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New Test Offers More Information on Genetic Causes of Stillbirth

Published: Friday, December 07, 2012
Last Updated: Friday, December 07, 2012
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NIH network study confirms more detailed information from microarray analysis.

A more precise method for examining a fetus' genetic material may help detect abnormalities in 40 percent more cases of stillbirth than does the traditional method, according to a National Institutes of Health network study.

A stillbirth (http://www.nichd.nih.gov/health/topics/Stillbirth.cfm) occurs when a baby dies in the womb prior to delivery at or after 20 weeks of gestation. In the United States, stillbirth occurs in 1 of every 160 births.

When pregnancy ends in stillbirth, doctors may attempt to examine the baby's chromosomes with a technique known as a karyotype (http://www.genome.gov/dmd/img.cfm?node=Photos/Graphics&id=85192).

The karyotype is an image of an individual's chromosomes and is used to look for an abnormal number of chromosomes or for abnormally shaped chromosomes.

However, karyotyping requires cells to be grown in culture, which is often not possible in a stillbirth. So the researchers sought a technique that would be more reliable.

The researchers compared the results of karyotypes from more than 500 stillbirths to results from microarray analysis, a genetic method which detects small segments of missing parts of chromosomes (deletions) or additional sections of genetic material (duplications) that cannot be seen by karyotype.

"Previous studies suggest that 25 to 60 percent of stillbirths are unexplained," said the article's first author, Uma Reddy, M.D., of the Pregnancy and Perinatology Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute leading the research. "Microarray may explain genetic causes of stillbirths that previously were not identifiable by karyotype."

The research was coordinated through the Stillbirth Collaborative Research Network (SCRN), supported by the NICHD.

Dr. Reddy collaborated with 17 co-authors from the NICHD, RTI International, Research Triangle Park, N.C.; University of Texas Medical Branch at Galveston; University of Utah and Intermountain Health Care, Salt Lake City; Brown University, Providence, R.I.; Emory University and Children's Health Care of Atlanta; University of Texas Health Science Center at San Antonio; and Columbia University Medical Center, New York City.

Their findings appear in the New England Journal of Medicine.

The SCRN researchers analyzed samples from all stillbirths in a population-based study in five areas, covered by 59 hospitals over a period of 2.5 years.

Shortly after each stillbirth, parents gave research staff permission to collect blood from the umbilical cord and tissue from the fetus and the placenta.

Researchers obtained results from 70 percent of the karyotype tests that were performed, with 30 percent failing to yield any results.

Of those from which results were obtained, 8.3 percent had an extra chromosome, a missing chromosome, or other major chromosome alterations.

By comparison, microarray analysis provided results in 87 percent of stillbirths tested, a significantly higher yield than with karyotyping. For the most part, the microarray results confirmed the results of the karyotype analysis.

However, microarray analysis detected genetic abnormalities in 6 percent of cases in which the karyotype analysis returned no result and in 3 percent of those with normal karyotype results - a total of 18 stillbirths.

Of the 44 stillbirths with genetic abnormalities detected through microarray analysis, 41 percent had a normal karyotype or a result was not obtained. Microarray analysis yielded a 41.9 percent increase in the detection rate (8.3 percent vs. 5.8 percent).

Stillbirths in which a major birth defect was apparent were significantly more likely than stillbirths without a birth defect to have genetic abnormalities.

Microarray analysis detected more abnormalities (29.9 percent) than did karyotype analysis (19.4 percent) in stillbirths with a major birth defect - a 53.8 percent increase in the detection rate.

The authors noted that in some cases, the microarray analysis revealed genetic abnormalities carried by the parents. These genetic abnormalities had no apparent effect on the parents' health but could potentially increase the risk for another stillbirth or for certain health conditions in future offspring. Knowledge of these genetic abnormalities would allow for improved management of future pregnancies, the authors noted.

"The primary benefit of using microarray analysis rather than karyotype analysis is the greater likelihood of obtaining results," said Dr. Reddy. "However, microarray analysis is more expensive than karyotyping. Microarray analysis is especially useful in stillbirth cases in which the karyotype has failed or there is a birth defect present."

The microarray analysis also revealed genetic variations that have not previously been classified as either harmless or disease-causing. Future research is needed to determine if these variations are related to stillbirth, Dr. Reddy explained.

In the same issue of the New England Journal of Medicine, researchers in an NICHD-supported research study compared karyotyping to microarray analysis as a method of prenatal diagnosis.

That study was led by Ronald J. Wapner, M.D., of Columbia University Medical Center. The researchers concluded that microarray analysis revealed genetic conditions in 2.5 percent of pregnancies with a normal karyotype.


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