of an abnormality in any of these areas may result into specific therapeutic measures, with varying degrees of success. However, the majority of cases of RSA remains unexplained and is found to be associated with certain autoimmune (APA, ANA, ACA, ATA, AECA) and alloimmune (APCA, Ab2, MLR-Bf) antibodies that may play major role in the immunologic failure of pregnancy and may lead to abortion. Alteration in the expression of HLA-G molecules, T-helper-1 (Th-1) pattern of cytokines and natural killer (NK) cells activity may also induce abortion. Various forms of treatment like antithrombotic therapies such as aspirin and heparin, intravenous immunoglobulin (IVIg) therapy, immunotherapy with paternal lymphocytes and vitamin D3 therapy are effective mode of treatment for unexplained cause of fetal loss in women with RSA.

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References

  1. Acien P (1993) Reproductive performance of women with uterine malformations. Hum Reprod 8:122–126

    CAS  PubMed  Google Scholar 

  2. Acien P (1996) Uterine anomalies and recurrent miscarriage. Infert Reprod Med Clin N Am 7:689–719

    Google Scholar 

  3. Adachi H, Takakuwa K, Mitsui T, Ishii K, Tamura M, Tanaka K (2003) Results of immunotherapy for patients with unexplained secondary abortions. Clin Immunol 106:175–180

    Article  CAS  PubMed  Google Scholar 

  4. Agrawal S, Pandey MK (2003) The potential role of HLA-G polymorphism in maternal tolerance to the developing fetus. J Hematother Stem Cell Res 12:749–756

    Article  CAS  PubMed  Google Scholar 

  5. Agrawal S, Pandey MK, Mandal S, Mishra L, Agarwal S (2002) Humoral immune response to an allogenic foetus in normal fertile women and recurrent aborters. BMC Pregnancy and Childbirth 2(1):6

    Article  PubMed  Google Scholar 

  6. Agrawal S, Pandey MK, Pandey A (2000) Prevalence of MLR blocking antibodies before and after immunotherapy. J Hematother Stem Cell Res 9:257–262

    Article  CAS  PubMed  Google Scholar 

  7. Aldrich CL, Stephenson MD, Karrison T, Odem RR, Branch DW, Scott JR, Schreiber JR, Ober C (2001) HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod 7(12):1167–1172

    Article  CAS  PubMed  Google Scholar 

  8. American College of Obstetricians and Gynecologists (2001) Management of recurrent early pregnancy loss. ACOG practice bulletin. American College of Obstetricians and Gynecologists, Washington, DC.

  9. Anwar R, Gallivan L, Edmonds SD, Markham AF (1999) Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity. Blood 93:897–905

    CAS  PubMed  Google Scholar 

  10. Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, Gleicher N (1995) Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet 345(8961):1340–1342

    Article  CAS  PubMed  Google Scholar 

  11. Arck P, Dietl J, Clark D (1999) From the decidual cell internet: trophoblast-recognizing T cells. Biol Reprod 60:227–233

    CAS  PubMed  Google Scholar 

  12. Arck PC, Rose M, Hertwig K, Hagen E, Hildebrandt M, Klapp BF (2001) Stress and immune mediators in miscarriage. Hum Reprod 16:1505–1511

    Article  CAS  PubMed  Google Scholar 

  13. Arias F, Romero R, Joist H, Kraus FT (1998) Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med 7:277–286

    Article  CAS  PubMed  Google Scholar 

  14. Armstrong BG, McDonald AD, Sloan MI (1992) Cigarette, alcohol, and coffee consumption and spontaneous abortion. Am J Public Health 82:85–87

    CAS  PubMed  Google Scholar 

  15. Beaman K, Angkachatchai V, Gilman-Sachs A (1996) TJ6: the pregnancy-associated cytokine. Am J Reprod Immunol 35:338–341

    CAS  PubMed  Google Scholar 

  16. Beer AE, Semprini AE, Zhu XY, Quebbeman JF (1985) Pregnancy outcome in human couples with recurrent spontaneous abortions: HLA antigen profiles; HLA antigen sharing; female serum MLR blocking factors and paternal leukocyte immunization. Exp Clin Immunogenet 2(3):137–153

    CAS  PubMed  Google Scholar 

  17. Beever CL, Stephenson MD, Penaherrera MS, Jiang RH, Kalousek DK, Hayden M, Field L, Brown CJ, Robinson WP (2003) Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies. Am J Hum Genet 72:399–407

    CAS  PubMed  Google Scholar 

  18. Behar E, Carp H, Livneh A, Gazit E (1993) Differential suppression activity induced by paternal leukocyte immunization in habitual abortion. Gynecol Obstet Invest 36:202–207

    CAS  PubMed  Google Scholar 

  19. Benito CW, Vostrovsky ET, Day-Salvatore DL, Trout S, Shen-Schwarz S (2001) Anticardiolipin antibodies in first- and second-trimester pregnancy loss. Obstet Gynecol 97:32

    Google Scholar 

  20. Berger MJ, Goldstein DP (1980) Impaired reproductive performance in DES-exposed women. Obstet Gynecol 55:25–27

    CAS  PubMed  Google Scholar 

  21. Berns KI, Bohenzky RA (1987) Adeno-associated viruses: an update. Adv Virus Res 32:243–306

    CAS  PubMed  Google Scholar 

  22. Berry CW, Brambati B, Eskes TK, Exalto N, Fox H, Geraedts JP, Gerhard I, Gonzales Gomes Grudzinskas JG, Hustin J (1995) The Euro-Team Early Pregnancy (ETEP) protocol for recurrent miscarriage. Hum Reprod 10:1516–1520

    CAS  PubMed  Google Scholar 

  23. Boue A, Gallano PA (1984) Collaborative study of the segregation of inherited chromosome structural arrangements in 1356 prenatal diagnoses. Prenat Diagn 4:45–67

    PubMed  Google Scholar 

  24. Braulke I, Pruggmayer M, Melloh P, Hinney B, Kostering H, Gunther E (1993) Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters? Fertil Steril 59:98–101

    CAS  PubMed  Google Scholar 

  25. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N (1999) Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 82:6–9

    CAS  PubMed  Google Scholar 

  26. Bubanovic I (2004) 1alpha,25-dihydroxy-vitamin-D3 as new immunotherapy in treatment of recurrent spontaneous abortion. Med Hypotheses 63:250–253

    CAS  PubMed  Google Scholar 

  27. Buchholz T, Lohse P, Rogenhofer N, Kosian E, Pihusch R, Thaler CJ (2003) Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Reprod 18:2473–2477

