Original Research Article

Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges

  • Genetics in Medicine volume 19, pages 8389 (2017)
  • doi:10.1038/gim.2016.69
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Abstract

Purpose:

Chromosomal microarray analysis (CMA) is currently considered first-tier testing in pediatric care and prenatal diagnosis owing to its high diagnostic sensitivity for chromosomal imbalances. The aim of this study was to determine the efficacy and diagnostic power of CMA in both fresh and formalin-fixed paraffin-embedded (FFPE) samples of products of conception (POCs).

Methods:

Over a 44-month period, 8,118 consecutive samples were received by our laboratory for CMA analysis. This included both fresh (76.4%) and FFPE samples (22.4%), most of which were ascertained for recurrent pregnancy loss and/or spontaneous abortion (83%). The majority of samples were evaluated by a whole-genome single-nucleotide polymorphism (SNP)-based array (81.6%); the remaining samples were evaluated by array-comparative genomic hybridization (CGH).

Results:

A successful result was obtained in 7,396 of 8,118 (91.1%), with 92.4% of fresh tissue samples and 86.4% of FFPE samples successfully analyzed. Clinically significant abnormalities were identified in 53.7% of specimens (3,975 of 7,396), 94% of which were considered causative.

Conclusion:

Analysis of POC specimens by karyotyping fails in 20–40% of cases. SNP-based CMA is a robust platform, with successful results obtained in >90% of cases. SNP-based CMA can identify aneuploidy, polyploidy, whole-genome homozygosity, segmental genomic imbalances, and maternal cell contamination, thus maximizing sensitivity and decreasing false-negative results. Understanding the etiology of fetal loss enables clarification of recurrence risk and assists in determining appropriate management for future family planning.

Genet Med 19 1, 83–89.

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References

  1. 1.

    Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012;98:1103–1111.

  2. 2.

    , Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol 2009;2:76–83.

  3. 3.

    , Pregnancy loss. In: , , , eds. Obstetrics: Normal and Problem Pregnancies, 6th edn. Elsevier Saunders: Philadelphia, PA, 2012.

  4. 4.

    , , , Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med 2005;7:251–263.

  5. 5.

    , Cytogenetic abnormalities in products of conception: a relationship revisited. Am J Reprod Immunol 2004;52:88–96.

  6. 6.

    , , , , , Chromosome abnormalities identified in 347 spontaneous abortions collected in Japan. J Obstet Gynaecol Res 2004;30:237–241.

  7. 7.

    , , , et al. An efficient protocol for the detection of chromosomal abnormalities in spontaneous miscarriages or foetal deaths. Eur J Obstet Gynecol Reprod Biol 2009;147:144–150.

  8. 8.

    , , , , 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;13:545–552.

  9. 9.

    , , The role of DNA microarrays in the evaluation of fetal death. Prenat Diagn 2012;32:371–375.

  10. 10.

    , , , et al. Array-based comparative genomic hybridization is more informative than conventional karyotyping and fluorescence in situ hybridization in the analysis of first-trimester spontaneous abortion. Mol Cytogenet 2012;5:33.

  11. 11.

    , Evaluation and management of recurrent early pregnancy loss. Clin Obstet Gynecol 2007;50:132–145.

  12. 12.

    , , , et al.; NICHD Stillbirth Collaborative Research Network. Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 2012;367:2185–2193.

  13. 13.

    , , , , , Karyotype of the abortus in recurrent miscarriage. Fertil Steril 2001;75:678–682.

  14. 14.

    , , , et al. Genetic analysis of first-trimester miscarriages with a combination of cytogenetic karyotyping, microsatellite genotyping and arrayCGH. Clin Genet 2009;75:133–140.

  15. 15.

    , , , et al. Array-based comparative genomic hybridization (aCGH) in the genetic evaluation of stillbirth. Am J Med Genet A 2009;149A:2437–2443.

  16. 16.

