Comparative cytogenetic analysis of early reproductive losses depending of maternal age

  • I. R. Tkach
  • N. L. Huleyuk
  • D. V. Zastavna
  • K. O. Sosnina
  • G. M. Bezkorovaina
  • N. V. Helner


Aim. Human reproduction characterized by a high incidence of aneuploidies. Approximately 99 % of conceptions with anomalies of karyotype terminate of pregnancy loss, mainly during the first 14 weeks of intrauterine development. The frequency and spectrum of karyotype anomalies in the chorionic villus of early reproductive losses were studied depending of maternal age. Methods. Banding cytogenetic and interphase mFISH with the centromeric probe panel for chromosomes 13, 14, 15, 16, 17, 18, 21, 22, X and Y were used. Results. The contribution of different karyotype abnormalities in the genesis of the early reproductive losses depends on the age of the woman, namely, with age significantly increases the proportion of aneuploidy due to autosomal trisomies and reduced contribution of polyploidy and gonosomal monosomy. The main autosomal trisomy in the material of lost pregnancies from women under the age of 35 is 16, 21 and 15, 22, 13 and 18 in order of decreasing frequency, and from older women 16, 15, 22, 21, 13 and 14. Conclusions. The structure and rate of karyotype anomalies in the material of lost pregnancies varies with maternal age.

Keywords: early reproductive loss, maternal age, karyotype abnormalities.


Macklon N.S., Geraedts J.P., Fauser B.C. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update. 2002. Vol. 8. P. 333–343. doi: 10.1093/humupd/8.4.333

Hassold T., Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet. 1985. Vol. 70. P. 11–17. doi: 10.1007/BF00389450

Eiben B., Bartels I., Bähr-Porsch S., Borgmann S., Gatz G., Gellert G., Goebel R., Hammans W., Hentemann M., Osmers R., Rauskolb R., Hansmann I. Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage. Am J Hum Genet. 1990. Vol. 47. P. 656–663.

Lebedev I. Mosaic aneuploidy in early fetal losses. Cytogenet Genome Res. 2011. Vol. 133. P.169–183. doi: 10.1159/000324120

Levy B., Sigurjonsson S., Pettersen B., Maisenbacher M.K., Hall M.P., Demko Z., Lathi R.B., Tao R., Aggarwal V., Rabinowitz M. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis. Obstet Gynecol. 2014. Vol. 124. P. 202–209. doi: 10.1097/AOG.0000000000000325.

Menasha J., Levy B., Hirschhorn K., Kardon N.B. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med. 2005. Vol. 7. P. 251–263. doi: 10.1097/01.GIM.0000160075.96707.04.

Kalousek D.K., Lau A.E. Pathology of spontaneous abortion. In: Dimmick JE, Kalousek DK (eds). Developmental Pathology of the Embryo and Fetus. Philadelphia: Lippincot, 1992. P. 55–82.

Reddy U.M., Ko C.W., Willinger M. Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol. 2006. Vol. 195 (3). P. 764–70. doi: 10.1016/j.ajog.2006.06.019.

Berkowitz G.S., Skovron M.L., Lapinski P.H., Berkowitz R.L. Delayed childbearing and the outcome of pregnancy. N Engl J Med. 1990. Vol. 322. P. 659–664. doi: 10.1056/NEJM199003083221004.

Nybo Andersen A.M., Wohlfahrt J., Christens P., Olsen J., Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000. Vol. 320. P. 1708–1712. doi: 10.1136/bmj.320.7251.1708.

Ogasawara M., Aoki K., Okada S., Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000. Vol. 73 (2). P. 300–304. doi: 10.1016/S0015-0282(99)00495-1.

Carp H., Toder V., Aviram A., Daniely M., Mashiach S., Barkai G. Karyotype of the abortus in recurrent miscarriage. Fertil Steril. 2001. Vol. 75. P. 678–682. doi: 10.1016/S0015-0282(00)01801-X.

Stephenson M.D., Kutton W. Evaluation and management of recurrent early pregnancy loss. Clin Obstet Gynecol. 2007. Vol. 50 (1). P. 132–145. doi: 10.1097/GRF.0b013e31802f1c28.

Diego-Alvarez D., Ramos-Corrales C., Garcia-Hoyos M., Bustamante-Aragones A., Cantalapiedra D., Diaz-Recasens J., Vallespin-Garcia E., Ayuso C., Lorda-Sanchez I. Double trisomy in spontaneous miscarriages: cytogenetic and molecular approach. Human Reproduction. 2006. Vol. 21 (4). P. 958–966. doi: 10.1093/humrep/dei406.