    CAS  PubMed  Google Scholar 

  28. Buchholz T, Thaler CJ (2003) Inherited thrombophilia: impact on human reproduction. Am J Reprod Immunol 49:1–13

    PubMed  Google Scholar 

  29. Buckett WM, Luckas MJ, Aird IA, Farquharson RG, Kingsland CR, Lewis-Jones DI (1997) The hypo-osmotic swelling test in recurrent miscarriage. Fertil Steril 68:506–509

    CAS  PubMed  Google Scholar 

  30. Bussen SS, Steck T (1997) Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters). Eur J Obstet Gynecol Reprod Biol 74:139–143

    CAS  PubMed  Google Scholar 

  31. Cadavid A, Pena B, Garcia G, Botero J, Sanchez F, Ossa J, Beer A (1999) Heparin plus aspirin as a “single” therapy for recurrent spontaneous abortion associated with both allo- and autoimmunity. Am J Reprod Immunol 41:271–278

    CAS  PubMed  Google Scholar 

  32. Carp H, Feldman B, Oelsner G, Schiff E (2004) Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril 81:1296–1301

    PubMed  Google Scholar 

  33. Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G (2001) Karyotype of the abortus in recurrent miscarriage. Fertil Steril 75(4):678–682

    CAS  PubMed  Google Scholar 

  34. Chaouat G, Lankar D (1988) Vaccination against spontaneous abortion in mice by preimmunization with an anti-idiotypic antibody. Am J Reprod Immunol Microbiol 16:146–150

    CAS  PubMed  Google Scholar 

  35. Check JH, Szekeres-Bartho J, O’Shaughnessy A (1996) Progesterone induced blocking factor seen in pregnancy Lymphocytes soon after implantation. Am J Reprod Immunol 35:277–280

    CAS  PubMed  Google Scholar 

  36. Christiansen OB (1998) Intravenous immunoglobulin in the prevention of recurrent spontaneous abortion: the European experience. Am J Reprod Immunol 39:77–81

    CAS  PubMed  Google Scholar 

  37. Clark DA, Daya S (1991) Trials and tribulation in the treatment of recurrent spontaneous abortion. Am J Reprod Immunol 25:18–24

    CAS  PubMed  Google Scholar 

  38. Clark DA, Drake B, Head JR, Stedronska-Clark J, Banwatt D (1990) Decidua-associated suppressor activity and viability of individual implantation sites of allopregnant C3H mice. J Reprod Immunol 17:253–264

    CAS  PubMed  Google Scholar 

  39. Clifford K, Flanagan AM, Regan L (1999) Endometrial CD56+ natural killer cells in women with recurrent miscarriage: a histomorphometric study. Hum Reprod 14:2727–2730

    CAS  PubMed  Google Scholar 

  40. Clifford K, Rai R, Watson H, Regan L (1994) An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 9:1328–1332

    CAS  PubMed  Google Scholar 

  41. Conn CM, Harper JC, Winston RML, Delhanty JD (1998) Infertile couples with Robertsonian translocations: preimplantation genetic analysis of embryos reveals chaotic cleavage divisions. Hum Genet 102:117–123

    CAS  PubMed  Google Scholar 

  42. Coulam CB, Beaman KD (1995) Reciprocal alteration in circulating TJ6+ CD19+ and TJ6+ CD56+ leukocytes in early pregnancy predicts success or miscarriage. Am J Reprod Immunol 34:219–224

    CAS  PubMed  Google Scholar 

  43. Coulam CB, Stern JJ (1994) Endocrine factors associated with recurrent spontaneous abortion. Clin Obstet Gynecol 37:730–744

    CAS  PubMed  Google Scholar 

  44. Coulam CB, Clark DA, Beer AE, Kutteh WH, Silver R, Kwak J, Stephenson M (1997) Current clinical options for diagnosis and treatment of recurrent spontaneous abortion. Clinical Guidelines Recommendation Committee for Diagnosis and Treatment of Recurrent Spontaneous Abortion. Am J Reprod Immunol 38:57–74

    CAS  PubMed  Google Scholar 

  45. Creus M, Ballast J, Fabregues F, Martorell J, Boada M, Penarrubia J, Barri PN, Vanrell JA (1998) Parental human leukocyte antigens and implantation failure after in-vitro fertilization. Hum Reprod 13:39–43

    CAS  PubMed  Google Scholar 

  46. Crosignani PG, Rubin BL (1991) Recurrent spontaneous abortion. Hum Reprod 6(4):609–610

    CAS  PubMed  Google Scholar 

  47. Daher S, Fonseca F, Mattar R, Musatti CC, de Lima MG (1997) Inhibitory serum factor of lymphoproliferative response to allogeneic cells in pregnancy. Rev Paul Med 115(4):1485–1489

    CAS  Google Scholar 

  48. Daya S, Gunby J, Clark DA (1998) Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol 39:69–76

    CAS  PubMed  Google Scholar 

  49. De Braekeleer M, Dao TN (1990) Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 5(5):519–528

    CAS  PubMed  Google Scholar 

  50. Dizon-Townson DS, Meline M, Nelson M, Varner M, Ward K (1997) Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 177: 402–405

    CAS  PubMed  Google Scholar 

  51. Dorling A, Monk N, Lechler R (2000) HLA-G inhibits the transendothelial cell migration of human NK cells: a strategy for inhibiting xenograft rejection. Transplant Proc 32:938

    CAS  PubMed  Google Scholar 

  52. Dwyer JS (1982) Hospital incident reports: protected from discovery? Hosp Prog 63(10):38–39.

    CAS  Google Scholar 

  53. Eblen AC, Gercel-Taylor C, Shields LB, Sanfilippo JS, Nakajima ST, Taylor DD (2000) Alterations in humoral immune responses associated with recurrent pregnancy loss. Fertil Steril 73:305–313

    CAS  PubMed  Google Scholar 

  54. Erard F, Wild MT, Garcia-Sanz JA, Le Gros G (1993) Switch of CD8 T cells to noncytolytic CD8-CD4-cells that make TH2 cytokines and help B cells. Science 260:1802–1805

    CAS  PubMed  Google Scholar 

  55. Eroglu GE, Scopelitis E (1996) Antiphospholipid antibodies in healthy women with recurrent spontaneous abortions. Am J Reprod Immunol 4:4008–4014

    Google Scholar 

  56. Ferguson TA, Beaman KD, Iverson GM (1985) Isolation and characterization of a T suppressor factor by using a monoclonal antibody. J Immunol 134:3163–3171

    CAS  PubMed  Google Scholar 

  57. Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A (2000) Factor V Leiden prothrombin G20210A mutation, but not methyl tetrahydrofolate reductase(C677T) are associated with recurrent miscarriage. Hum Reprod 15:458–462

