Time to reduce the rate of idiopathic recurrent pregnancy losses





recurrent pregnancy loss, aneuploidy, balanced structural chromosome abnormalities, karyotyping, FISH, chromosomal microarray analysis, antiphospholipid syndrome, chronic endometritis


Recurrent pregnancy loss (RPL) is a polyetiological pathology, with the majority of causes and risk factors still not fully understood. The paper provides an overview of the current clinical guidelines on RPL, which shows the contradictions of recommendations for certain positions of examination and treatment. Taking into account the differences in the recommendations for genetic testing a detailed review of primary sources on the contribution of chromosomal pathology to RPL was done that confirms the value of cytogenetic testing of the conception product and need for attention to study of other than mother’s age factors that increase the risk of recurrent quantitative chromosomal abnormalities (aneuploidies, polyploidies). Balanced structural chromosomal abnormalities are the cause 5% of RPL. Carriers of balanced structural abnormalities do not phenotypically differ from people with a normal karyotype, but have a high risk of infertility, recurrent miscarriage, stillbirth, and birth of a child with chromosomal abnormalities. Examination of spouses with RPL for balanced structural chromosome abnormalities is the first and mandatory stage of examination, especially if cytogenetic examination of the conception products was not performed or was not informative.
This article also includes a review of studies in 2019–2020 years on improving diagnostic algorithms for the RPL causes to reduce the idiopathic cases. Scientific researches prove that a complete examination to identify all possible causes of RPL regardless of the result of the conception product karyotype determining can reduce the frequency of idiopathic RPL to 10–15%.
Thus, the exhaustive examination of all couples with RPL (diagnosis of genetic, anatomical, autoimmune, hormonal and microbiological causes, as well as a thorough assessment of risk factors) can significantly reduce the proportion of idiopathic forms of RPL. This reduces the stress of uncertainty and unreasonable empirical treatment in patients and provides a possibility to develop an individual plan for reproduction, using assisted reproductive technologies if necessary.

Author Biographies

T. M. Tutchenko, SI “O.M. Lukyanova IPOG of the NAMS of Ukraine”; SSI “CIMT of the NAS of Ukraine”; “DILA” Medical Laboratory, Kyiv

PhD, senior researcher of the Endocrine Gynecology Department;

Department of Reproductive Health;

Scientific consultant of “DILA” Medical Laboratory

O. A. Burka, Bogomolets National Medical University; “DILA” Medical Laboratory, Kyiv

PhD, associate professor at the Obstetrics and Gynaecology Department No. 1;

Scientific consultant of “DILA” Medical Laboratory

V. S. Samilyk, “DILA” Medical Laboratory; Center of Medical Genetic, National children hospital “OKHMATDYT”, Kyiv

Scientific consultant of “DILA” Medical Laboratory

O. V. Trokhymovych, SI “O.M. Lukyanova IPOG of the NAMS of Ukraine”, Kyiv

MD, chief researcher, Department of Family Planning

O. I. Krotik, Clinic of reproductive technology, Ukrainian State Institute of Reproductology, P.L. Shupyk NMAPE of the MoH of Ukraine, Kyiv

Head of Department of family planning and ART with cabinet of endocrine gynecology

O. L. Gromova, Bogomolets National Medical University, Kyiv

Assistant, Obstetrics and gynecology department of postgraduate education


Regan, L., Backos, M., Rai, R. Recurrent Miscarriage, Investigation and Treatment of Couples (Green-top Guideline No. 17). Royal College of Obstetricians & Gynaecologists (2011). Available from: [https://www.rcog.org. uk/en/guidelines-research-services/guidelines/gtg17/], last accessed Nov 11, 2020.

The Practice Committee of the American Society for Reproductive Medicine. “Evaluation and treatment of recurrent pregnancy loss: A committee opinion.” Fertil Steril 98 (2012): 1103–11. DOI: 10.1016/j.fertnstert.2012.06.048

Bender Atik, R., Christiansen, O.B., Elson, J., et al. “ESHRE guideline: recurrent pregnancy loss.” Hum Reprod Open 2018 (2018). DOI: 10.1093/hropen/hoy004

Toth, B., Würfel, W., Bohlmann, M., et al. “Recurrent miscarriage: Diagnostic and therapeutic procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF registry number 015/050).” Geburtshilfe Frauenheilkd 78 (2018): 364–81. DOI: 10.1055/a-0586-4568

Jaslow, C.R., Carney, J.L., Kutteh, W.H. “Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses.” Fertil Steril 93 (2010): 1234–43. DOI: 10.1016/j.fertnstert.2009.01.166

World Health Organization; The International Federation of Gynecology and Obstetrics. “WHO: recommended definitions, terminology and format for statistical tables related to the perinatal period and use of a new certificate for cause of perinatal deaths. Modifications recommended by FIGO as amended October 14, 1976.” Acta Obstet Gynecol Scand 56.3 (1977): 247–53. Available from: [https://pubmed.ncbi.nlm.nih.gov/560099/], last accessed Nov 11, 2020.

