Skip to main content
Journal of Assisted Reproduction and Genetics logoLink to Journal of Assisted Reproduction and Genetics
. 2003 Feb;20(2):63–72. doi: 10.1023/A:1021788024214

Is There Any Evidence for Immunologically Mediated or Immunologically Modifiable Early Pregnancy Failure?

David A Clark 1,2,3
PMCID: PMC3455793  PMID: 12688590

Abstract

Purpose: Human reproduction is an inefficient process. There is a high rate of loss of early pregnancies, often before the mother (or physician) knows she is pregnant. Genetic abnormalities can explain much of the wastage, but can it explain all of the failures? As embryos bear paternal and embryonic antigens foreign to the maternal immune system, could some otherwise normal embryos be “rejected”?

Methods: Critical review of existing data.

Results and Conclusions: Otherwise normal embryos can fail prior to implantation, at implantation, in the periimplantation period as occult/chemical pregnancies, and as clinically evident miscarriages. The maternal immune system and its products (e.g., cytokines) can have innocent bystander effects, and a good case for direct recognition and “rejection” can also be made. The tools needed for accurate clinical diagnosis of such situations require further development and validation. Deliberate modification of the maternal host defence system can improve the chance of success, but the best evidence for efficacy of immunotherapeutic interventions is the situation of recurrent spontaneous abortions, which constitutes only a small percentage of losses. There is also evidence of clinical efficacy for several types of treatment to improve implantation and early pregnancy success.

Keywords: Implantation failure, IVF, occult pregnancy loss, reproductive immunology

Full Text

The Full Text of this article is available as a PDF (86.4 KB).

