Conventional aneuploidy screening remains “most appropriate” choice for general population

OpinionThe American Congress of Obstetricians and Gynecologists (ACOG) have updated their guidance on cell-free DNA (cfDNA) screening tests for fetal aneuploidy. In it, they state that any patient (i.e. women at high-risk OR low-risk for having an affected pregnancy) may choose cfDNA testing but they caution that conventional screening tests are more appropriate. This document replaces an earlier opinion, published in 2012, which clearly stated that cfDNA screening tests should not be offered to the general obstetrical population because they are considered to be at low-risk.

So ACOG went from recommending that cfDNA testing not be performed on low-risk women to say that they may choose cfDNA testing. Why the subtle change? Well, as ACOG correctly notes, the landscape of cfDNA is changing rapidly. New studies are published frequently and those that have examined the performance of cfDNA tests in  low-risk women have reported that the test performs just as well in them as it does in high-risk women.

However, they make an important point about a metric that doesn't get the attention it deserves. The positive predictive value (PPV). See here for background. Because the prevalence of fetal aneuploidy in low-risk women is lower than it is in high-risk women, a "positive" or "abnormal" test result in low-risk women is more likely to be a false-positive result. For example, a positive result in a 25-year-old woman gives a 33% chance that the fetus is affected but that chance increases to 87% in a high-risk woman.

The report also calls out the "no result" problem. cfDNA tests fail to produce a result in 1-8% of samples tested, usually due to a low amount of fetal DNA in the blood sample. It's becoming clear that women with samples that fail to produce a result are at increased risk of having an affected fetus. According to ACOG, these women she be offered diagnostic testing such as fetal karyotyping using amniotic fluid obtained by amniocentesis.

Other notable points contained within the updated guidance include:

  • Caution about not routinely performing microdeletion screening (offered by some labs) because it has not been fully validated in clinical studies.
  • Clearly indicating that a negative or normal result does not rule out the possibility of an affected fetus.
  • Providing genetic counseling to patients about test limitations and that decisions such as pregnancy termination should not be based on these screening tests.
  • A reminder that cfDNA tests do not screen for neural tube or ventral wall defects

This certainly won't be the final say that ACOG has on cfDNA aneuploidy screening tests. Indeed, they state that "It will be critical to remain abreast of this rapidly changing technology to provide patients with the most effective, accurate, and cost-conscious methods for aneuploidy screening."

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