Bhattacharya, S., Townend, J., Bhattacharya, S. “Recurrent miscarriage: Are three miscarriages one too many? Analysis of a Scottish population-based database of 151,021 pregnancies.” Eur J Obstet Gynecol Reprod Biol 150 (2010): 24–7. DOI: 10.1016/j.ejogrb.2010.02.015

Sugiura-Ogasawara, M., Ozaki, Y., Suzumori, N. “Management of recurrent miscarriage.” J Obstet Gynaecol Res 40 (2014): 1174–9. DOI: 10.1111/jog.12388

Silva, M., de Leeuw, N., Mann, K., et al. “European guidelines for constitutional cytogenomic analysis.” Eur J Hum Genet 27 (2019): 1–16. DOI: 10.1038/s41431-018-0244-x

Garcia, D., Erkan, D. “Diagnosis and Management of the Antiphospholipid Syndrome.” N Engl J Med 378 (2018): 2010–21. DOI: 10.1056/nejmra1705454

Salmon, J.E., Mineo, C., Giles, I., et al. “Mechanisms of Antiphospholipid Antibody-Mediated Pregnancy Morbidity.” In: Antiphospholipid Syndrome. Springer International Publishing (2017): 117–43. DOI: 10.1007/978-3-319-55442-6_6

Hills, F.A., Abrahams, V.M., González-Timón, B., et al. “Heparin prevents programmed cell death in human trophoblast.” Mol Hum Reprod 12 (2006): 237–43. DOI: 10.1093/molehr/gal026

Tong, M., Viall, C.A., Chamley, L.W. “Antiphospholipid antibodies and the placenta: A systematic review of their In vitro effects and modulation by treatment.” Hum Reprod Update 21 (2015): 97–118. DOI: 10.1093/humupd/dmu049

Miyakis, S., Lockshin, M.D., Atsumi, T., et al. “International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).” J Thromb Haemost 4 (2006): 295–306. DOI: 10.1111/j.1538-7836.2006.01753.x

Nakamura, H., Oku, K., Amengual, O., et al. “First-Line, Non-Criterial Antiphospholipid Antibody Testing for the Diagnosis of Antiphospholipid Syndrome in Clinical Practice: A Combination of Anti-β 2 -Glycoprotein I Domain I and Anti-Phosphatidylserine/Prothrombin Complex Antibodies Tests.” Arthritis Care Res (Hoboken) 70 (2018): 627–34. DOI: 10.1002/acr.23310

Kacprzak, M., Chrzanowska, M., Skoczylas, B., et al. “Genetic causes of recurrent miscarriages.” Ginekol Pol 87 (2016): 722–6. DOI: 10.5603/GP.2016.0075

Blue, N.R., Page, J.M., Silver, R.M. “Genetic abnormalities and pregnancy loss.” Semin Perinatol 43 (2019): 66–73. DOI: 10.1053/j. semperi.2018.12.002

Colley, E., Hamilton, S., Smith, P., et al. “Potential genetic causes of miscarriage in euploid pregnancies: A systematic review.” Hum Reprod Update 25 (2019): 452–72. DOI: 10.1093/humupd/dmz015

Hardy, K., Hardy, P.J., Jacobs, P.A., et al. “Temporal changes in chromosome abnormalities in human spontaneous abortions: Results of 40 years of analysis.” Am J Med Genet Part A 170 (2016): 2671–80. DOI: 10.1002/ajmg.a.37795

Meka, A., Reddy, B.M. “Recurrent Spontaneous Abortions: An Overview of Genetic and Non-Genetic Backgrounds.” Int J Hum Genet 6 (2006): 109–17. DOI: 10.1080/09723757.2006.11885950

Wu, T., Yin, B., Zhu, Y., et al. “Molecular cytogenetic analysis of early spontaneous abortions conceived from varying assisted reproductive technology procedures.” Mol Cytogenet 9 (2016): 1–6. DOI: 10.1186/s13039-016-0284-2

