Abstract

Approximately 15–25% of pregnancies end in spontaneous abortion, which is an expulsion from the mother body of the fetus weighing less than 500 g or before the 20th week of gestation. Determining abortions etiology is difficult due to its multifactorial character. Chromosomal abnormalities cause 38.6–80% of miscarriages. The largest group (93%) of chromosomal aberrations found in miscarried fetuses are numerical changes – aneuploidies and polyploidies. Much rarer (7%) are unbalanced structural aberrations, which can arise de novo or can be inherited from a carrier parent. In couples with spontaneous abortions, reciprocal chromosomal translocations (RCT) occur the most frequently, next are Robertsonian translocations and inversions. More complex chromosome abnormalities, e.g. double aneuploidies are found in 3.8% of fetuses. Another group of causes responsible for abortions are monogenic diseases of embryo or fetus resulting from autosomal dominant, autosomal recessive or X-linked mutations. Among mutations which may contribute to pregnancy loss are factor V Leiden gene mutations (c.1601G>A, earlier 1691G>A) and prothrombin gene mutation (c.97G>A, earlier 20210G>A). The research on mutations in candidate genes, eg.: ALOX15, CR1, CYP1A1, CYP17, CYP2D6, FOXP3, HLA-G, IL-6, KHDC3L, NLRP7, NOS3, PLK4, SYCP3, TLR3, TNF, TP53 and VEGFA is still ongoing.

References

• 1. Al-Khateeb G.M., Mustafa F.E., Sater M.S., Almawi W.Y.: Effectof the functional VEGFA -583C/T variant on vascular endothelialgrowth factor levels and the risk of recurrent spontaneous miscarriage.Fertil. Steril., 2011; 95: 2471–2473
  Google Scholar
• 2. Andreasen L., Christiansen O.B., Niemann I., Bolund L., SundeL.: NLRP7 or KHDC3L genes and the etiology of molar pregnanciesand recurrent miscarriage. Mol. Hum. Reprod., 2013; 19: 773–781
  Google Scholar
• 3. Bałajewicz-Nowak M., Pityński K., Milewicz T.: Polimorfizmy 1691 G>A (czynnik Leiden) i 1328 T>C genu V czynnika krzepnięciaa występowanie poronień nawracających. Ginekol. Pol., 2015; 86:46–52
  Google Scholar
• 4. Barlik M., Seremak-Mrozikiewicz A., Kraśnik W., Drews K.: Polimorfizmy20210G>A i 19911A>G genu protrombiny a występowanieporonień nawracających. Ginekol. Pol., 2013; 84: 830–834
  Google Scholar
• 5. Bender Atik R., Christiansen O.B., Elson J., Kolte A.M., Lewis S.,Middeldorp S., Nelen W., Peramo B., Quenby S., Vermeulen N., GoddijnM.: ESHRE guideline: recurrent pregnancy loss. Hum. Reprod.Open, 2018; 2018: hoy004
  Google Scholar
• 6. Celep F., Karagüzel A., Ozeren M., Bozkaya H.: The frequency ofchromosomal abnormalities in patients with reproductive failure.Eur. J. Obstet. Gynecol. Reprod. Biol., 2006; 127: 106–109
  Google Scholar
• 7. Cinar C., Beyazyurek C., Ekmekci C.G., Aslan C., Kahraman S.:Sperm fluorescence in situ hybridization analysis reveals normalsperm cells for 14;14 homologous male Robertsonian translocationcarrier. Fertil. Steril., 2011; 95: 289.e5–e9
  Google Scholar
• 8. Colley E., Hamilton S., Smith P., Morgan N.V., CoomarasamyA., Allen S.: Potential genetic causes of miscarriage in euploidpregnancies: A systematic review. Hum. Reprod. Update, 2019;25: 452–472
  Google Scholar