    CAS  PubMed  Google Scholar 

  58. Fonesca DSF, Matter R, Musatte CC, De Lima MC (1997) Inhibitory serum factor of lymphoproliferative response to allogenic cells in pregnancy. Rev Paul Med 115:1485–1489

    CAS  Google Scholar 

  59. Frankenne F, Rentier-Delrue F, Scippo ML, Martial J Hennen G (1987) Expression of the growth hormone variant gene in human placenta. J Clin Endocrinol 64:635–637

    CAS  Google Scholar 

  60. Gafter U, Sredni B, Segal J, Kalechman Y (1997) Suppressed cell-mediated immunity and monocyte and natural killer cell activity following allogeneic immunization of women with spontaneous recurrent abortion. J Clin Immunol 17:408–419

    CAS  PubMed  Google Scholar 

  61. Gill TJ III (1983) Immunogenetics of spontaneous abortions in humans. Transplantation 35:1–6

    PubMed  Google Scholar 

  62. Golan A, Langer R, Wexler S, Segev E, Niv D, David MP (1990) Cervical cerclage–its role in the pregnant anomalous uterus. Int J Fertil 35:164–170

    CAS  PubMed  Google Scholar 

  63. Goldenberg M, Sivan E, Sharabi Z, Mashiach S, Lipitz S, Seidman DS (1995) Reproductive outcome following hysteroscopic management of intrauterine septum and adhesions. Hum Reprod 10:2663–2665

    CAS  PubMed  Google Scholar 

  64. Grandone E, Margaglione M, Colaizzo D, D’Addedda M, Cappucci G, Vecchione G, Scianname N, Pavone G, Di Minno G (1997) Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 77: 822–824

    CAS  PubMed  Google Scholar 

  65. Graphou O, Chioti A, Pantazi A, Tsukoura C, Kontopoulou V, Guorgiadou E, Balafoutas C, Koussoulakos S, Margaritis LH, Varla-Leftherioti M (2003) Effect of intravenous immunoglobulin treatment on the Th1/Th2 balance in women with recurrent spontaneous abortions. Am J Reprod Immunol 49:21–29

    PubMed  Google Scholar 

  66. Hammer A, Blaschitz A, Daxbock C, Walcher W, Dohr G (1999) Fas and Fas-ligand are expressed in the uteroplacental unit of first-trimester pregnancy. Am J Reprod Immunol 41:41–51

    CAS  PubMed  Google Scholar 

  67. Hanna N, Hanna I, Hleb M, Wanger E, Dougherty Balkundi D, Padbury J, Sharma S (2000) Gestational age dependent expression of IL 10 and its receptor in human placental tissues and isolated cytotrophoblasts. J Immunol 164:5721–7728

    CAS  PubMed  Google Scholar 

  68. Harlap S, Shiono PH (1980) Alcohol, smoking, and incidence of spontaneous abortions in the first and second trimester. Lancet 2:173–176

    CAS  PubMed  Google Scholar 

  69. Hasegawa I, Tani H, Takakuwa K, Goto S, Yamada K, Kanazawa K (1991) A new lymphocyte serotyping using cytotoxic antibodies from secondary recurrent aborters and its application in cases of recurrent abortion and infertility. Fertil Steril 55:906–910

    CAS  PubMed  Google Scholar 

  70. Hassold T, Jacobs PA, Pettay D (1988) Cytogenetic studies of couples with repeated spontaneous abortions of known karyotype. Genet Epidemiol 5:65–74

    CAS  PubMed  Google Scholar 

  71. Hassold TJ, Chen N, Funkhouser T, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA (1980) A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet 44:151–178

    CAS  PubMed  Google Scholar 

  72. Haviid TV, Hylenius S, Hoegh AM , Kruse C, Christiansen OB (2002) HLA-G polymorphisms in couples with recurrent spontaneous abortions. Tissue Antigens 60:122–132

    PubMed  Google Scholar 

  73. Hayakawa S, Karasaki-Suzuki M, Itoh T, Ishii M, Kanaeda T, Nagai N, Takahashi-Yamamoto N, Tochigi M, Chishima F, Fujii TK, Oyama J, Kitanaka S, Satoh K (2000) Effects of paternal lymphocyte immunization on peripheral Th1/Th2 balance and TCR V beta and V gamma repertoire usage of patients with recurrent spontaneous abortions. Am J Reprod Immunol 43:107–115

    CAS  PubMed  Google Scholar 

  74. Hayakawa S, Nagai N, Kanaeda T, Karasaki-Suzuki M, Ishii M, Chishima F, Satoh K (1999) Interleukin-12 augments cytolytic activity of peripheral and decidual lymphocytes against choriocarcinoma cell lines and primary culture human placental trophoblasts. Am J Reprod Immunol 41:320–329

    CAS  PubMed  Google Scholar 

  75. Hennen G, Frankenne F, Closset J, Gomez F, Pirens G, el Khayat N (1985) A human placental GH: increasing levels during second half of pregnancy with pituitary GH suppression as revealed by monoclonal antibody radioimmunoassays. Int J Fertil 30:27–33

    CAS  PubMed  Google Scholar 

  76. Hermonat PL, Kechelava S, Lowery CL, Korourian S (1998) Trophoblasts are the preferential target for human papilloma virus infection in spontaneously aborted products of conception. Hum Pathol 29:170–174

    CAS  PubMed  Google Scholar 

  77. Hidaka Y, Amino N, Iwatani Y, Kaneda T, Mitsuda N, Morimoto Y, Tanizawa O, Miyai K (1991) Changes in natural killer cell activity in normal pregnant and postpartum women: increases in the first trimester and postpartum period and decrease in late pregnancy. J Reprod Immunol 20:73–83

    CAS  PubMed  Google Scholar 

  78. Hill JA, III, Choi BC (2000) Immunodystrophism evidence for a novel alloimmune hypothesis for recurrent pregnancy loss involving Th1- type immunity to trophoblast. Semin Reprod Med 18:401–405

    PubMed  Google Scholar 

  79. Hill JA, Polgar K, Anderson DJ (1995) T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. JAMA 273:1933–1936

    CAS  PubMed  Google Scholar 

  80. Homburg R, Givdice LC, Change RJ (1996) Polycystic ovary syndrome. Hum Reprod 11:465–466

    CAS  Google Scholar 

  81. Hori S, Nakano Y, Furukawa TA, Ogasawara M, Katano K, Aoki K, Kitamura T (2000) Psychosocial factors regulating natural-killer cell activity in recurrent spontaneous abortions. Am J Reprod Immunol 44:299–302

    CAS  PubMed  Google Scholar 

  82. Hunt JS, Vassmer D, Ferguson TA, Miller L (1997) Fas ligand is positioned in mouse uterus and placenta to prevent trafficking of activated leukocytes between the mother and the conceptus. J Immunol 158:4122–4128