References

  • 1.Roberts CJ, Lowe CR. Where have all the conceptions gone? Lancet. 1975;i:498–499. [Google Scholar]
  • 2.Zinaman MJ, O'Connor J, Clegg ED, Selevan SG, Brown CC. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65:503–509. [PubMed] [Google Scholar]
  • 3.Coulam CB, Stephenson M, Stern JJ, Clark DA. Immunotherapy for recurrent pregnancy loss: Analysis of results from clinical trials. Am J Reprod Immunol. 1996;35:330–337. doi: 10.1111/j.1600-0897.1996.tb00493.x. [DOI] [PubMed] [Google Scholar]
  • 4.Hertig AT, Rock J, Adams EC, Menkin MC. Thirty-four fertilized human ova, good, bad, and indifferent, recovered from 210 women of known fertility. Pediatrics. 1959;23:202–211. [PubMed] [Google Scholar]
  • 5.Clark DA, Coulam CB, Daya S, Chaouat G. Unexplained sporadic and recurrent miscarriage in the new millennium: A critical analysis of immune mechanisms and treatment. Hum Reprod Update. 2001;7:501–511. doi: 10.1093/humupd/7.5.501. [DOI] [PubMed] [Google Scholar]
  • 6.Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: Evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod. 2002;17:809–816. doi: 10.1093/humrep/17.3.809. [DOI] [PubMed] [Google Scholar]
  • 7.Martin RH, Ko E, Rademaker A. Distribution of aneuploidy in human gametes: Comparison between human sperm and oocytes. Am J Med Genet. 1991;39:321–331. doi: 10.1002/ajmg.1320390315. [DOI] [PubMed] [Google Scholar]
  • 8.Plachot M. In: Oocyte-genetic aspects. <surname>Grudzinskas J., Yovich JL, editors. New York: Cambridge University Press; 1995. pp. 95–107. [Google Scholar]
  • 9.Lea RG, Clark DA. Macrophages and migratory cells in endometrium relevant to implantation. Bailliére's Clin Obst Gynecol. 1991;5:25–59. doi: 10.1016/s0950-3552(05)80069-0. [DOI] [PubMed] [Google Scholar]
  • 10.Haq A, Mothi BA, Al-Hussein K, Al-Tufail M, Hollanders J, Jaroudi K, Al-Waili N, Shabani M. Isolation, purification and partial characterization of early pregnancy factor (EPF) from sera of pregnant women. Eur J Med Res. 2001;6:209–214. [PubMed] [Google Scholar]
  • 11.Roussev RG, Barnea ER, Thomason EJ, Coulam CB. A novel bioassay for detection of preimplantation factor (PIF) Am J Reprod Immunol. 1995;33:68–73. doi: 10.1111/j.1600-0897.1995.tb01140.x. [DOI] [PubMed] [Google Scholar]
  • 12.Smart YC, Fraser IS, Clancy RL, Roberts TK, Cripps AW. Fertilization and early pregnanacy loss in healthy women attempting conception. Clin Reprod Fertil. 1982;1:177–184. [PubMed] [Google Scholar]
  • 13.Rolfe BE. Detection of fetal wastage. Fertil Steril. 1982;37:655–660. doi: 10.1016/s0015-0282(16)46278-3. [DOI] [PubMed] [Google Scholar]
  • 14.Fan XG, Zheng ZQ. A study of early pregnancy factor activity in preimplantation. Am J Reprod Immunol. 1997;37:359–364. [PubMed] [Google Scholar]
  • 15.Shahani SK, Moniz CL, Gokral JS, Meherji PK. Early pregnancy factor (EPF) as a marker for detecting subclinical embryonic loss in clomiphene citrate-treated women. Am J Reprod Immunol. 1995;33:350–353. doi: 10.1111/j.1600-0897.1995.tb00903.x. [DOI] [PubMed] [Google Scholar]
  • 16.Pieters MHEC, Geraedts JPM, Dumoulin JCM, Evers JLH, Bras M, Kornips FHAC, Menheere PPCA. Cytogenetic analysis of in vitro fertilization (IVF) failures. Hum Genet. 1989;81:367–370. doi: 10.1007/BF00283693. [DOI] [PubMed] [Google Scholar]
  • 17.Laverge H, van der Elst J, de Sutter P, Verschraegen-Spae MR, de Paepe A, Dhont M. Fluorescent in-situ hybridization on human embryos showing cleavage arrest after freezing and thawing. Hum Reprod. 1998;13:425–429. doi: 10.1093/humrep/13.2.425. [DOI] [PubMed] [Google Scholar]
  • 18.Munné S, Lee A, Rosenwaks Z, Grifo J, Cohen J. Diagnosis of major chromosome aneuploidies in human preimplantation embryos. Hum Reprod. 1993;8:2185–2191. doi: 10.1093/oxfordjournals.humrep.a138001. [DOI] [PubMed] [Google Scholar]
