the AJMG SEQUENCE
ACOG approves new trisomy screen for high-risk pregnancies
Can clinical use of the screening for the genetic disorder in low-risk pregnancies be far behind?
A new opinion from the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) says obstetricians can offer noninvasive prenatal testing (NIPT) to women at high risk of delivering babies with Down syndrome and trisomies 13 and 18.
These women include those over age 35, those with a prior pregnancy affected by a fetal trisomy, those with an increased risk of aneuploidy due to conventional serum screening or ultrasound findings, or those who are carriers of a balanced Roberstonian translocation with increased risk of fetal trisomy 13 or 21.
The screening tests, which use circulating cell-free DNA in maternal plasma, have identified approximately 98% of cases of Down syndrome with a false-positive rate of less than 0.5% in published studies, the opinion notes. It emphasizes that the tests should be used for screening only, and that positive results need confirmation with diagnostic testing such as chronic villus sampling or amniocentesis (ACOG, 2012).
This position echoes that of the National Society of Genetic Counselors and the International Society for Prenatal Diagnosis, which previously urged that NIPT be offered only in the context of informed consent, education, and counseling by a qualified provider, and that women with positive results receive genetic counseling and the option of confirmatory diagnostic testing [Devers et al., 2012, and Benn et al., 2012].
Such approval of NIPT for high-risk women sends two messages, says Diana Bianchi, MD, Professor of Pediatrics, Obstetrics, and Gynecology at Tufts University in Boston, Massachusetts, past president of the International Society of Prenatal Diagnosis, and Editor-in-Chief of Prenatal Diagnosis.
“The first is about a better mousetrap. This screening test requires no special training [for physicians], isn't dependent on specific gestational age, and has lower false positive and false negative rates, for women at high risk than other tests,” Dr. Bianchi explains.
The second message is “a brave new world story,” she adds, noting that sequencing of noninvasively collected fetal DNA has been used to detect other genetic disorders and to sequence a fetal genome, leaving some to wonder when these uses will reach the clinic.
New noninvasive prenatal screening tests have identified approximately 98% of Down syndrome cases.
An Emphasis on Counseling
The ACOG statement is squarely focused on use of NIPT in pregnancies at high risk for aneuploidy only. Cell-free DNA testing should be an informed patient choice after pre-test counseling and should not be part of routine prenatal laboratory assessment, the ACOG statement emphasizes.
“Patients must understand that the screening is for a small number of disorders, just the three trisomies, and fetal sex. Some [labs also] now offer sex chromosome aneuploidy results,” says Nancy C. Rose, MD, Chair of ACOG's Committee on Genetics, Director of Reproductive Genetics at Intermountain Healthcare, and Professor of Obstetrics and Gynecology at University of Utah in Salt Lake City.
Cell-free DNA testing should not be offered to women with average-risk pregnancies, or to women with multiple gestations, because the test has not been sufficiently evaluated in these groups, the opinion says. It also emphasizes the importance of post-test counseling and notes that women with positive results should be referred for genetic counseling and offered invasive prenatal diagnosis for confirmation of test results.
Patients must understand that although the test has the highest sensitivity and specificity of all the screening methods, false positives are still possible, the statement adds.
False positives may result from mosaicism in placental cells, but a more frequent cause may be the quantitative nature of testing and how the results are interpreted in a clinical report, notes Michael Mennuti, MD, Chief of Reproductive Genetics and Director of the Cytogenetic Lab at the Hospital of the University of Pennsylvania in Philadelphia.
Dr. Mennuti explains that the test counts DNA fragments from chromosomes 13, 18, and 21 in maternal blood, so each lab must establish its own cutoff for saying the pregnancy is at high risk for one of the disorders.
“A patient with a normal pregnancy could have numbers just above the cutoff, but the lab would report her as high risk. Likewise, a patient with numbers just below the cutoff could have an affected pregnancy but be considered low risk,” Dr. Mennuti explains.
It will be a long time before NIPT replaces current diagnostic tests, he says, adding that doing so would require that NIPT has comparable accuracy, which is very close to 100%, he adds.
Looking Toward the future
NIPT is already changing the testing algorithm for high-risk women, who have had clinical access to the screen for a little more than a year, Dr. Bianchi notes. Tufts' unpublished, internal study of use of amniocentesis in the first six months of offering NIPT shows a 44% reduction in amniocentesis, Dr. Bianchi reports. The upshot for geneticists is that they may see fewer pregnant women seeking diagnostic testing for trisomy, she adds.
Many predict that women with average risk pregnancies will be offered this test eventually, although some suspect that the fraction of fetal cell-free DNA (cfDNA) in maternal blood would be lower in average-risk women. Researchers at Riverside Perinatal Diagnostic Center in California have shown otherwise in a study. They performed a comparative analysis on fetal cfDNA amounts from subjects stratified into risk groups based on maternal age, prenatal screening results, and nuchal translucency measurement, and found no significant differences in the fetal cfDNA fraction among these groups (Braretal., 2013).
By contrast, researchers from Britain's Kings College Hospital in London found that fetal fraction is affected by maternal and fetal characteristics, based on a study of 1,949 singleton pregnancies at 11 to 13 weeks' gestation. Fetal fraction decreased with increased maternal weight and was lower in women of Afro-Caribbean origin than Caucasians. Fetal fraction increased with fetal crown-rump length, serum pregnancy-associated plasma protein-A, serum free β-human chorionic gonadotropin, smoking, and trisomy 21 karyotype [Ashoor et al., 2013].
“Right now, there's not enough evidence to say one way or another whether the test should be used in average-risk women,” Dr. Bianchi says. But when it is, adequate counseling will be a big concern, she notes.
That's because the predictive value of a positive NIPT screen will not be as accurate in average-risk women, Dr. Mennuti predicts. He anticipates that a larger proportion of positive results in this population will be false ones.
The Brave New world
Researchers led by Jay Shendure, PhD, at the University of Washington in Seattle, recently used cell-free fetal DNA to sequence an entire fetal genome and predicted that noninvasive analysis of inherited variation and de novo mutations in fetal genomes will enhance comprehensive prenatal diagnosis of both recessive and dominant Mendelian disorders after researchers work out the technical issues [Kitzman et al., 2012].
“I appreciate the technical accomplishment, but the use of whole fetal genome sequencing in patient care presents huge issues,” Dr. Bianchi says. These include the challenge of educating practitioners and parents, communicating results, and a myriad of ethical issues including proper informed consent, reporting of adult-onset diseases, cost, and equity. But these concerns shouldn't undermine NIPT's current use as a powerful prenatal screening technology for fetal aneuploidy, she emphasizes.
The rapidly evolving prenatal testing landscape is one that geneticists and genetic counselors must watch closely, says Jennifer Hoskovec, Director of Prenatal Counseling Services at the University of Texas in Houston, and President Elect of the National Society of Genetic Counselors (NSGC).
To help genetics professionals and other healthcare providers, NSGC recently published recommendations regarding which prenatal Down syndrome screening or diagnostic testing should be offered based on availability, insurance coverage, and timing of a patient's entry into prenatal care [Wilson et al., 2012].
Medical geneticists and genetic counselors “need to stay on top of new data and continue to evaluate NIPT and be a resource to nongenetics colleagues, the public, and patients,” Hoskovec says.
“Right now, there's not enough evidence to say one way or another whether the test should be used in average-risk women,” says Diana Bianchi, MD, Professor of Pediatrics, Obstetrics, and Gynecology at Tufts University in Boston. But when it is, adequate counseling will be a big concern, she notes.