    CAS  PubMed  Google Scholar 

  83. Ito K, Tanaka T, Tsutsumi N, Obata F, Kashiwagi N (1999) Possible mechanisms of immunotherapy for maintaining pregnancy in recurrent spontaneous aborters: analysis of anti-idiotypic antibodies directed against autologous T-cell receptors. Hum Reprod 14:650–655

    CAS  PubMed  Google Scholar 

  84. Jablonowska B, Palfi M, Ernerudh J, Kjellberg S, Selbing A (2001) Blocking antibodies in blood from patients with recurrent spontaneous abortion in relation to pregnancy outcome and intravenous immunoglobulin treatment. Am J Reprod Immunol 45:226–231

    CAS  PubMed  Google Scholar 

  85. Jerzak M, Rechberger T, Baranowski W, Semczuk M (2003) Immunotherapy as an effective treatment of recurrent spontaneous abortion own experience. Genekol Pol 1107–1111

  86. Kahraman S, Bahce M, Samli H, Imirzalioglu N, Yaskin K, Cengiz G, Donmez E (2000) Healthy births and ongoing pregnancies obtained by preimplantation genetic diagnosis in patients with advanced maternal age. Hum Reprod 15:2003–2007

    CAS  PubMed  Google Scholar 

  87. Kalter H (1987) Diabetes and spontaneous abortion: a historical. Am J Obstet Gynecol 156:1243–1253

    CAS  PubMed  Google Scholar 

  88. Kilpatrick DC (1992) Soluble interleukin-2 receptors in recurrent miscarriage and the effect of leukocyte immunotherapy. Immunol Lett 34:201–206

    CAS  PubMed  Google Scholar 

  89. King A, Hiby SE, Verma S, Burrows T, Gardner L, Loke YW (1997) Uterine NK cells and trophoblast HLA class I molecules. Am J Reprod Immunol 37:459–462

    CAS  PubMed  Google Scholar 

  90. Kokawa K, Shikone T, Nakano R (1998) Apoptosis in human chorionic villi and deciduas during normal embryonic development and spontaneous abortion in first trimester. Placenta 19:21–26

    CAS  PubMed  Google Scholar 

  91. Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R (1990) A class I antigen, HLA-G, expressed in human trophoblasts. Science 248:220–223

    CAS  PubMed  Google Scholar 

  92. Kruse N, Greif M, Moriabadi NF, Marx L, Toyaka KV, Rieck-mann (2000) Variations in cytokine mRNA expression during normal pregnancy. Clin Exp Immunol 119:317–322

    CAS  PubMed  Google Scholar 

  93. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB (1999) Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:9–13

    CAS  PubMed  Google Scholar 

  94. 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 174:1584–1589

    CAS  PubMed  Google Scholar 

  95. Kutteh WH, Park VM, Deitcher SR (1999) Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 71:1048–1054

    CAS  PubMed  Google Scholar 

  96. Kwak JY, Beaman KD, Gilman-Sachs A (1997) Humoral and cellular autoimmune abnormalities in women with infertility of unknown etiology and IVF fatures. Am J Reprod Immunol 37:354

    Google Scholar 

  97. Kwak JY, Beaman KD, Gilman-Sachs A, Ruiz JE, Schewitz D, Beer AE (1995) Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol 34:93–99

    CAS  PubMed  Google Scholar 

  98. Kwak JY, Gilman-Sachs A, Moretti M, Beaman KD, Beer AE (1998) Natural killer cell cytotoxicity and paternal lymphocyte immunization in women with recurrent spontaneous abortions. Am J Reprod Immunol 40:352–358

    CAS  PubMed  Google Scholar 

  99. Lea RG, al-Sharekh N, Tulppala M, Critchley HO (1997) The immunolocalization of bcl-2 at the maternal-fetal interface in healthy and failing pregnancies. Hum Reprod 12:153–158

    CAS  Google Scholar 

  100. Lea RG, Riley SC, Antipatis C, Hannah L, Ashworth CJ, Clark DA, Critchley HO (1999) Cytokines and the regulation of apoptosis in reproductive tissues: a review. Am J Reprod Immunol 42:100–109

    CAS  PubMed  Google Scholar 

  101. Lea RG, Underwood J, Flanders KC, Hirte H, Banwatt D, Finotto S, Ohno I, Daya S, Harley C, Michel M, et al (1995)A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor beta-2-producing “suppressor cells” in uterine tissue near the placental attachment site. Am J Reprod Immunol 34:52–64

    CAS  PubMed  Google Scholar 

  102. Li D, Li C, Zhu Y (1998) Comparative study of the third party and paternal leukocyte immunization in recurrent spontaneous abortion of lowered maternal-fetal immuno-recognition. Zhonghua Fu Chan Ke Za Zhi 33:597–600

    CAS  PubMed  Google Scholar 

  103. Lim KJ, Odukoya OA, Ajjan RA, Li TC, Weetman AP, Cooke ID (2000) The role of T-helper cytokines in human reproduction. Fertil Steril 73:136–142

    CAS  PubMed  Google Scholar 

  104. Lopez-Botet M, Navarro F, Llano M (1999) How do NK cells sense the expression of HLA-G class Ib molecules? Semin Cancer Biol 9:19–26

    CAS  PubMed  Google Scholar 

  105. Malinowski A, Wilezynski J, Zemen K, Glowacka E, Kolasa D, Szpakowski A, Oszukowski P, Szpakowski M (1998) Immunological characteristics of non-pregnant women with unexplained recurrent spontaneous abortion who underwent paternal lymphocyte immunization. Zentralbl Gynakol 120:493–502

    CAS  PubMed  Google Scholar 

  106. Malinowski A, Zemen K, Wilczynski J, Glowacka E, Banasik M, Powierza S, Pokoca L, Szpakowski M (1997) Immunologic characteristics of women with recurrent spontaneous abortion of unknown etiology – II. Characterisation of humoral immunology. Ginekologia Polska 68:240–247

    CAS  PubMed  Google Scholar 

  107. Mandelboim O, Pazmany L, Davis DM, Vales-Gomez M, Reyburn HT, Rybalov B, Strominger JL (1997) Multiple receptors for HLA-G on human natural killer cells. Proc Natl Acad Sci USA 94:14666–14670

    CAS  PubMed  Google Scholar 

  108. Martin DH. Koutsky L, Eschenbach DA, Daling JR, Alexander E R, Benedetti JK, Holmes KK (1982) Prematurity and perinatal mortality in pregnancies complicated by maternal Chlamydia trachomatis infections. JAMA 247:1585–1588