  • 19.Delhanty JD, Harper JC, Ao A, Handyside AH, Winston RM. Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients. Hum Genet. 1997;99:755–760. doi: 10.1007/s004390050443. [DOI] [PubMed] [Google Scholar]
  • 20.Nogueira D, Staessen C, van de Velde H, van Steirteghem A. Nuclear status and cytogenetics of embryos derived from in vitro-matured oocytes. Fertil Steril. 2000;74:295–298. doi: 10.1016/s0015-0282(00)00642-7. [DOI] [PubMed] [Google Scholar]
  • 21.Wells D, Delhanty JDA. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization. Mol Hum Reprod. 2000;6:1055–1062. doi: 10.1093/molehr/6.11.1055. [DOI] [PubMed] [Google Scholar]
  • 22.Voullaire L, Slater H, Williamson R, Wilton L. Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum Genet. 2000;106:210–217. doi: 10.1007/s004390051030. [DOI] [PubMed] [Google Scholar]
  • 23.Pellestor F, Dufour M-C, Arnal F, Humeau C. Direct assessment of the rate of chromosomal abnormalities in grade IV human embryos produced by in-vitro fertilization procedure. Hum Reprod. 1994;9:293–302. doi: 10.1093/oxfordjournals.humrep.a138497. [DOI] [PubMed] [Google Scholar]
  • 24.Sandalinas M, Sadowy S, Calderon G, Escudero T, Alikani M, Cohen J, Munné S: Survival of chromosome abnormalities to blastocyst stage. Hum Reprod 2000;ESHRE Abstr. Book 1:11–12
  • 25.Munné S, Magli C, Adler A, Wright G, de Boer K, Mortimer D, Tucker M, Cohen J, Gianaroli L. Treatment-related chromosome abnormalities in human embryos. Hum Reprod. 1997;12:780–784. doi: 10.1093/humrep/12.4.780. [DOI] [PubMed] [Google Scholar]
  • 26.Wolkersdorfer GW, Bornstein SR, Hilbers U, Zimmermann G, Biesold C, Lehmann M, Alexander H. The presence of chorionic gonadotrophin β subunit in normal cyclic human endometrium. Mol Hum Reprod. 1998;4:179–184. doi: 10.1093/molehr/4.2.179. [DOI] [PubMed] [Google Scholar]
  • 27.Buster JE, Bustillo M, Rodi IA, Cohen SW, Hamilton M, Simon JA, Thorneycroft IH, Marshall JR. Biologic and morphologic development of donated human ova recovered by nonsurgical uterine lavage. Am J Obstet Gynecol. 1985;153:211–217. doi: 10.1016/0002-9378(85)90116-4. [DOI] [PubMed] [Google Scholar]
  • 28.Coulam CB, Roussev R: Chemical pregnancies: Immunological and ultrasonographic studies. Am J Reprod Immunol (In press) [DOI] [PubMed]
  • 29.Clark DA: Immunology of pregnancy. In Medical Complications of Pregnancy, 6th edn., GN Burrow, (ed), Saunders, Philadelphia, In press
  • 30.Lein E, Ingalls RR. Toll-like receptors. Crit Care Med. 2002;30(Suppl):S1–S11. [PubMed] [Google Scholar]
  • 31.Neilson IR, Neilson KA, Yunis EJ, Rowe MI. Failure of tumor necrosis factor to produce hypotensive shock in the absence of endotoxin. Surgery. 1989;106:439–443. [PubMed] [Google Scholar]
  • 32.Clark DA, Croitoru K. TH1/TH2,3 imbalance due to cytokine-producing NK, γδT and NK-γδT cells in success or failure of pregnancy. Am J Reprod Immunol. 2001;45:257–265. doi: 10.1111/j.8755-8920.2001.450501.x. [DOI] [PubMed] [Google Scholar]
  • 33.Wuu Y-D, Pampfer S, Becquet P, Vanderheyden I, Lee K-H, de Hertogh R. Tumor necrosis factor a decreases the viability of mouse blastocyts in vitro and in vivo. Biol Reprod. 1999;60:479–483. doi: 10.1095/biolreprod60.2.479. [DOI] [PubMed] [Google Scholar]
  • 34.Nothnick WB. Treating endometriosis as an autoimmune disease. Fertil Steril. 2001;76:223–231. doi: 10.1016/s0015-0282(01)01878-7. [DOI] [PubMed] [Google Scholar]
  • 35.Smart YC, Fraser IS, Clancy RL, Roberts TK, Cripps AW. Early pregnancy factor as a monitor for fertilization in women wearing intrauterine devices. Fertil Steril. 1982;37:201–204. [PubMed] [Google Scholar]
  • 36.Klenteris LD, Bulmer JN, Warren MA, Morrison L, Li TC, Cooke ID. Lymphoid tissue in the endometrium of women with unexplained infertility: Morphometric and immunohistochemical aspects. Hum Reprod. 1994;9:646–652. doi: 10.1093/oxfordjournals.humrep.a138564. [DOI] [PubMed] [Google Scholar]