Hassold, T., Abruzzo, M., Adkins, K., et al. “Human aneuploidy: Incidence, origin and etiology.” Environ Mol Mutagen 28 (1996): 167–75. DOI: 10.1002/(SICI)1098-2280(1996)28:3<167::AID-EM2>3.0.CO;2-B

Hassold, T., Hunt, P. “Maternal age and chromosomally abnormal pregnancies: What we know and what we wish we knew.” Curr Opin Pediatr 21 (2009): 703–8. DOI: 10.1097/MOP.0b013e328332c6ab

Mikwar, M., MacFarlane, A.J., Marchetti, F. “Mechanisms of oocyte aneuploidy associated with advanced maternal age.” Mutat Res 785 (2020): 108320. DOI: 10.1016/j.mrrev.2020.108320

Ioannou, D., Fortun, J., Tempest, H.G. “Meiotic nondisjunction and sperm aneuploidy in humans.” Reproduction 157 (2019): R15–R31. DOI: 10.1530/REP-18-0318

Sheth, F.J., Liehr, T., Kumari, P., et al. “Chromosomal abnormalities in couples with repeated fetal loss: An Indian retrospective study.” Indian J Hum Genet 19 (2013): 415–22. DOI: 10.4103/0971-6866.124369

Jobanputra, V., Roy, K.K., Kriplani, A., Kucheria, K. “Prenatal diagnosis of chromosomal abnormalities in women with high risk pregnancies.” Indian J Med Res 114 (2001): 148–55.

Bonomi, M., Rochira, V., Pasquali, D., et al. “Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism.” J Endocrinol Invest 40 (2017): 123–34. DOI: 10.1007/s40618-016-0541-6

Roberts, A.J., Fechner, P.Y. “Description of Turner Syndrome.” In: Turner Syndrome. Springer International Publishing (2020): 1–12. DOI: 10.1007/978-3-030-34150-3_1

Filges, I., Manokhina, I., Peñaherrera, M.S., et al. “Recurrent triploidy due to a failure to complete maternal meiosis II: Wholeexome sequencing reveals candidate variants.” Mol Hum Reprod 21 (2014): 339–46. DOI: 10.1093/molehr/gau112

Hardy, K., Hardy, P.J. “1(st) trimester miscarriage: four decades of study.” Transl Pediatr 4 (2015): 189–200. DOI: 10.3978/j.issn.2224-4336.2015.03.05

Atia, T.A. “Overview of genetic causes of recurrent miscarriage and the diagnostic approach.” Biocell 43.4 (2019): 253–62. DOI: 10.32604/biocell.2019.08180

Stephenson, M.D., Awartani, K.A., Robinson, W.P. “Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: A case-control study.” Hum Reprod 17 (2002): 446–51. DOI: 10.1093/humrep/17.2.446

Nikitina, T.V., Sazhenova, E.A., Tolmacheva, E.N., et al. “Comparative Cytogenetic Analysis of Spontaneous Abortions in Recurrent and Sporadic Pregnancy Losses.” Biomed Hub 1 (2016): 1–11. DOI: 10.1159/000446099

Nikitina, T.V., Sazhenova, E.A., Zhigalina, D.I., et al. “Karyotype evaluation of repeated abortions in primary and secondary recurrent pregnancy loss.” J Assist Reprod Genet 37 (2020): 517–25. DOI: 10.1007/s10815-020-01703-y

Robinson, W.P., McFadden, D.E., Stephenson, M.D. “The origin of abnormalities in recurrent aneuploidy/polyploidy.” Am J Hum Genet 69 (2001): 1245–54. DOI: 10.1086/324468

Enciso, M., Sarasa, J., Xanthopoulou, L., et al. “Polymorphisms in the MTHFR gene influence embryo viability and the incidence of aneuploidy.” Hum Genet 135 (2016)V: 555–68. DOI: 10.1007/s00439-016-1652-z

McCoy, R.C., Demko, Z., Ryan, A., et al. “Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos.” Science 348.6231 (2015): 235–8. DOI: 10.1126/science.aaa3337

Scriven, P.N. “Squaring the circle of recurrent pregnancy loss (RPL).” J Assist Reprod Genet 37 (2020): 1067–8. DOI: 10.1007/s10815-020-01780-z

Massalska, D., Zimowski, J.G., Bijok, J., et al. “First trimester pregnancy loss: Clinical implications of genetic testing.” J Obstet Gynaecol Res 43 (2017): 23–9. DOI: 10.1111/jog.13179

