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Semin Reprod Med 2000; 18(4): 425-432
DOI: 10.1055/s-2000-13732
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Genetic Factors in Recurrent Pregnancy Loss

Kenneth J. Ward
  • 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

Technologies such as fluorescent in situ hybridization (FISH) are facilitating analysis of tissue that cannot be cultured. Increasing recognition and knowledge of confined placental mosaicism are giving us greater appreciation of the role of aneuploidies in cases of spontaneous and recurrent abortion. Newer molecular analyses suggest important roles for single-gene mutations, X inactivation, and imprinting effects. In the coming years, our increased understanding of the genetics of recurrent spontaneous abortion should result in new and more expedient diagnoses and potential treatments.

KEYWORD

Recurrent abortion - cytogenetics - mutation

REFERENCES

  • 1 Byrne J, Ward K. Genetic factors in recurrent abortion.  Clin Obstet Gynecol . 1994;  37 693-704
    PubMedGoogle Scholar
  • 2 Imai A, Tamaya T. Chromosome abnormalities associated with recurrent abortion.  Res Commun Mol Pathol Pharmacol . 1996;  94 323-326
    PubMedGoogle Scholar
  • 3 Baltaci V, Aygun N, Akyol K, Karakaya A E, Sardas S. Chromosomal aberrations and alkaline comet assay in families with habitual abortion.  Mutat Res . 1998;  417 47-55
    PubMedGoogle Scholar
  • 4 Vidal F, Gimenez C, Rubio C. FISH preimplantation diagnosis of chromosome aneuploidy in recurrent pregnancy wastage.  J Assist Reprod Genet . 1998;  15 310-313
    CrossrefPubMedGoogle Scholar
  • 5 Giorlandino C, Bettio D, Simoni G. Spermatozoa with chromosomal abnormalities may result in a higher rate of recurrent abortion.  Fertil Steril . 1998;  70 576-577
    CrossrefPubMedGoogle Scholar
  • 6 Rubio C, Simon C, Blanco J. Implications of sperm chromosome abnormalities in recurrent miscarriage.  J Assist Reprod Genet . 1999;  16 253-258
    CrossrefPubMedGoogle Scholar
  • 7 Stene J, Stene E, Mikkelsen M. Risk for chromosome abnormality at amniocentesis following a child with a non-inherited chromosome aberration.  Prenat Diagn . 1984;  4 81-95
    PubMedGoogle Scholar
  • 8 Warburton D, Kline J, Stein Z, Hutzler M, Chin A, Hassold T. Does the karyotype of a spontaneous abortion predict the karyotype of a subsequent abortion?.  <~>Evidence from 273 women with two karyotyped spontaneous abortions. Am J Hum Genet . 1987;  41 465-483
    PubMedGoogle Scholar
  • 9 Hook E B, Cross P. Spontaneous abortion and subsequent Down syndrome live births.  Hum Genet . 1983;  64 267-270
    PubMedGoogle Scholar
  • 10 Lippman A, Ayme S. Fetal death rates in mothers of children with trisomy 21 (Down syndrome).  Ann Hum Genet . 1984;  48 303-312
    PubMedGoogle Scholar
  • 11 Kohn G, Shohat M. Trisomy 18 mosaicism in an adult with normal intelligence.  Am J Med Genet . 1987;  26 929-931
    CrossrefPubMedGoogle Scholar
  • 12 Nielsen G, Poulsen H, Mikkelsen M, Steuber E. Multiple recurrence of trisomy 21 Down syndrome.  Hum Genet . 1988;  78 103-105
    PubMedGoogle Scholar
  • 13 Gersdorf E, Utermann B, Utermann G. Trisomy 18 mosaicism in an adult woman with normal intelligence and history of miscarriage.  Hum Genet . 1990;  84 298-299
