Cell-free DNA (cfDNA) screening shows promise as a non-invasive method for detecting fetal aneuploidy, but given its limitations, medical groups are recommending that pregnant women opt for more conventional methods as a first-line screening tool.
The screening method first became available in 2011, and was recommended for women at high risk for fetal aneuploidy by the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal–Fetal Medicine (SMFM). Women who fall into this category may be older than age 35, have a history of trisomy-affected offspring, a positive first-trimester or second-trimester screening test result, or an ultrasound that showed the fetus was at high risk of aneuploidy.
Women are also considered high risk in instances where a parent carries a balanced robertsonian translocation with an increased risk of trisomy 13 or trisomy 21.
A recent committee opinion issued by ACOG and SMFM updates their position on this screening tool, outlining its strengths and limitations, and why it’s important to counsel patients about using cfDNA.
Laboratories use a variety of cfDNA methods to screen for fetal aneuploidy. Data for these tests usually rely on advanced bioinformatic analyses and next-generation sequencing technologies, according to the opinion issued by the medical groups.
Irrespective of which molecular technology is used, cfDNA tests yield particularly high sensitivity and specificity results for trisomy 18 and trisomy 21. Sensitivity and specificity for Trisomy 21, for example, rank at 99.3% and 99.8%, respectively. Specificity for trisomy 13 and sex chromosome abnormalities also ranks in the 99% range, although sensitivity for these conditions is somewhat lower, in the 80%–90% range.
The limitation of cfDNA testing, however, is that it only screens for common trisomies and sex chromosome composition, if requested. It also doesn’t assess risk for neural tube or ventral wall defects in the fetus. “Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha-fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results,” ACOG and SMFM advised.
And although the levels of sensitivity and specificity rank similarly for women in the general population and those at high risk, the positive predictive value for these tests isn’t as high in the general obstetric population—mainly because aneuploidy isn’t as prevalent as it is in high-risk populations.
“That is, fewer women with a positive test result will actually have an affected fetus, and there will be more false-positive test results,” the groups explained in their opinion.
Due to this test’s limitations in identifying all chromosome abnormalities, doctors should advise patients that cfDNA screening is not a substitute for more accurate diagnostic tests, such as chorionic villus sampling or amniocentesis, the groups recommended. Any women with a positive cfDNA test should follow up with a more conventional diagnostic test.
The groups also recommended against using this method in women with multiple gestations. No screening method, cfDNA or otherwise, has been able to detect aneuploidy in multiple gestations with great accuracy.
“With any method based on maternal blood (serum analytes or DNA), only a single composite result for the entire gestation is provided, with no ability to distinguish a differential risk between fetuses. The data regarding the performance of cell-free DNA screening in twin gestations are limited,” the opinion stated.
In specific advice to labs, ACOG and SMFM called for more specificity in the reporting of cfDNA test results for aneuploidy. Instead of just indicating that a test was positive or negative, or that a chance of aneuploidy exists, lab results should include positive predictive values and residual risk values, to better inform patients and obstetric providers.