Skip to main content
SpringerLink
Log in

Chromosomal abnormalities in recurrent pregnancy loss and its association with clinical characteristics

  • Genetics
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Objective

To evaluate the distribution of chromosomal abnormalities in a recurrent pregnancy loss (RPL) cohort and explore the associations between chromosomal abnormalities and clinical characteristics.

Method

Over a 5-year period, fresh products of conception (POC) from women with RPL were analyzed by single-nucleotide polymorphism (SNP) array at our hospital. After obtaining the information on clinical characteristics, we investigated the associations between the causative chromosomal abnormalities and clinical characteristics by the chi-squared test or Fisher’s exact test and logistic regression.

Results

A total of 2383 cases were enrolled. Overall, 56.9% (1355/2383) were identified with causative chromosomal abnormalities, of which 92.1% (1248/1355) were numerical abnormalities, 7.5% (102/1355) were structural variants, and 0.4% (5/1355) were loss of heterozygosity (LOH). The risk of numerical abnormalities was increased in women with maternal age ≥ 35 years (OR, 1.71; 95% CI, 1.41–2.07), gestational age at pregnancy loss ≤ 12 weeks (OR, 2.78; 95% CI, 1.79–4.33), less number of previous pregnancy losses (twice: OR, 2.32; 95% CI, 1.84–2.94; 3 times: OR, 1.59; 95% CI, 1.23–2.05, respectively), and pregnancy with a female fetus (OR, 1.37; 95% CI, 1.15–1.62). The OR of pregnancy loss with recurrent abnormal CMA was 4.00 (95% CI: 1.87–8.58, P < 0.001) and the adjusted OR was 5.05 (95% CI: 2.00–12.72, P = 0.001). However, the mode of conception was not associated with the incidence of numerical abnormality. No association was noted between structural variants and clinical characteristics.

Conclusion

Chromosomal abnormality was the leading cause of RPL. Numerical chromosome abnormality was more likely to occur in cases with advanced maternal age, an earlier gestational age, fewer previous pregnancy losses, and pregnancy with a female fetus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  1. Practice Committee of the American Society for Reproductive M. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103–11.

    Google Scholar 

  2. Bender Atik R, Christiansen OB, RPL EGGo, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018(2):4.

    Google Scholar 

  3. Rai R, Regan L. Recurrent miscarriage. The Lancet. 2006;368(9535):601–11.

    Google Scholar 

  4. Grande M, Borrell A, Garcia-Posada R, et al. The effect of maternal age on chromosomal anomaly rate and spectrum in recurrent miscarriage. Hum Reprod. 2012;27(10):3109–17.

    PubMed  Google Scholar 

  5. Sullivan AE, Silver RM, LaCoursiere DY, Porter TF, Branch DW. Recurrent fetal aneuploidy and recurrent miscarriage. Obstet Gynecol. 2004;104(4):784–8.

    PubMed  Google Scholar 

  6. Sheng YR, Hou SY, Hu WT, et al. Characterization of copy-number variations and possible candidate genes in recurrent pregnancy losses. Genes (Basel). 2021;12(2):141.

  7. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000;73(2):300–4.

    CAS  PubMed  Google Scholar 

  8. Gu C, Li K, Li R, et al. Chromosomal aneuploidy associated with clinical characteristics of pregnancy loss. Front Genet. 2021;12:667697.

    PubMed  PubMed Central  Google Scholar 

  9. Goldstein M, Svirsky R, Reches A, Yaron Y. Does the number of previous miscarriages influence the incidence of chromosomal aberrations in spontaneous pregnancy loss? J Matern Fetal Neonatal Med. 2017;30(24):2956–60.

    PubMed  Google Scholar 

  10. Nikitina TV, Sazhenova EA, Zhigalina DI, Tolmacheva EN, Sukhanova NN, Lebedev IN. Karyotype evaluation of repeated abortions in primary and secondary recurrent pregnancy loss. J Assist Reprod Genet. 2020;37(3):517–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hardy K, Hardy PJ, Jacobs PA, Lewallen K, Hassold TJ. Temporal changes in chromosome abnormalities in human spontaneous abortions: Results of 40 years of analysis. Am J Med Genet A. 2016;170(10):2671–80.