    PubMedGoogle Scholar
  • 14 Sachs E S, Jahoda M G, Los F J, Pijpers L, Wladimiroff J W. Trisomy 21 mosaicism in gonads with unexpectedly high recurrence risks.  Am J Med Genet . 1990;  7 186-188
    PubMedGoogle Scholar
  • 15 Pangalos C G, Talbot Jr C C, Lewis J G. DNA polymorphism analysis in families with recurrence of free trisomy 21.  Am J Hum Genet . 1992;  51 1015-1027
    PubMedGoogle Scholar
  • 16 Tseng L H, Chuang S M, Lee T Y, Ko T M. Recurrent Down's syndrome due to maternal ovarian trisomy 21 mosaicism.  Arch Gynecol Obstet . 1994;  255 213-216
    CrossrefPubMedGoogle Scholar
  • 17 Satge D, Geneix A, Goburdhun J. A history of miscarriages and mild prognathism as possible mode of presentation of mosaic trisomy 18 in women.  Clin Genet . 1996;  50 470-473
    PubMedGoogle Scholar
  • 18 Uchida I A, Freeman V C. Trisomy 21 Down syndrome: parental mosaicism.  Hum Genet . 1985;  70 246-248
    PubMedGoogle Scholar
  • 19 Hunt P, LeMaire R, Embury P, Sheean L, Mroz K. Analysis of chromosome behavior in intact mammalian oocytes: monitoring the segregation of a univalent chromosome during female meiosis.  Hum Mol Genet . 1995;  4 2007-2012
    PubMedGoogle Scholar
  • 20 Warburton D. The effect of maternal age on the frequency of trisomy: change in meiosis or in utero selection?. In: Hassold TJ, Epston CJ, eds. Molecular and Cytogenetic Studies on Non-disjunction New York: Alan R Liss 1989: 165-181
    Google Scholar
  • 21 Stavropolos D J, Bick D, Kalousek D K. Molecular cytogenetic detection of confined gonadal mosaicism in a conceptus with trisomy 16 placental mosaicism.  Am J Hum Genet . 1998;  63 1912-1914
    CrossrefPubMedGoogle Scholar
  • 22 Silver R M, Branch D. Sporadic and recurrent pregnancy loss. In: Reese EA, Hobbins JC, eds. Medicine of the Fetus and Mother Philadelphia: Lippincott-Raven 1999: 95-216
    Google Scholar
  • 23 De Braekeleer M, Dao T N. Cytogenetic studies in couples experiencing repeated pregnancy losses.  Hum Reprod . 1990;  5 519-528
    PubMedGoogle Scholar
  • 24 Fryns J P, Kleczkowska A, Kubien E, van den Berghe H. Structural chromosomal rearrangements in couples with repeated miscarriages: experience in Louvain.  J Genet Hum . 1998;  36 59-61
    PubMedGoogle Scholar
  • 25 Portnoi M F, Joye N, van den Akker J, Morlier G, Taillemite J L. Karyotypes of 1142 couples with recurrent abortion.  Obstet Gynecol . 1988;  72 31-34
    PubMedGoogle Scholar
  • 26 Boue A, Gallano P. A collaborative study of the segregation of inherited chromosome structural arrangements in 1356 prenatal diagnoses.  Prenat Diagn . 1984;  4(special issue) 45-67
    PubMedGoogle Scholar
  • 27 Frizzley J K, Stephan M J, Lamb A N. Ring 22 duplication/deletion mosaicism: clinical, cytogenetic, and molecular characterisation.  J Med Genet . 1999;  36 237-241
    PubMedGoogle Scholar
  • 28 Lacassie Y, Arriaza M I, Vargas A, La Motta I. Ring 2 chromosome: ten-year follow-up report.  Am J Med Genet . 1999;  85 117-122
    CrossrefPubMedGoogle Scholar
  • 29 Vejerslev L O, Mikkelsen M. The European collaborative study on mosaicism in chorionic villus sampling: data from 1986 to 1987.  Prenat Diagn . 1989;  9 575-588
    PubMedGoogle Scholar
  • 30 Johnson A, Wapner R J, Davis G H, Jackson L G. Mosaicism in chorionic villus sampling: an association with poor perinatal outcome.  Obstet Gynecol . 1990;  75 573-577
