DNA Test Uncovers Clues to Past Miscarriages

Ricki Lewis, PhD

March 20, 2014

DNA analysis of tissue archived from dilation and curettage (D&C) procedures after miscarriage can identify chromosomal abnormalities that might have caused the pregnancy loss, according to a study published in Reproductive Biology and Endocrinology.

The chromosome constitution of a spontaneously aborted embryo or fetus is often unknown because a patient could not collect products of conception or the physician could not culture fresh cells from chorionic villi. The American College of Obstetrics and Gynecology and the American Society for Reproductive Medicine recommend karyotyping only after the second or third loss, attributing most events to aneuploidy, which is unlikely to repeat. However, in nonaneuploid cases, knowing the chromosomal status of past losses can provide valuable information.

Rashmi Kudesia MD, from the Department of Obstetrics and Gynecology and Women's Health at Albert Einstein College of Medicine, Bronx, New York, and colleagues used array-based comparative genomic hybridization (aCGH) in "rescue karyotyping" to detect copy number variants in partially degraded DNA from paraffin-embedded archival D&C tissue. The technique offers finer resolution than standard karyotyping, down to 1 kb of DNA.

aCGH has become a standard approach to identifying microdeletions and microduplications in children with unexplained developmental delay. In cancer genetics, automated aCGH detects cytogenetic abnormalities in paraffin-embedded tumor samples, providing the precedent of working on preserved tissue that inspired the new study.

The researchers conducted a retrospective case series using rescue karyotyping on 20 specimens from 17 women who had recurrent pregnancy loss. Thirteen (76.5%) of the women had not had karyotypes done, and the other 4 had had them done, but 3 of the attempts had failed.

Fetal or chorionic villus cells were dissected from material in the preserved tissue blocks. Sixteen samples (80.0%) yielded sufficient DNA for analysis, the oldest of which came from tissue archived 4.2 years earlier. Gestational age at the time of loss ranged from 6 to 20 weeks.

Eight of the 16 specimens had copy number variants: 3 trisomies, 1 mosaic trisomy, 2 partial deletions, and 2 unclassified variants. The 3 full trisomies were in women older than 40 years. Sample age, gestational age, and method used to obtain the products of conception did not influence the ability to acquire DNA information.

Rescue karyotyping offers several benefits. In some cases it can account for the miscarriage, and therefore provide information on recurrence risks. A second benefit is in comforting an expectant couple who might be blaming themselves. Once the strategy is validated and standards established, implementation may be simple, the investigators point out, requiring sending tissue blocks to a testing facility.

"In summary, aCGH testing holds potential for cost-effective use in rescue karyotyping by enabling cytogenetic evaluation of archived fetal tissue. This can provide physicians and patients with clinically relevant cytogenetic information on prior pregnancy losses," the researchers conclude.

Limitations of the study include the small sample size. Limitations of the technology include mosaicism of chorionic villi and the fact that a copy number variants can be of uncertain clinical significance.

The study received institutional and National Institutes of Health support. The authors have disclosed no relevant financial relationships.

Reprod Biol Endocrinol. 2014;12:19. Full text

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