  • 37.Stewart-Akers AM, Krasnow JS, Brekosky J, DeLoia JA. Endometrial leukocytes are altered numerically and functionally in women with implantation defects. Am J Reprod Immunol. 1998;39:1–11. doi: 10.1111/j.1600-0897.1998.tb00326.x. [DOI] [PubMed] [Google Scholar]
  • 38.Formigli L, Formigli G, Roccio C. Donation of fertilized uterine ova to infertile women. Fertil Steril. 1987;47:162–165. [PubMed] [Google Scholar]
  • 39.Pellicier A, Navarro J, Bosch E, Garrido N, Garcia-Velasco JA, Remohi J, Simon C. Endometrial quality in infertile women with endometriosis. Ann New York Acad Sci. 2001;943:122–130. doi: 10.1111/j.1749-6632.2001.tb03796.x. [DOI] [PubMed] [Google Scholar]
  • 40.Muzikova E, Clark DA. In spontaneous resorption in the DBA/2-mated CBA/J mouse due to a defect in “seed” or in “soil”? Am J Reprod Immunol. 1995;33:81–85. doi: 10.1111/j.1600-0897.1995.tb01142.x. [DOI] [PubMed] [Google Scholar]
  • 41.Clark DA, Banwatt D, Chaouat G. Stress-triggered abortion in mice is prevented by alloimmunization. Am J Reprod Immunol. 1993;29:141–147. doi: 10.1111/j.1600-0897.1993.tb00579.x. [DOI] [PubMed] [Google Scholar]
  • 42.Gallinelli A, Roncagglia R, Matteo ML, Ciaccio I, Volpe A, Facchinetti F. Immunological changes and stress are associated with different implantation rates in patients undergoing in vitro fertilization-embryo transfer. Fertil Steril. 2001;76:85–91. doi: 10.1016/s0015-0282(01)01826-x. [DOI] [PubMed] [Google Scholar]
  • 43.Clark DA, Chaouat G, Gorczynski RM. Thinking outside the box: Mechanisms of environmental selective pressures on the outcome of the materno-fetal relationship. Am J Reprod Immunol. 2002;47:275–282. doi: 10.1034/j.1600-0897.2002.01093.x. [DOI] [PubMed] [Google Scholar]
  • 44.Clark DA, Brierley J, Banwatt D, Chaouat G. Hormone-induced pre-implantation Lyt-2+ murine suppressor cellspersist after implantation and may reduce the spontaneous abortion rate in CBA/J mice. Cell Immunol. 1989;123:334–343. doi: 10.1016/0008-8749(89)90294-3. [DOI] [PubMed] [Google Scholar]
  • 45.Ghazeeri GS, Clark DA, Kutteh WH. Immunologic factors in implantation. Infert Reprod Med Clinics N Am. 2001;12:315–337. [Google Scholar]
  • 46.Robertson SA, Sharkey DJ. The role of semen in induction of maternal immune tolerance to pregnancy. Sem Immunol. 2001;13:243–254. doi: 10.1006/smim.2000.0320. [DOI] [PubMed] [Google Scholar]
  • 47.Piccinni M-P, Beloni L, Livi C, Maggi E, Scarselli G, Romagnani S. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med. 1998;9:1020–1024. doi: 10.1038/2006. [DOI] [PubMed] [Google Scholar]
  • 48.Takabatake K, Fujiwara H, Goto Y, Nakayama T, Higuchi T, Fujita J, Maeda M, Mori T. Splenocytes in early pregnancy promote embryo implantation by regulating endometrial differentiation in mice. Hum Reprod. 1997;12:2102–2107. doi: 10.1093/humrep/12.10.2102. [DOI] [PubMed] [Google Scholar]
  • 49.Beer AE, Billingham RE: Host responses to intra-uterine tissue cellular and fetal allografts. J Reprod Fertil 1974;Suppl 21:59–88
  • 50.Ledray N, Lapree-Delage G, Taupin JL, Dubanchet S, Olivennes F, Moreau JF, Frydman R, Chaouat G. Concentration of leukemia inhibitory factor (LIF) and tumor necrosis factor (TNF) in uterine flushings is highly predictive of embryo implantation. Am J Reprod Immunol. 2002;47:350. doi: 10.1093/humrep/17.1.213. [DOI] [PubMed] [Google Scholar]
  • 51.Clark DA, Yu G, Levy GA, Gorczysnki RM. Procoagulants in fetus rejection: The role of the OX-2 (CD200) tolerance signal. Sem Immunol. 2001;13:255–263. doi: 10.1006/smim.2001.0315. [DOI] [PubMed] [Google Scholar]
  • 52.Mellor AL, Sivakumar J, Chandler P, Smith K, Molina H, Mao D, Munn DH. Prevention of T cell-driven activation and inflammation by tryptophan catabolism during pregnancy. Nat Immunol. 2001;2:64–68. doi: 10.1038/83183. [DOI] [PubMed] [Google Scholar]