    PubMedGoogle Scholar
  • 31 Balmer D, Baumer A, Rothlisberger B, Schinzel A. Severe intra-uterine growth retardation in a patient with maternal uniparental disomy 22 and a 22-trisomic placenta.  Prenat Diagn . 1999;  19 1061-1064
    CrossrefPubMedGoogle Scholar
  • 32 Hsu L Y, Yu M T, Neu R L. Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20, and 21: karyotype/phenotype correlations.  Prenat Diagn . 1997;  17 201-242
    CrossrefPubMedGoogle Scholar
  • 33 Kalousek D K, Langlois S, Robinson W P. Trisomy 7 CVS mosaicism: pregnancy outcome, placental and DNA analysis in 14 cases.  Am J Med Genet . 1996;  65 348-352
    CrossrefPubMedGoogle Scholar
  • 34 Hsu W T, Shchepin D A, Mao R. Mosaic trisomy 16 ascertained through amniocentesis: evaluation of 11 new cases.  Am J Med Genet . 1998;  80 473-480
    Google Scholar
  • 35 Copp A J. Death before birth: clues from gene knockouts and mutations.  Trends Genet . 1995;  11 87-93
    CrossrefPubMedGoogle Scholar
  • 36 Blackburn M R, Wakamiya M, Caskey C T, Kellems R E. Tissue-specific rescue suggests that placental adenosine deaminase is important for fetal development in mice.  J Biol Chem . 1995;  270 23891-23894
    CrossrefPubMedGoogle Scholar
  • 37 Meneton P, Lesage F, Barhanin J. Potassium ATPases, channels, and transporters: an overview.  Semin Nephrol . 1999;  1999 438-457
    PubMedGoogle Scholar
  • 38 Bertina R M, Loeleman B P, Koster T, Rosendaal F R, Dirven R J, de Ronde H. Mutation in blood coagulation factor V associated with resistance to activated protein C.  Nature . 1994;  369 64-67
    CrossrefPubMedGoogle Scholar
  • 39 Dahlback B. Inherited resistance to activated protein C, a major cause of venous thrombosis, is due to a mutation in the factor V gene.  Haemostasis . 1994;  24 139-151
    PubMedGoogle Scholar
  • 40 Arias F, Romero R, Joist H, Kraus F T. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta.  J Matern Fetal Med . 1998;  7 277-286
    CrossrefPubMedGoogle Scholar
  • 41 Meinardi J R, Middeldorp S, de Kam J P. Increased risk for fetal loss in carriers of the factor V Leiden mutation.  Ann Intern Med . 1999;  130 736-739
    PubMedGoogle Scholar
  • 42 Pablos J L, Caliz R A, Carreira P E. Risk of thrombosis in patients with antiphospholipid antibodies and factor V Leiden mutation.  J Rheumatol . 1999;  26 588-590
    PubMedGoogle Scholar
  • 43 Ehrenforth S, Klinke S, von Depka Prondzinski M, Kreuz W, Ganser A, Scharrer I. Activated protein C resistance and venous thrombophilia: molecular genetic prevalence study in the German population.  Dtsch Med Wochenschr . 1999;  124 783-787
    PubMedGoogle Scholar
  • 44 Grandone E, Margaglione M, Colaizzo D. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses.  Thromb Haemost . 1997;  77 822-824
    PubMedGoogle Scholar
  • 45 Dizon-Townson D S, Kinney S, Branch D W, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage.  J Reprod Immunol . 1997;  34 217-223
    PubMedGoogle Scholar
  • 46 Preston F E, Rosendaal F R, Walker I D. Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
    CrossrefPubMedGoogle Scholar
  • 47 Nelen W L, Steegers E A, Eskes T K, Blom H J. Genetic risk factor for unexplained recurrent early pregnancy loss [letter].  Lancet . 1997;  350 861