    CAS  PubMed  Google Scholar 

  12. Qu S, Wang L, Cai A, et al. Exploring the cause of early miscarriage with SNP-array analysis and karyotyping. J Matern Fetal Neonatal Med. 2019;32(1):1–10.

    PubMed  Google Scholar 

  13. Munne S, Sandalinas M, Magli C, Gianaroli L, Cohen J, Warburton D. Increased rate of aneuploid embryos in young women with previous aneuploid conceptions. Prenat Diagn. 2004;24(8):638–43.

    PubMed  Google Scholar 

  14. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000;73(2):300–4.

    CAS  PubMed  Google Scholar 

  15. Ma S, Philipp T, Zhao Y, Stetten G, Robinson WP, Kalousek D. Frequency of chromosomal abnormalities in spontaneous abortions derived from intracytoplasmic sperm injection compared with those from in vitro fertilization. Fertil Steril. 2006;85(1):236–9.

    PubMed  Google Scholar 

  16. Lathi RB, Milki AA. Rate of aneuploidy in miscarriages following in vitro fertilization and intracytoplasmic sperm injection. Fertil Steril. 2004;81(5):1270–2.

    PubMed  Google Scholar 

  17. Causio F, Fischetto R, Sarcina E, Geusa S, Tartagni M. Chromosome analysis of spontaneous abortions after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Europ J Obstet Gynecol Reprod Biol. 2002;105(1):44–8.

    Google Scholar 

  18. Sahoo T, Dzidic N, Strecker MN, et al. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges. Genet Med. 2017;19(1):83–9.

    CAS  PubMed  Google Scholar 

  19. Wang Y, Li Y, Chen Y, et al. Systematic analysis of copy-number variations associated with early pregnancy loss. Ultrasound Obstet Gynecol. 2020;55(1):96–104.

    CAS  PubMed  Google Scholar 

  20. Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020;22(2):245–57.

    PubMed  Google Scholar 

  21. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47, XXX). Orphanet J Rare Dis. 2010;5:8.

    PubMed  PubMed Central  Google Scholar 

  22. Bardsley MZ, Kowal K, Levy C, et al. 47, XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr. 2013;163(4):1085–94.

    PubMed  PubMed Central  Google Scholar 

  23. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984;18:69–97.

    CAS  PubMed  Google Scholar 

  24. Gruhn JR, Zielinska AP, Shukla V, et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science. 2019;365(6460):1466–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gardner RJM, Amor DJ. Gardner and Sutherland’s chromosome abnormalities and genetic counseling. 5th ed. Oxford University Press; 2018. p. 781.

  26. Qiao Y, Wen J, Tang F, et al. Whole exome sequencing in recurrent early pregnancy loss. Mol Hum Reprod. 2016;22(5):364–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao C, Chai H, Zhou Q, et al. Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss. Genet Med. 2021;23(3):435–42.

    CAS  PubMed  Google Scholar 

  28. Gourhant L, Bocher O, De Saint ML, et al. Whole exome sequencing, a hypothesis-free approach to investigate recurrent early miscarriage. Reprod Biomed Online. 2021;42(4):789–98.

    CAS  PubMed  Google Scholar 

  29. Del Fabro A, Driul L, Anis O, et al. Fetal gender ratio in recurrent miscarriages. Int J Womens Health. 2011;3:213–7.

    PubMed  PubMed Central  Google Scholar 

  30. Cheng HH, Ou CY, Tsai CC, et al. Chromosome distribution of early miscarriages with present or absent embryos: female predominance. J Assist Reprod Genet. 2014;31(8):1059–64.

    PubMed  PubMed Central  Google Scholar 

  31. Patten MM. The X chromosome favors males under sexually antagonistic selection. Evolution. 2019;73(1):84–91.

    PubMed  Google Scholar 

  32. Evdokimova VN, Nikitina TV, Lebedev IN, Sukhanova NN, Nazarenko SA. Sex ratio in early embryonal mortality in man. Ontogenez. 2000;31(4):251–7.