    , , , et al. Comparative genomic hybridization in combination with flow cytometry improves results of cytogenetic analysis of spontaneous abortions. Am J Hum Genet 2000;66:1516–1521.

  17. 17.

    , , , Cytogenetic diagnosis of “normal 46,XX” karyotypes in spontaneous abortions frequently may be misleading. Fertil Steril 1999;71:334–341.

  18. 18.

    , , , Diagnosis of miscarriages by molecular karyotyping: benefits and pitfalls. Genet Med 2009;11:646–654.

  19. 19.

    , , , Genetics of early miscarriage. Biochim Biophys Acta 2012;1822:1951–1959.

  20. 20.

    , , , et al. Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)—re-evaluation of chromosome aberration rates in early spontaneous abortions. Eur J Hum Genet 2001;9:539–547.

  21. 21.

    , , , , , Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am J Hum Genet 2004;74:1168–1174.

  22. 22.

    , , , et al. Detecting sex chromosome anomalies and common triploidies in products of conception by array-based comparative genomic hybridization. Prenat Diagn 2006;26:333–339.

  23. 23.

    , , , et al. Array comparative genomic hybridization analysis in first-trimester spontaneous abortions with ‘normal’ karyotypes. Am J Med Genet A 2006;140:1931–1935.

  24. 24.

    , , , et al. Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2011;37:6–14.

  25. 25.

    , , , et al. Genomic imbalance in products of conception: single-nucleotide polymorphism chromosomal microarray analysis. Obstet Gynecol 2014;124(2 Pt 1):202–209.

  26. 26.

    , , , et al. Abnormalities in spontaneous abortions detected by G-banding and chromosomal microarray analysis (CMA) at a national reference laboratory. Mol Cytogenet 2014;7:33.

  27. 27.

    , , , , Rescue karyotyping: a case series of array-based comparative genomic hybridization evaluation of archival conceptual tissue. Reprod Biol Endocrinol 2014;12:19.

  28. 28.

    , , , 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 2014;121:11–21.

  29. 29.

    , , , Chromosomal anomalies in early spontaneous abortions: interphase FISH analysis on 855 FFPE first trimester abortions. Prenat Diagn 2016;36:186–191.

  30. 30.

    American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013;122:1374–1377.

  31. 31.

    , , The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. RCOG Green-top Guideline No. 17. April 2010. .

  32. 32.

    , , Cost-effectiveness of cytogenetic evaluation of products of conception in the patient with a second pregnancy loss. Fertil Steril 2012;98:151–155.

  33. 33.

    , , , , A national survey on public perceptions of miscarriage. Obstet Gynecol 2015;125:1313–1320.

  34. 34.

    , , , The effect of reproductive history on future pregnancy outcomes. Hum Reprod 1999;14:2863–2867.

  35. 35.

    , Genetic and nongenetic causes of pregnancy loss. Global Library of Women’s Medicine, 2013. .

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Author information

Affiliations

  1. CombiMatrix Diagnostics, Irvine, California, USA

    • Trilochan Sahoo
    • , Natasa Dzidic
    • , Michelle N. Strecker
    • , Sara Commander
    • , Mary K. Travis
    • , Charles Doherty
    •  & Karine Hovanes
  2. Department of Pathology, SCL Health System, Denver, Colorado, USA

    • R. Weslie Tyson
  3. Department of Pathology, Sharp Memorial Hospital, San Diego, California, USA

    • Arturo E. Mendoza
  4. Department of Obstetrics and Gynecology, University of Illinois Hospital, Chicago, Illinois, USA

    • Mary Stephenson
  5. Morristown Medical Center, Morristown, New Jersey, USA

    • Craig A. Dise
    •  & Carlos W. Benito
  6. Memorial Regional Hospital, Hollywood, Florida, USA

    • Mandolin S. Ziadie

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Corresponding author

Correspondence to Trilochan Sahoo.

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