    PubMed  Google Scholar 

  109. Martinelli E, Taioli I, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM (2000) Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 343:1015–1018

    CAS  PubMed  Google Scholar 

  110. Maruyama K, Zhang JZ, Kojima Y, Iwatsuki K, Ono I, Kaneko F (1995) In vitro effects of antipsoriatic agents on cytokine secretion and cell proliferation of normal human keratinocytes (NHK) and dermal fibroblasts (HDF). Jpn J Dermatol 105:699–706

    CAS  Google Scholar 

  111. Masayuki M, Takashi N, Akiko N, Yoshimichi I, Keiji Fumio K (1998) Regulatory effects of 1alpha, 25-dihydroxyvitamin D3 on inflammatory responses in psoriasis. Eur J Dermatol 81:16–20

    Google Scholar 

  112. Masuko-Hongo K, Hayashi K, Yonamine K, Tokuyama M, Nishioka K, Kato T (2001) Disappearance of clonally expanded T cells after allogeneic leukocyte immunotherapy in peripheral blood of patients with habitual abortion. Hum Immunol 62:1111–1121

    CAS  PubMed  Google Scholar 

  113. Matovina M, Husnjak K, Milutin N, Ciglar S, Grce M (2004) Possible role of bacterial and viral infections in miscarriages. Fertil Steril 81:662–669

    CAS  PubMed  Google Scholar 

  114. Matsubayashi H, Maruyama T, Ozawa N, Izumi SI, Sugi T, Yoshikata K, Yoshimura Y, Makino T (2000) Anti-paternal antibodies by flow cytometry in the management of alloimmunization on recurrent miscarriages. Am J Reprod Immunol 44:284–288

    CAS  PubMed  Google Scholar 

  115. McDonald HM, Chambers HM (2000) Intrauterine infection and spontaneous midgestation abortion: is the spectrum of microorganisms similar to that in preterm labor? Infect Dis Obstet Gynecol 8:220–227

    CAS  PubMed  Google Scholar 

  116. McIntyre JA, Coulam CB, Faulk WP (1989) Recurrent spontaneous abortion. Am J Reprod Immunol 21:100–104

    CAS  PubMed  Google Scholar 

  117. Moreau P, Paul P, Rouas-Freiss N, Kirszenbaum M, Dausset J Carosella ED (1998) Molecular and immunologic aspects of the nonclassical HLA class I antigen HLA-G: evidence for an important role in the maternal tolerance of the fetal allograft. Am J Reprod Immunol 40:136–144.

    CAS  PubMed  Google Scholar 

  118. Morikawa M, Yamada H, Kato EH, Shimada S, Kishi T, Yamada T, Kobashi G, Fujimoto S (2001) Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity andsubsets. Am J Reprod Immunol 46:399–404

    CAS  PubMed  Google Scholar 

  119. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193

    CAS  PubMed  Google Scholar 

  120. Munné S, Sandalinas M, Escudero T, Fung J, Gianaroli L, Cohen J (2000) Outcome of preimplantation genetic diagnosis of translocations. Fertil Steril 73:1209–1218

    PubMed  Google Scholar 

  121. Nagata S (1994) Fas and Fas ligand: a death factor and its receptor. Adv Immunol 57:129–144

    CAS  PubMed  Google Scholar 

  122. Nagel TC, Malo JW (1993) Hysteroscopic metroplasty in the diethylstilbestrol-exposed uterus and similar nonfusion anomalies: effects on subsequent reproductive performance; a preliminary report. Fertil Steril 59:502–506

    CAS  PubMed  Google Scholar 

  123. Nichols TC, Kang JA, Angkachatchai V, Beer AE, Beaman KD (1994) Expression of a membrane form of the pregnancy-associated protein TJ6 on lymphocytes. Cell Immunol 155:219–229

    CAS  PubMed  Google Scholar 

  124. Nydegger UE, Castelli D (1991)Review on therapeutic options in HIV associated thrombocytopenia with emphasis on i.v immunoglobulin treatment. Immunol Invest 20(2):223–229

    CAS  PubMed  Google Scholar 

  125. Ogasawara M, Aoki K, Okada S, Suzumori K (2000) Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 73:300–304

    CAS  PubMed  Google Scholar 

  126. Ogasawara MS, Aoki K, Katano K, Ozaki Y, Suzumori K (2001) Factor XII but not protein C, protein S, antithrombin III, or factor XIII is a predictor of recurrent miscarriage. Fertil Steril 75:916–919

    CAS  PubMed  Google Scholar 

  127. Orgad S, Loewenthal R, Gazit E, Sadetzki S, Novikov I, Carp H (1999) The prognostic value of anti-paternal antibodies and leukocyte immunizations on the proportion of live births in couples with consecutive recurrent miscarriages. Hum Reprod 14:2974–2979

    CAS  PubMed  Google Scholar 

  128. Pandey MK, Agrawal S (2003) Prevalence of anti-idiotypic antibodies in pregnancy v/s recurrent spontaneous (RSA) women. Obstet Gynae Today 7:574–578

    Google Scholar 

  129. Pandey MK, Agrawal S (2004) Induction of MLR-Bf and protection of fetal loss: a current double blind randomized trial of paternal lymphocyte immunization for women with recurrent spontaneous abortion. Int Immunopharmacol 4:289–298

    CAS  PubMed  Google Scholar 

  130. Pandey MK, Saxena V, Agrawal S (2003) Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy. BMC Pregnancy Childbirth 3:2

    PubMed  Google Scholar 

  131. Pandey MK, Thakur S, Agrawal S (2004) Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion. Arch Gynecol Obstet 269:161–172

    PubMed  Google Scholar 

  132. Pauer HU, Voigt-Tschirschwitz T, Hinney B, Burfeind P, Wolf C, Emons G, Neesen J (2003) Analyzes of three common thrombophilic gene mutations in German women with recurrent abortions. Acta Obstet Gynecol Scand 82:942–947

    PubMed  Google Scholar 

  133. Payne SG, Smith SC, Davidge ST, Baker PN, Guilbert LJ (1999) Death receptor Fas/Apo-1/CD95 expressed by human placental cytotrophoblasts does not mediate apoptosis. Biol Reprod 60:1144–1150

    CAS  PubMed  Google Scholar 

  134. Pazmany L, Mandelboim O, Vales-Gomez M, Davis DM, Becker TC, Reyburn HT, Seebach JD, Hill JA, Strominger JL (1999) Human leucocyte antigen-G and its recognition by natural killer cells. J Reprod Immunol 43:127–137

    CAS  PubMed  Google Scholar 

  135. Pearlman SA, Meek RS, Cowchock FS, Smith JB, McFarland J, Aster RH (1992) Neonatal alloimmune thrombocytopenia after maternal immunization with paternal mononuclear cells: successful treatment with intravenous gamma globulin. Am J Perinatal 9:448–451