    CAS  PubMed  Google Scholar 

  33. Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum Reprod. 2012;27(8):2297–303.

    PubMed  Google Scholar 

  34. Finley J, Hay S, Oldzej J, et al. The genomic basis of sporadic and recurrent pregnancy loss: a comprehensive in-depth analysis of 24,900 miscarriages. Reprod Biomed Online. 2022;45(1):125–34.

    CAS  PubMed  Google Scholar 

  35. Sangha KK, Stephenson MD, Brown CJ, Robinson WP. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion. Am J Hum Genet. 1999;65(3):913–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Beever CL, Stephenson MD, Penaherrera MS, et al. Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies. Am J Hum Genet. 2003;72(2):399–407.

    CAS  PubMed  Google Scholar 

  37. Kim SY, Park SY, Choi JW, et al. Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy. Am J Reprod Immunol. 2011;66(4):252–8.

    PubMed  Google Scholar 

  38. Wang Y, Cheng Q, Meng L, et al. Clinical application of SNP array analysis in first-trimester pregnancy loss: a prospective study. Clin Genet. 2017;91(6):849–58.

    CAS  PubMed  Google Scholar 

  39. Fan L, Wu J, Wu Y, et al. Analysis of chromosomal copy number in first-trimester pregnancy loss using next-generation sequencing. Front Genet. 2020;11:545856.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Belva F, Bonduelle M, Buysse A, et al. Chromosomal abnormalities after ICSI in relation to semen parameters: results in 1114 fetuses and 1391 neonates from a single center. Hum Reprod. 2020;35(9):2149–62.

    CAS  PubMed  Google Scholar 

  41. Samli H, Solak M, Imirzalioglu N, Beyatli Y, Simsek S, Kahraman S. Fetal chromosomal analysis of pregnancies following intracytoplasmic sperm injection with amniotic tissue culture. Prenat Diagn. 2003;23(10):847–50.

    PubMed  Google Scholar 

  42. Kim JW, Lee WS, Yoon TK, et al. Chromosomal abnormalities in spontaneous abortion after assisted reproductive treatment. BMC Med Genet. 2010;11:153.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Orzack SH, Stubblefield JW, Akmaev VR, et al. The human sex ratio from conception to birth. Proc Natl Acad Sci U S A. 2015;112(16):E2102–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Liang D, Wang Y, Ji X, et al. Clinical application of whole-genome low-coverage next-generation sequencing to detect and characterize balanced chromosomal translocations. Clin Genet. 2017;91(4):605–10.

    CAS  PubMed  Google Scholar 

  45. Chen Y, Bartanus J, Liang D, et al. Characterization of chromosomal abnormalities in pregnancy losses reveals critical genes and loci for human early development. Hum Mutat. 2017;38(6):669–77.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all patients in our study, physicians who recorded the clinical data, and center members who supported us.

Funding

The study was supported by the National Key Research and Development Program of China (2022YFC2704700, 2022YFC2704703).

Author information

Authors and Affiliations

  1. Department of Fetal Medicine & Prenatal Diagnosis Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Dan Zhu, Xing Wei, Xin-yao Zhou, Lin-bei Deng, Shi-yi Xiong, Jian-ping Chen, Guang-quan Chen, Gang Zou & Lu-ming Sun

Authors
  1. Dan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xin-yao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lin-bei Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shi-yi Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian-ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guang-quan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gang Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lu-ming Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lu-ming Sun.

Ethics declarations

Ethics approval

The study was reviewed and approved by the Ethical Committee of Shanghai First Maternity and Infant Hospital (KS2203).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, D., Wei, X., Zhou, Xy. et al. Chromosomal abnormalities in recurrent pregnancy loss and its association with clinical characteristics. J Assist Reprod Genet 40, 1713–1720 (2023). https://doi.org/10.1007/s10815-023-02816-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-023-02816-w

Keywords

Search

Navigation