Microarray testing is more likely to identify a genetic abnormality than is standard karyotyping in cases of stillbirth, according to a report published online Dec. 6 in the New England Journal of Medicine.
Microarray analysis is more productive in such cases chiefly because it can be used on nonviable tissue, even on macerated tissue, with some success, said Dr. Uma M. Reddy of the National Institute of Child Health and Human Development, Bethesda, Md., and her associates.
Dr. Uma M. Reddy
Until now, only two small studies, involving only 44 stillbirths in all, have assessed the usefulness of microarray testing to identify a cause in stillbirths.
The investigators performed a population-based study of genetic findings in cases of stillbirth using data from the Stillbirth Collaborative Research Network, a racially and ethnically diverse cohort drawn from five geographic catchment areas in the United States. They assessed 532 stillbirths (from 524 pregnancies) that occurred at 59 hospitals during 2006-2008.
Standard karyotyping was attempted on fetal tissue, placental tissue, cord blood, fetal muscle, and/or fetal liver, and results were obtained in 375 (71%) of these stillbirths. A total of 31 were classified as abnormal, with findings including trisomy 21, trisomy 18, trisomy 13, monosomy X, and other sex-chromosome abnormalities.
When microarray testing was performed on the same samples, results were obtained in 465 (87.4%) of the stillbirths, which is a significantly greater yield than that obtained with karyotyping. "We thus were able to obtain a result in 90 more cases (24% more) than we would have done using karyotype analysis alone," the researchers said.
Microarray testing showed no "benign" or "probably benign" chromosomal abnormalities in these stillbirths. It showed aneuploidy in 32, other pathogenic variants in 12, and variants "of unknown significance" in 25.
"Microarray analysis provided improved detection of genomic abnormalities, as compared with karyotype analysis (8.3% vs. 5.8%), a 41.9% increase. ... When we included variants of unknown significance in this comparison, we observed an even greater detection of abnormalities with the use of microarray analysis, as compared with karyotype analysis (13% vs. 5.8%), a 122.6% increase," Dr. Reddy and her colleagues said.
"Of the 157 stillbirths for which karyotype analysis failed to provide a definitive result, 79.6% yielded a definitive microarray result: 73.9% were normal or probably benign, and 5.7% were abnormal," they noted.
Looked at another way, karyotyping either failed altogether or produced normal results in 41% of the 44 stillbirths in which microarray testing demonstrated aneuploidy or a known pathogenic chromosomal variant (N. Engl. J. Med. 2012 Dec. 6 [doi:10.1056/NEJMoa1201569]).
The investigators also performed a subgroup analysis of the 443 antepartum stillbirths in this series. As with the entire study cohort, microarray analysis detected more abnormalities (8.8%) in this subgroup than did karyotyping (6.5%), representing a 35% increase in diagnostic yield.
In a subgroup analysis of the 472 stillbirths in which postmortem examinations were conducted, microarray analysis also detected more abnormalities (29.9%) than did karyotyping (19.4%), which represents a 54% increase in diagnostic yield.
In addition, the microarray technique, but not karyotyping, identified three stillbirths with abnormalities on chromosome 22q11.2, a region that is known to be disrupted in DiGeorge syndrome (also known as velocardiofacial syndrome). One of these fetuses was found to have multiple cardiopulmonary, facial, skeletal, urogenital, and thymic anomalies on postmortem examination.
This result suggests that genomic imbalances in the 22q11.2 region may be associated with stillbirth as well as with DiGeorge syndrome. Identifying such variations in cases of stillbirth would be important so that parental studies can be performed. The risk of recurrence of DiGeorge syndrome in subsequent pregnancies can vary from less than 0.1% in genotypically normal parents to 50% if one parent has a deletion, Dr. Reddy and her associates said.
In another eight stillbirths, the microarray method, but not karyotyping, also identified variations "of unknown significance" in the region of chromosome 19p13.3. This region is known to harbor frequent variations that are not yet understood. No congenital anomalies were present in these eight cases on postmortem examination, but there were "substantially abnormal" placental findings, including chronic deciduitis, villous infarction, chronic cytomegalovirus villitis, and abruption.
Chromosomal variations in this region previously have been associated with disease but not with stillbirth, so the variation identified on microarray testing in these eight stillbirths may be benign or may confer a risk of stillbirth; further research should supply the answer, the investigators said.
This study was supported by NICHD. Dr. Reddy reported no potential financial conflicts of interest, and her associates reported numerous ties to industry sources.