Q: Should the presence of soft markers of aneuploidy be reported in women who have already had cfDNA screening?
The concept of soft markers was introduced in an era predating methods of screening for Down syndrome other than maternal age, when the detection rate for Down syndrome was only 20%–30%. This approach was promoted as a means to detect aneuploidy in otherwise low-risk women who had no other screening options. Since the sensitivity of cfDNA screening for Down syndrome approaches 99%, the residual risk for Down syndrome is exceedingly low in patients who have had a negative cfDNA screen.
Recommending diagnostic testing in women when a soft marker is identified would, however, result in a substantial increase in the number of diagnostic tests. Therefore, we recommend that diagnostic testing not be recommended to patients solely for an isolated soft marker in the setting of a negative cfDNA screen. Because the residual risk for Down syndrome in a woman with a negative cfDNA screen is so low, when an isolated soft marker is noted on second-trimester ultrasound examination, the sonographer may choose to state that it is a normal variant or likely of no clinical significance.
When more than one marker is found, the likelihood of aneuploidy is higher than in the presence of an isolated marker, but the actual magnitude of the increase depends on the markers. Due to these complexities and the limitations of prenatal ultrasound in the setting of a negative cfDNA screen with multiple soft markers, genetic counseling should include consideration for diagnostic testing. Prenatal risk assessment for aneuploidy and/or chromosomal abnormalities based on soft markers should be limited to individuals and centers with training and/or experience in prenatal diagnosis
Some soft markers (eg, choroid plexus cysts and echogenic intracardiac foci) have minimal clinical significance in the absence of a higher pretest risk of fetal aneuploidy. However, other sonographic soft markers, such as mild pelviectasis and echogenic bowel, may indicate a fetal abnormality other than aneuploidy. Even if cfDNA screening has been performed, such cases require additional prenatal or postnatal evaluation.
Q: When soft markers of aneuploidy are detected in an otherwise low-risk woman, should cfDNA screening be offered?
In general, isolated soft markers have limited utility in detection of aneuploidy in low-risk patients. In women who have already had traditional aneuploidy screening with normal results, risk of trisomy 21 typically remains low even in the presence of an isolated soft marker given the low a priori risk and the relatively low positive likelihood ratios for the soft markers.
Although the addition of negative cfDNA screening could potentially alleviate patient anxiety, it has been reported that even with normal diagnostic testing, presence of soft markers is still anxiety-provoking, and many patients are not completely reassured by normal results on diagnostic testing. Presumably, negative results on cfDNA screening would likewise not completely alleviate anxiety. Therefore, providers should carefully consider a consistent approach to such findings. For a woman who has an identified isolated soft marker on a second-trimester ultrasound in the setting of a negative serum screen, a reasonable approach is to consider the presence of the isolated soft marker to be a “normal variant.” In an effort to achieve further reassurance (without the risks of diagnostic testing), cfDNA screening may be made available to these patients, however, they should be counseled that their risk of aneuploidy is low based on their initial screening result and the amount of additional risk reduction with a negative cfDNA screening result is unclear.