    CAS  Google Scholar 

  136. Pena RB, Cadavid AP, Botero JH, Garcia GP, Gallego MI, Ossa JE (1998) The production of MLR-blocking factors after lymphocyte immunotherapy for RSA doesnot predict the outcome of pregnancy. Am J Reprod Immunol 39:120–124

    CAS  PubMed  Google Scholar 

  137. Perricone R, De Carolis C, Giacomelli R, Guarino MD, De Sanctis G, Fontana L (2003) GM-CSF and pregnancy: evidence of significantly reduced blood concentrations in unexplained recurrent abortion efficiently reverted by intravenous immunoglobulin treatment. Am J Reprod Immunol 50:232–237

    PubMed  Google Scholar 

  138. Piccinni M-P, Romagnani S (1996) Regulation of fetal allograft survival by hormone controlled Th1-and Th2-type cytokines. Immunol Res 15:141–150

    CAS  PubMed  Google Scholar 

  139. Pichler J, Gerstmayr M, Szepfalusi Z, Urbanek R, Peterlik M, Willheim M (2002) 1 alpha,25 (OH)2D3 inhibits not only Th1 but also Th2 differentiation in human cord blood T cells. Pediatr Res 52:12–18

    CAS  PubMed  Google Scholar 

  140. Pihusch R, Buchholz T, Lohses P (2001) Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 46:124–131

    CAS  PubMed  Google Scholar 

  141. Pijenborg R, Robertson WB, Brosens I, Dixon G (1981) Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2:71–91

    PubMed  Google Scholar 

  142. Poddar AS, Kim JG, Gill KP, Bates BN, Santanam N, Rock JA, Murphy AA, Parthasarathy S (1998) Generation and characterization of a polyclonal antipeptide antibody to human glycodelin. Fertil Steril 69:543–548

    CAS  PubMed  Google Scholar 

  143. Polifka JE, Friedman JM (1991) Environmental toxins and recurrent pregnancy loss. Infertil Reprod Med Clin North Am 2:175–213

    Google Scholar 

  144. Poort SR, Rosendahl FR, Reissma PH, Bertina RM (1996) A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels, and an increase in venous thrombosis. Blood 88:3698–3703

    CAS  PubMed  Google Scholar 

  145. Power DA, Mather AJ, Macleod AM, Lind T, Catto GR (1986) Maternal antibodies to paternal B-lymphocytes in normal & abnormal pregnancy. Am J Reprod Immunol Microbiol 10:10–13

    CAS  PubMed  Google Scholar 

  146. Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ (1996) Increased fetal loss in women with heritable Thrombophilia. Lancet 38:913–916

    Google Scholar 

  147. Prigoshin N, Tambutti ML, Redal MA, Gorgorza S, Lancuba SM, Nicholson R, Testa R (1999) Microchimerism and blocking activity in women with recurrent spontaneous abortion (RSA) after alloimmunization with the partner’s lymphocytes. J Reprod Immunol 44:41–54

    CAS  PubMed  Google Scholar 

  148. Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, Vince G (1999) Pre-implantation endometrial leukocytes in women with recurrent miscarriage. Hum Reprod 14:2386–2391

    CAS  PubMed  Google Scholar 

  149. Raghupathy R (1997) Maternal anti-placental cell-mediated reactivity and spontaneous abortions. Am J Reprod Immunol 37(6):478–484

    CAS  PubMed  Google Scholar 

  150. Raghupathy R, Tangri S (1996) Immunodystrophism, T cells, cytokines, and pregnancy failure. Am J Reprod Immunol 35:291–296

    CAS  Google Scholar 

  151. Rai R, Backos M, Elgaddal S, Shlebak A, Regan L (2002) Factor V Leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum Reprod 17(2):442–445

    CAS  PubMed  Google Scholar 

  152. Ramhorst R, Agriello E, Zittermann S, Pando M, Larriba J, Irigoyen M, Cortelezzi M, Auge L, Lombardi E, Etchepareborda JJ, Contreras Ortiz C, Fainboim L (2000) Is the paternal mononuclear cells’ immunization a successful treatment for recurrent spontaneous abortion? Am J Reprod Immunol 44:129–135

    CAS  PubMed  Google Scholar 

  153. Recurrent Miscarriage Immunotherapy Trialists Group (RMITG) (1994) World wide collaborative observation study and meta-analysis on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 32:55–72

    PubMed  Google Scholar 

  154. Reed E, Beer AE, Hutcherson H, King DW, Suciu-Foca N (1991)The alloantibody response of pregnant women and its suppression by soluble HLA antigens and anti-idiotypic antibodies. J Reprod Immunol 20(2):115–128

    CAS  PubMed  Google Scholar 

  155. Reed E, Bonagura V, Kung P, King DW, Suciu-Foca N (1983) Anti-idiotypic antibodies to HLA-DR4 and DR2. J Immunol 131(6):2890–2894

    CAS  PubMed  Google Scholar 

  156. Regan L (1991) Recurrent miscarriage. BMJ 302:543–544

    CAS  PubMed  Google Scholar 

  157. Regan L, Braude PR, Hill DP (1991) A prospective study of the incidence, time of appearance and significance of anti-paternal lymphocytotoxic antibodies in human pregnancy. Hum Reprod 6:294–298

    CAS  PubMed  Google Scholar 

  158. Regan L, Braude PR, Trembath PL (1989) Influence of past reproductive performance on risk of spontaneous abortion. BMJ 299:541–545

    CAS  PubMed  Google Scholar 

  159. Rey E, Kahn SR, David M, Shrier I (2003) Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 15:901–908

    Google Scholar 

  160. Ribbing SL, Hoversland RC, Beaman KD (1988) T-cell suppressor factors play an integral role in preventing fetal rejection. J Reprod Immunol 14:83–95

    CAS  PubMed  Google Scholar 

  161. Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA (1998) Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 128:1000–1003

    CAS  PubMed  Google Scholar 

  162. Robertson SA, Seamark RF, Guilbert LJ, Wegmann TG (1994) The role of cytokines in gestation. Crit Rev Immunol 14:239–292

    CAS  PubMed  Google Scholar 

  163. Roussev RG, Stern JJ, Kaider BD (1998) Anti-endothelial cell antibodies: another cause for pregnancy loss? Am J Reprod Immunol 39:89–95

    CAS  PubMed  Google Scholar 

  164. Royal College of Obstetricians and Gynaecologists (1998) Guideline No. 17. The management of recurrent miscarriage. Royal College of Obstetricians and Gynaecologists, London