    PubMedGoogle Scholar
  • 48 Holmes Z R, Regan L, Chilcott I. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss.  Br J Haematol . 1999;  105 98-101
    CrossrefPubMedGoogle Scholar
  • 49 Ward K, Edwin S S, Nelson L. Analysis of parental human leukocyte antigen-G (HLA-G) gene in recurrent pregnancy loss [abstract]. Presented at the annual meeting of the Society for Gynecologic Investigation, March 30-April 4, 1993
    Google Scholar
  • 50 Laitinen T, Lokki M L, Partanen J, Tulppala M, Ylikorkala O, Koskimies S. Major histocompatibility complex located complement C4 and steroid 21-hydroxylase gene rearrangements in couples with recurrent spontaneous abortions.  Eur J Immunogenet . 1992;  19 413-418
    PubMedGoogle Scholar
  • 51 Laitinen T, Koskimies S, Westman P. Foeto-maternal compatibility in HLA-DR, -DQ, and -DP loci in Finnish couples suffering from recurrent spontaneous abortions.  Eur J Immunogenet . 1993;  20 249-258
    PubMedGoogle Scholar
  • 52 Laitinen T. A set of MHC haplotypes found among Finnish couples suffering from recurrent spontaneous abortions.  Am J Reprod Immunol . 1993;  29 148-154
    PubMedGoogle Scholar
  • 53 Steck T, van der Ven K, Kwak J, Beer A, Ober C. HLA-DQA1 and HLA-DQB1 haplotypes in aborted fetuses and couples with recurrent spontaneous abortion.  J Reprod Immunol . 1995;  29 95-104
    PubMedGoogle Scholar
  • 54 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L.)  Nature . 1962;  190 372-373
    PubMedGoogle Scholar
  • 55 Busque L, Mio R, Mattioli J. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.  Blood . 1996;  88 59-65
    PubMedGoogle Scholar
  • 56 Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman E P. Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28.  Am J Hum Genet . 1997;  61 160-170
    CrossrefPubMedGoogle Scholar
  • 57 Sangha K K, Stephenson M D, Brown C J, Robinson W P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion.  Am J Hum Genet . 1999;  65 913-917
    CrossrefPubMedGoogle Scholar
  • 58 Lanasa M C, Hogge W A, Hoffman E. The X chromosome and recurrent spontaneous abortion: the significance of transmanifesting carriers.  Am J Hum Genet . 1999;  64 934-938
    CrossrefPubMedGoogle Scholar
  • 59 Crossley P H, Little P FR. A cluster of related zinc finger protein genes is deleted in the mouse embryonic lethal mutation tw18.  Proc Natl Acad Sci U S A . 1991;  88 7923-7927
    PubMedGoogle Scholar
  • 60 Ragoussi J, Senger G, Mockridge I. A testis-expressed Zn finger gene (ZNF76) in human 6p21.3 centromeric to the MHC is closely linked to the human homolog of thet-complex gene tcp-11.  Genomics . 1992;  14 673-679
    PubMedGoogle Scholar
  • 61 Lawler S D, Porey S, Fisher R A, Pickthall V J. Genetic studies on hydatidiform moles.  Ann Hum Genet . 1982;  46 209-222
    PubMedGoogle Scholar
  • 62 McFadden D E, Kalousek D. Two different phenotypes of fetuses with chromosomal triploidy: correlation with parental origin of extra haploid set.  Am J Med Genet . 1991;  38 535-538
    CrossrefPubMedGoogle Scholar
  • 63 Nowaczyk M J, Ramsay J A, Mohide P, Tomkins D J. Multiple congenital anomalies in a fetus with 45,X/46,X, r(X) (p11.22q12) mosaicism.  Am J Med Genet . 1998;  77 306-309
    CrossrefPubMedGoogle Scholar