Chromosomal microarray analysis should be the first-line genetic test in pregnancies where ultrasound screens uncover signs of fetal abnormalities, according to the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.
ACOG and SMFM – two nonprofit professional organizations that are devoted to improving women's health and prenatal care, respectively – issued a joint committee opinion on the application of CMA as a prenatal genetic test earlier this month.
ACOG and SMFM also recommended that CMA be a preferred test to help identify the cause of death in stillbirths.
Still, ACOG and SMFM stopped short of recommending CMA to pregnant women with other reasons for seeking testing, such as recurrent miscarriage, advanced maternal age, and maternal anxiety.
Nancy Rose, chair of ACOG's committee on genetics and a professor of obstetrics and gynecology at the University of Utah in Salt Lake City, said that while patients undergoing invasive prenatal testing who have structurally normal fetuses are free to request either CMA or conventional karyotyping, it was ACOG and SMFM's conclusion that the data provided by CMA is best for fetal anomalies.
"With more information comes more complex results, and providers and patients are free to have the test that suits them with informed consent and counseling, however, the data [suggests CMA] is best for anomalies," Rose told BioArray News. "There isn't enough sound data available on the use of arrays for recurrent miscarriage, which is a presentation that can have been caused by many etiologies," she said.
Another nuance of the new committee opinion is its perspective on testing linked to advanced maternal age. While advanced maternal age is a common basis for women seeking CMA, ACOG and SMFM recommended that CMA should not be restricted to women aged 35 and older, as "most genetic mutations identified by chromosomal microarray analysis are not associated with increasing maternal age."
ACOG and SMFM's new committee opinion replaces a November 2009 recommendation that CMA not be used in a prenatal setting, citing its inability to detect balanced chromosomal rearrangements and copy number variants of uncertain clinical significance, and higher costs.
Rose said that the organizations were moved to update their recommendations because of the availability of more data about the benefits of using CMA as a prenatal test. In particular, she mentioned the publication last year of results obtained through a US National Institute of Child and Human Development-sponsored trial that compared CMA with conventional karyotyping. As reported in the New England Journal of Medicine, the study's investigators found that CMA was more informative than the older approach.
"Evidence has been gathering that arrays can be used to further understand disease," said Rose. "The NICHD trial is the first large multicenter prospective trial comparing its efficacy with conventional karyotype."
She also noted that CMA has become a "well-accepted, first-line test" in the evaluation of children with developmental delays and congenital anomalies. In 2010, the American College of Medical Genetics updated its own recommendations to support the use of CMA in pediatric cases. A year later, it published additional recommendations for array design and data interpretation.
According to ACOG and SMFM, another benefit of CMA over conventional karyotype is that it relies on array results analyzed by software. Karyotyping relies on microscope analysis, "which is prone to human error," the organizations stated. They also noted in their opinion that CMA results are usually available sooner than karyotype results.
A need for counseling
One common link between ACOG and SMFM's new committee opinion, last year's NEJM paper, and ACMG's recommendations, is a focus on counseling.
Like the NEJM paper's authors and ACMG, ACOG and SMFM stated that comprehensive genetic counseling from a qualified professional, such as a genetic counselor or geneticist, regarding the benefits, limitations, and results of CMA is "essential" in its application.
In addition, CMA "should not be ordered without informed consent," the organizations stated, "which should be documented in the medical record and include discussion of the potential to identify findings of uncertain significance, non-paternity, consanguinity, and adult-onset disease."
Other issues that should be discussed with patients are the ability of the test to identify genetic conditions that are unexpected; the fact that CMA does not detect all genetic diseases; and that identified diseases may vary in their severity, making it difficult to predict the outcome of carrying certain variants.
"We believe that, given the complex and sometimes uncertain results that can occur with this technology, that counseling is needed to be certain that the patient understands the types of results that can be obtained," Rose said.
The process of counseling patients undergoing CMA has been the focus of a number of papers in recent years. In July, geneticists from Brigham Women's Hospital in the UK addressed common misconceptions about CMA in an American Journal of Medical Genetics paper.
And last year, two papers appeared in the journal Prenatal Diagnosis that focused specifically on CMA counseling issues.
Preferred for stillbirth cases
In addition to recommending that CMA replace karyotyping in the case of abnormal ultrasound findings, ACOG and SMFM are now recommending that CMA be used to evaluate products of conception to identify the genetic causes of stillbirth.
CMA is increasingly being implemented in such cases, although adoption to date has been limited by the cost of CMA plus questions about how to best communicate findings of unknown clinical significance to mothers at risk of miscarriage.
Rose said that the organizations decided to recommend the use of CMA over karyotyping for stillbirth cases because it "can identify more clinically significant abnormalities." And since CMA does not require living tissue to produce data, she said that the technology offers an "improved way" to evaluate a stillbirth.
To support their recommendations, ACOG and SMFM noted the outcome of a study led by NICHD's Uma Reddy that was focused exclusively on stillbirth and found that arrays provided a genetic diagnosis 87 percent of the time, versus karyotyping, which yielded results 71 percent of the time. The results of the study were published in a separate NEJM paper last year.
While Rose said that she could not comment on whether or not the committee opinion would prompt increased adoption of CMA for stillbirth cases, she said that, overall, the organizations hope that "sophisticated testing, despite its complexity, will help patients, especially those with significant fetal anomalies, get the most information regarding their pregnancy."
She added that the use of CMA should provide "sound information for management of such a child and, in the case of a stillbirth, to help understand what happened and to help with recurrence risk counseling."