• 9. Diego-Alvarez D., Garcia-Hoyos M., Jose Trujillo M., Gonzalez-Gonzalez C., Rodriguez de Alba M., Ayuso C., Ramos-Corrales C.,Lorda-Sanchez I.: Application of quantitative fluorescent PCR withshort tandem repeat markers to the study of aneuploidies in spontaneousmiscarriages. Hum. Reprod., 2005; 20: 1235–1243
  Google Scholar
• 10. Diego-Alvarez D., Rodriguez de Alba M., Cardero-Merlo R.,Diaz-Recasens J., Ayuso C., Ramos C., Lorda-Sanchez I.: MLPA asa screening method of aneuploidy and unbalanced chromosomalrearrangements in spontaneous miscarriages. Prenat. Diag., 2007;27: 765–771
  Google Scholar
• 11. Dutta U.R., Rajitha P., Pidugu V.K., Dalal A.B.: Cytogenetic abnormalitiesin 1162 couples with recurrent miscarriages in Southernregion of India: Report and review. J. Assist. Reprod. Genet.,2011; 28: 145–149
  Google Scholar
• 12. Fallahian M., Sebire N.J., Savage P.M., Seckl M.J., Fisher R.A.:Mutations in NLRP7 and KHDC3L confer a complete hydatidiformmole phenotype on digynic triploid conceptions. Hum. Mutat.,2013; 34: 301–308
  Google Scholar
• 13. Fan H.T., Zhang M., Zhan P., Yang X., Tian W.J., Li R.W.: Structuralchromosomal abnormalities in couples in cases of recurrentspontaneous abortions in Jilin Province, China. Genet. Mol. Res.,2016; 15: 1–7
  Google Scholar
• 14. Flynn H., Yan J., Saravelos S.H., Li T.C.: Comparison of reproductiveoutcome, including the pattern of loss, between coupleswith chromosomal abnormalities and those with unexplained repeatedmiscarriages. J. Obstet. Gynaecol. Res., 2014; 40: 109–116
  Google Scholar
• 15. Grady W.W., Designan J.L.: Diagnostic molecular genetics. W: Emeryand Rimoin`s Principles and Practice of Medical Genetics, red.:D. Rimoin, R. Pyeritz, B. Korf. Academic Press, Cambrige, 2013, 1–21
  Google Scholar
• 16. Ljunger E., Cnattingius S., Lundin C., Anneren G.: Chromosomalanomalies in first-trimester miscarriages. Acta Obstet. Gynecol.Scand., 2005; 84: 1103–1107
  Google Scholar
• 17. McKinlay Gerdner R.J., Shutherland G.R., Shaffer L.G.: Chromosomeabnormalities and genetic counseling (Oxford Monographson Medical Genetics). Oxford University Press, Oxford 2012
  Google Scholar
• 18. Messaed C., Chebaro W., Di Roberto R.B., Rittore C., CheungA., Arseneau J., Schneider A., Chen M.F., Bernishke K., Surti U.,Hoffner L., Sauthier P., Buckett W., Qian J.H., Lau N.M., Bagga R.,Engert J.C., Coullin P., Touitou I., Slim R.: NLRP7 in the spectrumof reproductive wastage: Rare non-synonymous variants confergenetic susceptibility to recurrent reproductive wastage. J. Med.Genet., 2011; 48: 540–548
  Google Scholar
• 19. Mikhail F.M.: Chromosomal basic of inheritance. W: Emeryand Rimoin`s Principles and Practice of Medical Genetics, red.: D.Rimoin, R. Pyeritz, B. Korf. Academic Press, Cambrige, 2013, 1–26
  Google Scholar
• 20. Pylyp L.Y., Spynenko L.O., Verhoglyad N.V., Mishenko A.O.,Mykytenko D.O., Zukin V.D.: Chromosomal abnormalities in productsof conception of first-trimester miscarriages detected by conventionalcytogenetic analysis: a review of 1000 cases. J. Assist.Reprod. Genet., 2018; 35: 265–271
  Google Scholar
• 21. Qiao Y., Wen J., Tang F., Martell S., Shomer N., Leung P.C., StephensonM.D., Rajcan-Separovic E.: Whole exome sequencing in recurrentearly pregnancy loss. Mol. Hum. Reprod., 2016; 22: 364–372