Shearer, B.M., Thorland, E.C., Carlson, A.W., et al. “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 13 (2011): 545–52. DOI: 10.1097/GIM.0b013e31820c685b

Stephenson, M.D., Sierra, S. “Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement.” Hum Reprod 21 (2006): 1076–82. DOI: 10.1093/humrep/dei417

Priya, P.K., Mishra, V.V., Roy, P., Patel, H. “A study on balanced chromosomal translocations in couples with recurrent pregnancy loss.” J Hum Reprod Sci 11 (2018): 337–42. DOI: 10.4103/jhrs.JHRS_132_17

Page, J.M., Silver, R.M. “Genetic causes of recurrent pregnancy loss.” Clin Obstet Gynecol 59 (2016): 498–508. DOI: 10.1097/GRF.0000000000000217

Vandeweyer, G., Kooy, R.F. “Balanced translocations in mental retardation.” Hum Genet 126 (2009): 133–47. DOI: 10.1007/s00439-009-0661-6

Maithripala, S., Durland, U., Havelock, J., et al. “Prevalence and Treatment Choices for Couples with Recurrent Pregnancy Loss Due to Structural Chromosomal Anomalies.” J Obstet Gynaecol Canada 40 (2018): 655–62. DOI: 10.1016/j. jogc.2017.09.024

Dhillon, R.K., Hillman, S.C., Morris, R.K., et al. “Additional information from chromosomal microarray analysis (CMA) over conventional karyotyping when diagnosing chromosomal abnormalities in miscarriage: A systematic review and meta-analysis.” BJOG An Int J Obstet Gynaecol 121 (2014): 11–21. DOI: 10.1111/1471-0528.12382

Bernardi, L.A., Plunkett, B.A., Stephenson, M.D. “Is chromosome testing of the second miscarriage cost saving? A decision analysis of selective versus universal recurrent pregnancy loss evaluation.” Fertil Steril 98 (2012): 156–61. DOI: 10.1016/j.fertnstert.2012.03.038

Popescu, F., Jaslow, C.R., Kutteh, W.H. “Recurrent pregnancy loss evaluation combined with 24-chromosome microarray of miscarriage tissue provides a probable or definite cause of pregnancy loss in over 90% of patients.” Hum Reprod 33 (2018): 579–87. DOI: 10.1093/humrep/dey021

Foyouzi, N., Cedars, M.I., Huddleston, H.G. “Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss.” Fertil Steril 98 (2012): 151–5.e3. DOI: 10.1016/j.fertnstert.2012.04.007

Papas, R.S., Kutteh, W.H. “A new algorithm for the evaluation of recurrent pregnancy loss redefining unexplained miscarriage: review of current guidelines.” Curr Opin Obstet Gynecol 32 (2020): 371–9. DOI: 10.1097/GCO.0000000000000647

Khalife, D., Ghazeeri, G., Kutteh, W. “Review of current guidelines for recurrent pregnancy loss: new strategies for optimal evaluation of women who may be superfertile.” Semin Perinatol 43 (2019): 105–15. DOI: 10.1053/j. semperi.2018.12.008

Bi, W., Borgan, C., Pursley, A.N., et al. “Comparison of chromosome analysis and chromosomal microarray analysis: What is the value of chromosome analysis in today’s genomic array era?” Genet Med 15 (2013): 450–7. DOI: 10.1038/gim.2012.152

Dugoff, L., Norton, M.E., Kuller, J.A. “The use of chromosomal microarray for prenatal diagnosis.” Am J Obstet Gynecol 215 (2016): B2–B9. DOI: 10.1016/j.ajog.2016.07.016

Fakhro, K.A., Robay, A., Rodriguez-Flores, J.L., Crystal, R.G. “Genetic Evaluation of Male Infertility.” In: Genetic Male Infertility. Springer International Publishing (2020): 95–118. DOI: 10.1007/978-3-030-37972-8_6

Mumford, S.L., Garbose, R.A., Kim, K., et al. “Association of preconception serum 25-hydroxyvitamin D concentrations with livebirth and pregnancy loss: a prospective cohort study.” Lancet Diabetes Endocrinol 6 (2018): 725–32. DOI: 10.1016/S2213-8587(18)30153-0

Bunnewell, S.J., Honess, E.R., Karia, A.M., et al. “Diminished ovarian reserve in recurrent pregnancy loss: a systematic review and meta-analysis.” Fertil Steril 113 (2020): 818–27.e3. DOI: 10.1016/j.fertnstert.2019.11.014





Pregnancy and childbirth