  • 53.Gorczysnki RM, Yu G, Clark DA. Receptor engagement on cells expressing a ligand for the tolerance-inducing molecule OX-2 induces an immunoregulatory population that inhibits alloreactivity in vitro and in vivo. J Immunol. 2000;165:4854–4860. doi: 10.4049/jimmunol.165.9.4854. [DOI] [PubMed] [Google Scholar]
  • 54.Cao W, Brenner CA, Alikani M, Cohen J, Warner CM. Search for a human homolog of the mouse Ped gene. Mol Hum Reprod. 1999;5:541–547. doi: 10.1093/molehr/5.6.541. [DOI] [PubMed] [Google Scholar]
  • 55.Tartakovsky B, Bermas BL, Sthoeger Z, Shearer GM, Mozes E. Defective maternal-fetal interaction in a murine autoimmune model. Hum Reprod. 1996;11:2408–2411. doi: 10.1093/oxfordjournals.humrep.a019125. [DOI] [PubMed] [Google Scholar]
  • 56.Kutteh WH, Rote NS, Silver R. Antiphospholipid antibodies and reproduction: The antiphospholipid antibody syndrome. Am J Reprod Immunol. 1999;41:133–152. doi: 10.1111/j.1600-0897.1999.tb00087.x. [DOI] [PubMed] [Google Scholar]
  • 57.Siamopoulou-Mavridou A, Manoussakis MN, Mavridis AK, Moutrsopoulos HM. Outcome of pregnancy in patients with autoimmune rheumatic disease before the disease onset. Ann Rheum Dis. 1988;47:982–987. doi: 10.1136/ard.47.12.982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Gleicher N, el-Roeiy A, Confino E, Friberg J. Reproductive failure because of autoantibodies: Unexplained infertility and pregnancy wastage. Am J Obstet Gynecol. 1989;160:1376–1380. doi: 10.1016/0002-9378(89)90858-2. [DOI] [PubMed] [Google Scholar]
  • 59.Matsubayashi H, Arai T, Izumi S-I, Sugi T, McIntyre JA, Makino T. Anti-annexin V antibodies in patients with early pregnancy loss or implantation failure. Fertil Steril. 2001;76:694–699. doi: 10.1016/s0015-0282(01)02009-x. [DOI] [PubMed] [Google Scholar]
  • 60.Ober C, Karrison T, Harlow L, Elias S, Gleicher N. Autoantibodies and pregnancy history in a healthy population. Am J Obstst Gynecol. 1993;169:143–147. doi: 10.1016/0002-9378(93)90150-h. [DOI] [PubMed] [Google Scholar]
  • 61.Coulam CB, Stern JJ. Effect of seminal plasma on implantation rates. Early Pregnancy. 1995;1:33–36. [PubMed] [Google Scholar]
  • 62.Tremellen KP, Valbuena D, Landeras J, Ballesteros A, Martinez J, Mendoza S, Norman RJ, Robertson SA, Simon C. The effect of intercourse on pregnancy rates during assisted human reproduction. Hum Reprod. 2000;15:2653–2658. doi: 10.1093/humrep/15.12.2653. [DOI] [PubMed] [Google Scholar]
  • 63.Nugent D, Watson AJ, Killick SR, Balen AH, Rutherford AJ. A randomized controlled trial of tubal flushing with lipiodol for unexplained infertility. Fertil Steril. 2002;77:173–175. doi: 10.1016/s0015-0282(01)02925-9. [DOI] [PubMed] [Google Scholar]
  • 64.Coulam CB, Krysa LW, Bustillo M. Intravenous immunoglobulin for in-vitro fertilization failure. Hum Reprod. 1994;9:2265–2269. doi: 10.1093/oxfordjournals.humrep.a138435. [DOI] [PubMed] [Google Scholar]
  • 65.Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: A randomized, placebo-controlled Canadian trial. Fertil Steril. 2000;74:1108–1113. doi: 10.1016/s0015-0282(00)01622-8. [DOI] [PubMed] [Google Scholar]
  • 66.Sher G, Matzner W, Feinman M, Maassarani G, Zouves C, Chong P, Ching W. The selective use of heparin/aspirin therapy alone, or in combination with intravenous immunoglobulin G, in the management of anti-phospholipid antibody-positive women undergoing in vitro fertilization. Am J Reprod Immunol. 1998;40:74–82. doi: 10.1111/j.1600-0897.1998.tb00394.x. [DOI] [PubMed] [Google Scholar]
  • 67.Gorczynski RM, Hadidi S, Yu G, Clark DA. The same immunoregulatory molecules contribute to successful pregnancy and transplantation. Am J Reprod Immunol. 2002;48:18–26. doi: 10.1034/j.1600-0897.2002.01094.x. [DOI] [PubMed] [Google Scholar]
  • 68.Ober C, Elias S, Kostyu DD, Hauck WW. Decreased fecundability in Hutterite couples sharing HLA-DR. Am J Hum Genet. 1992;50:6–14. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Assisted Reproduction and Genetics are provided here courtesy of Springer Science+Business Media, LLC

RESOURCES