  Google Scholar
• 22. Quintero-Ronderos P., Mercier E., Fukuda M., Gonzalez R.,Suarez C.F., Patarroyo M.A., Vaiman D., Gris J.C., Laissue P.: Novelgenes and mutations in patients affected by recurrent pregnancyloss. PLoS One, 2017; 12: e0186149
  Google Scholar
• 23. Rae W., Gao Y., Bunyan D., Holden S., Gilmour K., Patel S.,Wellesley D., Williams A.: A novel F mutation causing fetal akinesiaand recurrent male miscarriages. Clin. Immunol., 2015; 161:284–285
  Google Scholar
• 24. Royal College of Obstetricians and Gynaecologists: The investigationand treatment of couples with recurrent first-trimesterand second-trimester miscarriage. Green Top Guideline No. 17.RCOG, London 2011, 1–18
  Google Scholar
• 25. Sahoo T., Dzidic N., Strecker M.N., Commander S., Travis M.K.,Doherty C., Tyson R.W., Mendoza A.E., Stephenson M, Dise C.A., BenitoC.W., Ziadie M.S., Hovanes K.: Comprehensive genetic analysisof pregnancy loss by chromosomal microarrays: outcomes, benefits,and challenges. Genet. Med., 2017; 19: 83–89
  Google Scholar
• 26. Schreck R., Williams III J. Fetal loss. W: Emery and Rimoin`sPrinciples and Practice of Medical Genetics, red.: D. Rimoin, R. Pyeritz,B. Korf. Academic Press, Cambrige, 2013, 1–21
  Google Scholar
• 27. Shi X., Xie X., Jia Y., Li S.: Maternal genetic polymorphismsand unexplained recurrent miscarriage: a systematic review andmeta-analysis. Clin. Genet., 2017; 91: 265–287
  Google Scholar
• 28. Skrzypczak J., Rajewski M., Wirstlein P., Goździewicz T.,Bręborowicz G., Leszczyńska-Gorzelak B., Ludwikowski G., PreisK., Wołczyński S., Zimmer M.: Częstość występowania trombofiliiwrodzonej u kobiet z utratą ciąż w wieloośrodkowych badaniachw Polsce. Ginekol. Pol., 2012; 83: 330–336
  Google Scholar
• 29. Stephenson M.D.: Frequency of factors associated with habitualabortion in 197 couples. Fertil. Steril., 1996; 66: 24–29
  Google Scholar
• 30. Stephenson M.D., Awartani K.A., Robinson W.P.: Cytogeneticanalysis of miscarriages from couples with recurrent miscarriage:a case-control study. Hum. Reprod., 2002; 17: 446–51
  Google Scholar
• 31. Stephenson M.D., Sierra S.: Reproductive outcomes in recurrentpregnancy loss associated with a parental carrier of a structuralchromosome rearrangement. Hum. Reprod., 2006; 21:1076–1082
  Google Scholar
• 32. The Practice Committee of the American Society for ReproductiveMedicine. Evaluation and treatment of recurrent pregnancyloss: A committee opinion. Fertil. Steril., 2012; 98: 1103–1111
  Google Scholar
• 33. Tunç E., Tanrıverdi N., Demirhan O., Süleymanova D., ÇetinelN.: Chromosomal analyses of 1510 couples who have experiencedrecurrent spontaneous abortions. Reprod. Biomed. Online, 2016;32: 414–410
  Google Scholar
• 34. Wolski H., Barlik M., Drews K., Klejewski A., Kurzawińska G.,Ożarowski M., Łowicki Z., Seremak-Mrozikiewicz A.: Contributionof inherited thrombophilia to recurrent miscarriage in the Polishpopulation. Ginekol. Pol., 2017; 88: 385–392
  Google Scholar
• 35. World Health Organization. International Classification ofDiseases. 11th ed; 18 June 2018 https://www.who.int/classifications/icd/en/ (14.08.2020)
  Google Scholar

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