    Google Scholar 

  165. Rubio C, Simon C, Vidal F, Rodrigo L, Pehlivan T, Remohi J, Pellicer A (2003) Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod 18:182–188

    CAS  PubMed  Google Scholar 

  166. Saito S (2000) Cytokine network at the feto-maternal interface. J Reprod Immunol 47:87–103

    CAS  PubMed  Google Scholar 

  167. Sakata K, Sakata A, Kong L, Dang H, Talal N (1998) Role of Fas/FasL interaction in physiology and pathology: the good and the bad. Clin Immunol Immunopathol 87:1–7

    CAS  PubMed  Google Scholar 

  168. Salat-Baroux J (1988) Recurrent spontaneous miscarriages. Reprod. Nutr Dev 28:1555–1568

    CAS  PubMed  Google Scholar 

  169. Sarig G, Younis JS, Hoffman R, Brenner B (2002) Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 77:342–347

    PubMed  Google Scholar 

  170. Schagen van Leeuwen JH, Christiaens GC, Hoogenraad TU (1991) Recurrent abortion and the diagnosis of Wilson disease.Obstet Gynecol 78(3 Pt 2):547–549

    CAS  PubMed  Google Scholar 

  171. Schmidt-Sarosi C, Schwartz LB, Lublin J, Kaplan-Grazi D, Sarosi P, Perle MA(1998) Chromosomal analysis of early fetal losses in relation to transvaginal ultrasonographic detection of fetal heart motion after infertility. Fertil Steril 69:274–277

    CAS  PubMed  Google Scholar 

  172. Scriven PN, Flinter FA, Braude PR, Ogilvie CM (2001) Robertsonian translocations: reproductive risks and indications for preimplantation genetic diagnosis. Hum Reprod 16:2267–2273

    CAS  PubMed  Google Scholar 

  173. Smith SC, Baker PN, Symonds EM (1997) Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 177:57–65

    CAS  PubMed  Google Scholar 

  174. Sompolinsky D, Solomon F, Elkina L, Weinraub Z, Bukovsky I, Caspi E (1975) Infections with mycoplasma and bacteria in induced midtrimester abortion and fetal loss. Am J Obstet Gynecol 121:610–616

    CAS  PubMed  Google Scholar 

  175. Souza S, Ferriani R, Pontes A, Zafo M, Franco R (1999) Factor V Leiden mutation in patients with recurrent abortion. Hum Reprod 4:2448–2450

    Google Scholar 

  176. Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF (1990) Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 264:1422–1425

    CAS  PubMed  Google Scholar 

  177. Stagno S, Pass RF, Dworsky ME, Henderson RE, Moore EG, Walton PD, Alford CA (1982) Congenital cytomegalovirus infection: the relative importance of primary and recurrent maternal infection. N Engl J Med 306:945–949

    CAS  PubMed  Google Scholar 

  178. Stephenson MD, Awartani KA, Robinson WP (2002) Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case–control study. Hum Reprod 17:446–451

    CAS  PubMed  Google Scholar 

  179. Stewart GM, Mason RJ, Thomson MA, MacLeod AM, Catto GR (1984) Noncytotoxic antibodies to paternal antigens in maternal sera and placental eluates. Transplantation 38:111–115

    CAS  PubMed  Google Scholar 

  180. Stirrat GM (1990) Recurrent miscarriage. Lancet 15:673–675

    Google Scholar 

  181. Stray-Pedersen B, Stray-Pedersen S (1984) Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol 148:140–146

    CAS  PubMed  Google Scholar 

  182. Stricker RB, Steinleitner A, Bookoff CN, Weckstein LN, Winger EE (2000) Successful treatment of immunologic abortion with low-dose intravenous immunoglobulin. Fertil Steril 73:536–540

    CAS  PubMed  Google Scholar 

  183. Strom CM, Ginsberg N, Applebaum M, Bogorzi N, White M, Caffarelli M, Verlinsky Y (1992) Analysis of 95 first-trimester spontaneous abortions by chorionic villus sampling and karyotype. J Assist Reprod Genet 9:458–461

    CAS  PubMed  Google Scholar 

  184. Suciu-Foca N, Reed E, Rohowsky C, Kung P, King DW (1983) Anti-idiotypic antibodies to anti-HLA receptors induced by pregnancy. Proc Natl Acad Sci USA 80:830–834

    CAS  PubMed  Google Scholar 

  185. Suciu-Foca N, Rohowsky-Kochan C, Reed E, Haars R, Bonagura V, King DW, Reemstma K (1985) Idiotypic network regulations of immune responses to HLA. Fed Proc 44(8):2483–2487

    CAS  PubMed  Google Scholar 

  186. Sugi T, Katsunuma J, Izumi S, McIntyre JA, Makino T (1999) Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil Steril 71:1060–1065

    CAS  PubMed  Google Scholar 

  187. Sugiura-Ogasawara M, Furukawa TA, Nakano Y, Hori S, Aoki K, Kitamura T (2002) Depression as a potential causal factor in subsequent miscarriage in recurrent spontaneous aborters. Hum Reprod 17:2580–2584

    CAS  PubMed  Google Scholar 

  188. Szekeres-Bartho J, Faust Z, Varga P (1995) The expression of a progesterone-induced immunomodulatory protein in pregnancy lymphocytes. Am J Reprod Immunol 34:342–348

    CAS  PubMed  Google Scholar 

  189. Szekeres-Bartho J, Szekeres G, Debre P, Autran B, Chaouat G (1990) Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody. Cell Immunol 125:273–283

    CAS  PubMed  Google Scholar 

  190. Szekeres-Bartho J, Wegmann TG (1996) A progesterone-dependent immunomodulatory protein alters the Th1/Th2 balance. J Reprod Immunol 31:81–95

    CAS  PubMed  Google Scholar 

  191. Takakuwa K, Adachi H, Hataya I, Ishii K, Tamura M, Tanaka K (2003) Molecular genetic studies of HLA-DRB1 alleles in patients with unexplained recurrent abortion in the Japanese population. Hum Reprod 18:728–733

    CAS  PubMed  Google Scholar 

  192. Tamura M, Takakuwa K, Arakawa M, Yasuda M, Kazama Y, Tanaka K (1998) Relationship between MLR blocking antibodies and the outcome of the third pregnancy in patients with two consecutive spontaneous abortions. J Perinat Med 26:49–53

    CAS  PubMed  Google Scholar 

  193. Tanaka T, Umesaki N, Nishio J, Maeda K, Kawamura T, Araki N, Ogita S (2000) Neonatal thrombocytopenia induced by maternal anti-HLA antibodies: a potential side effect of allogenic leukocyte immunization for unexplained recurrent aborters. J Reprod Immunol 46:51–57