Diego-Alvarez D., Rodriguez de Alba M., Cardero-Merlo R., Diaz-Recarens J., Ayuso C., Ramos C., Lorda-sanchez I. MLPA as a screening method of aneuploidy and unbalanced chromosomal rearrangements in spontaneous miscarriages. Prenat. Diagn. 2007. Vol. 27. P. 765–771. doi: 10.1016/j.bbadis.2012.07.001.

Menten B., Swerts K., Delle Chiaie B., Janssens S., Buysse K., Phillipe J., Speleman F. Array comparative genomic hybridization and flow cytometry analysis of spontaneous abortions and mors in utero samples. BMC Med. Genet. 2009. doi: 10.1186/1471-2350-10-89

Robberecht C., Schuddinck V., Fryns J.P., Vermeesch J.R. Diagnosis of miscarriages by molecular karyotyping: benefits and pitfalls. Genet. Med. 2009. V. 11. P. 646–654. doi: 10.1097/GIM.0b013e3181abc92a.

Zhang Y.X., Zhang Y.P., Gu Y., Guan F.J., Xie J.S., Shen Y., Wu B.L., Ju W., Jenkins E.C., Brown W.T., Zhong N. Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and arrayCGH. Clin.Genet. 2009. Vol. 75. P. 133–140. doi: 10.1111/j.1399-0004.2008.01131.x.

Doria S., Carvalho F., Ramalho C., Lima V., Francisco T., Machado A.P., Brandao O., Sousa M., Matias A., Barros A. An efficient protocol for the detection of chromosomal abnormalities in spontaneous miscarriages or foetal deaths. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2009. Vol. 147 (2). P. 144–150. doi: 10.1016/j.ejogrb.2009.07.023.

Shearer B.M., Thorland E.C., Carlson A.W., Jalal S.M., Ketterling R.P. Reflex fluorescent in situ hybridization testing for unsuccessful product of conception cultures: a retrospective analysis of 5555 samples attempted by conventional cytogenetics and fluorescent in situ hybridization. Genet. Med. 2011. Vol. 1. P. 545–552. doi: 10.1097/GIM.0b013e31820c685b.

Sullivan A.E., Silver R.M., Lacoursiere D.Y., Porter T.F., Branch D.W. Recurrent fetal aneuploidy and recurrent miscarriage. Obstet Gynecol. 2004. Vol. 104. P. 784–788. doi: 10.1097/01.AOG.0000137832.86727.e2.

Halder A., Fauzdar A. Skewed sex ratio & low aneuploidy in recurrent early missed abortion. Indian J. Med. Res. 2006. Vol. 124. P. 41–50.

Wang B.T., Chong T.P., Boyar F.Z., Kopita K.A., Ross L.P., El-Naggar M.M., Sahoo T., Wang J-C., Hemmat M., Haddadin M.H., Owen R., Anguiano A.L. Abnormalities in spontaneous abortions detected by G-banding and chromosomal microarray analysis (CMA) at a national reference laboratory. Molecular Cytogenetics. 2014. 7:33. doi: 10.1186/1755-8166-7-33

Kooper A.J.A., Faas B.H.W., Feenstra I., de Leeuw N., Smeets D.F.C.M. Best diagnostic approach for the genetic evaluation of fetuses after intrauterine death in first, second or third trimester: QF-PCR, karyotyping and/or genome wide SNP array analysis. Molecular Cytogenetics. 2014. 7:6. doi: 10.1186/1755-8166-7-6

Gao J., Liu C., Yao F., Hao N., Zhou J., Zhou Q., Zhang L., Liu X., Bian X., Liu J. Array-based comparative genomic hybridization is more informative than conventional karyotyping and fluorescence in situ hybridization in the analysis of first-trimester spontaneous abortion. Molecular Cytogenetics. 2012. 5:33. doi: 10.1186/1755-8166-5-33

Goddijn M., Leschot N.J. Genetic aspects of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol. 2000. Vol. 14 (5). P. 855–865. doi: 10.1053/beog.2000.0124.

Simpson J.L. Causes of fetal wastage. Clin Obstet Gynecol. 2007. Vol. 50. P. 10–30. doi: 10.1097/GRF.0b013e31802f11f6.

Ljunger E., Cnattingius S., Lundin C., Annerén G. Chromosomal anomalies in first-trimester miscarriages. Acta Obstet Gynecol Scand. 2005. Vol. 84 (11). P. 1103–1107. doi: 10.1111/j.0001-6349.2005.00882.x.

Stephenson M.D, Awartani K.A, Robinson W.P. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod. 2002. Vol. 17 (2). P. 446–451. doi: 10.1093/humrep/17.2.446

Philipp T., Philipp K., Reiner A., Beer F., Kalousek D.K. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod. 2003. Vol. 18 (8). P. 1724–1732. doi: 10.1093/humrep/deg309