    CAS  PubMed  Google Scholar 

  194. Thorton Ca, Bellow M (1993) Safety of intravenous immunoglobulin. Arch Neurol 50:135–136

    PubMed  Google Scholar 

  195. Tulppala M, Stenman UH, Cacciatore B, Ylikorkala O (1993) Polycystic ovaries and levels of gonadotrophins and androgens in recurrent miscarriage: prospective study in 50 women. Br J Obstet Gynaecol 100:348–352

    CAS  PubMed  Google Scholar 

  196. Uehara S, Hashiyada M, Sato K, Sato Y, Fujimori K, Okamura K (2001) Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. Fertil Steril 76:908–914

    CAS  PubMed  Google Scholar 

  197. Vinatier D, Dufour P, Cosson M, Houpeau JL (2001) Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 96:37–50

    CAS  PubMed  Google Scholar 

  198. Wang H, Zhang M, Soda K, Sama A, Tracey KJ (1997) Fetuin protects the fetus from TNF. Lancet 350:861–862

    CAS  Google Scholar 

  199. Watson H, Kiddy DS, Hamilton-Fairley D, Scanlon MJ, Barnard C, Collins WP, Bonney RC, Franks S (1993) Hypersecretion of luteinizing hormone andovarian steroids in women with recurrent early miscarriage. Hum Reprod 8:829–833

    CAS  PubMed  Google Scholar 

  200. Wegmann TG, Lin H, Guilbert L, Mosmann TR (1993) Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14:353–356

    CAS  PubMed  Google Scholar 

  201. Weltz JI (1997) Low molecular weight heparins. N Eng J Med 337:688–697

    Google Scholar 

  202. Witkin SS, Sultan KM, Neal GS, Jeremias J, Grifo JA, Rosenwaks Z (1994) Unsuspected Chlamydia trachomatis infection and in vitro fertilization outcome. Am J Obstet Gynecol 171:1208–1214

    CAS  PubMed  Google Scholar 

  203. Wramsby ML, Stien Linder M, Bremme K (2000) Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Sterl 4:987–991

    Google Scholar 

  204. Yamada H, Atsumi T, Kato EH, Shimada S, Morikawa M, Minakami H (2003) Prevalence of diverse antiphospholipid antibodies in women with recurrent spontaneous abortion. Fertil Steril 80:1276–1278

    PubMed  Google Scholar 

  205. Yamada H, Kato EH, Kobashi G, Ebina Y, Shimada S, Morikawa M, Sakuragi N, Fujimoto S (2001) High NK cell activity in early pregnancy correlates with subsequent abortion with normal chromosomes in women with recurrent abortion. Am J Reprod Immunol 46:132–136

    CAS  PubMed  Google Scholar 

  206. Yamada H, Kishida T, Kobayashi N, Kato H, Hoshi N, Fujimoto S (1998) Masive immunoglobulin treatment in women with four or more recurrent spontaneous primary abortions of unexplained etiology. Hum Reprod 13:2620–2623

    CAS  PubMed  Google Scholar 

  207. Younis JS, Brenner B, Ohel G, Tal J, Lanir N, Ben-Ami M (2000) Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 43:31–35

    CAS  PubMed  Google Scholar 

  208. Younis JS, Ohel G, Brenner B, Ben-Ami M (1997) Familial thrombophilia the scientific rationale for thrombophylaxis in recurrent pregnancy loss. Hum Reprod 12:1389–1390

    CAS  PubMed  Google Scholar 

  209. Zenclussen AC, Fest S, Busse P, Joachim R, Klapp BF, Arck PC (2002) Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of IL-12 are down-regulated in miscarriage patients. Am J Reprod Immunol 48:245–251

    PubMed  Google Scholar 

  210. Zenclussen AC, Gentile T, Kortebani G, Mazzolli A, Margni R (2001) Asymmetric antibodies and pregnancy. Am J Reprod Immunol 45:289–294

    CAS  PubMed  Google Scholar 

  211. Zhang JZ, Maruyama K, Ono I, Iwatsuki K, Kaneko F (1994) Regulatory effects of 1,25-dihydroxyvitamin D3 and a novel vitamin D3 analogue MC903 on secretion of interleukin-1 alpha (IL-1a) and IL-8 by normal human keratinocytes and a human squamous cell carcinoma cell line (HSC-1). J Dermatol Sci 7:24–31

    CAS  PubMed  Google Scholar 

  212. Zhang M, Caragine T, Wang H, Cohen PS, Botchkina G, Soda K, Bianchi M, Ulrich P, Cerami A, Sherry B, Tracey KJ (1997) Spermine inhibits proinflammatory cytokine synthesis in human mononuclear cells: a counterregulatory mechanism that restrains the immune response. J Exp Med 185:1759–1768

    CAS  PubMed  Google Scholar 

  213. Zhou HM, Ramachandran S, Kim JG, Raynor DB, Rock JA, Parthasarathy S (2000) Implications in the management of pregnancy: II. Low levels of gene expression but enhanced uptake and accumulation of umbilical cord glycodelin. Fertil Steril 73:843–847

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the Indian Council of Medical Research (ICMR) and Council of Science and Technology, U.P., India for financial support of their laboratory work and library of Mayo Clinic, Rochester, MN, USA for providing the related references.

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Affiliations

  1. Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center, MLC 7021 TCH RF 5503 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA

    Manoj Kumar Pandey

  2. Department of Biology, University of Texas, San Antonio, TX, USA

    Reena Rani

  3. Department of Medical Genetics, SGPGIMS, Lucknow, India

    Suraksha Agrawal

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  1. Manoj Kumar Pandey
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  2. Reena Rani
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Correspondence to Manoj Kumar Pandey.

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Pandey, M.K., Rani, R. & Agrawal, S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet 272, 95–108 (2005). https://doi.org/10.1007/s00404-004-0706-y

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Keywords

  • RSA (Recurrent spontaneous abortion)
  • Lymphocyte immunotherapy
  • Immunoglobulin (IVIg) therapy
  • Aspirin/Heparin therapy
  • 1α
  • 25 -dihydroxy-vitamin-D3 (VD3) therapy
  • APA (anti-phospho lipid antibody)
  • ANA (anti-nuclear antibody)
  • ACA (anti-cardiolipin antibody)
  • ATA (anti-thyroidantibody)
  • AECA (anti-endothelial cell antibody)
  • APCA (anti-paternal cytotoxic antibody)
  • Ab2 (anti-idiotypic antibody)
  • MLR-Bf (mixed lymphocyte reaction blocking antibodies)
  • Natural Killer (NK) cells
  • HLA-G
  • T-helper −1(TH-1) and T-helper −2(TH-2) cytokines