The introduction of cell-free DNA screening for aneuploidy into obstetric practice in 2011 revolutionized the strategies utilized for prenatal testing. The purpose of this document is to review the current data on the role of ultrasound in women who have undergone or are considering cell-free DNA screening. The following are Society for Maternal-Fetal Medicine recommendations: (1) in women who have already received a negative cell-free DNA screening result, ultrasound at 11–14 weeks of gestation solely for the purpose of nuchal translucency measurement (Current Procedural Terminology code 76813) is not recommended (GRADE 1B); (2) diagnostic testing should not be recommended to patients solely for the indication of an isolated soft marker in the setting of a negative cell-free DNA screen (GRADE 2B); (3) in women with an isolated soft marker that has no other clinical implications (ie, choroid plexus cyst or echogenic intracardiac focus) and a negative cell-free DNA screen, we recommend describing the finding as not clinically significant or as a normal variant (GRADE 2B); (4) in women with an isolated soft marker without other clinical implications (ie, choroid plexus cyst or echogenic intracardiac focus) and a negative first- or second-trimester screening result, we recommend describing the finding as not clinically significant or as a normal variant (GRADE 2B); (5) all women in whom a structural abnormality is identified by ultrasound should be offered diagnostic testing with chromosomal microarray (GRADE 1A); and (6) routine screening for microdeletions with cell-free DNA is not recommended (GRADE 1B).
The practice of medicine continues to evolve, and individual circumstances will vary. This publication reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal-Fetal Medicine.
The introduction of cell-free DNA (cfDNA) screening for aneuploidy into obstetric practice in 2011 revolutionized the strategies utilized for prenatal testing. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) both recommend that all women should be offered the option of aneuploidy screening or diagnostic testing for fetal genetic disorders.
The most recent guidance addressing this issue suggests that traditional screening with serum markers and nuchal translucency measurement remains the most appropriate option for low-risk patients, while in women at higher risk for common aneuploidies, cfDNA screening may be more accurate for detecting these aneuploidies. In addition, SMFM has stated that because of the ethics of patient autonomy, after appropriate genetic counseling regarding the benefits and limitations of cfDNA screening, this option should be available to women who request additional testing beyond what is currently recommended by professional societies.
The number of different screening and testing options has left many obstetric care providers with questions about how to incorporate cfDNA screening into traditional approaches to screening. The purpose of this document is to review the current data on the role of ultrasound in women who have undergone or are considering cfDNA screening, acknowledging that prospective evidence is limited.
What is the role of nuchal translucency measurement in women who plan to have, or have already had, cfDNA screening and received a negative or low-risk result?
With the introduction and increasing use of cfDNA screening, the question has arisen as to the value of first-trimester nuchal translucency (NT) ultrasound evaluation in patients who have chosen cfDNA instead of traditional aneuploidy screening. While cfDNA screening is very accurate for trisomies 21, 18, and 13 and potentially some sex chromosome aneuploidies, these tests do not provide information on other chromosomal aberrations that might be identified with conventional first- and second-trimester screening or the more comprehensive genetic information provided by diagnostic testing.
While the precise measurement of the NT is not required for aneuploidy risk estimation when cfDNA screening is performed, such assessment prior to cfDNA screening, especially in a higher-risk population, affords women in whom an enlarged NT is identified the option to proceed directly to diagnostic testing. While an enlarged NT has been associated with other aneuploidies, it has limited utility in the detection of chromosomal abnormalities other than trisomies 21, 18, and 13 because of their overall lower prevalence as well as lower sensitivity for these other conditions.
An increased NT has been associated with structural anomalies, neuromuscular disorders, and a variety of other genetic conditions. It has been noted that imaging the fetus at 11–14 weeks of gestation (first-trimester ultrasound [Current Procedural Terminology] [CPT] code 76801) provides an early opportunity to evaluate the pregnancy and to potentially identify a fetus at risk for additional genetic or structural abnormalities.
One study reported on 1739 patients who had an ultrasound at 11–14 weeks of gestation in the setting of a negative cfDNA screening result. The authors reported that a variety of findings were identified in 60 women who underwent first-trimester NT assessment (3.5%), including 13 women with unrecognized twins (0.7%) and 10 with an unrecognized fetal demise (0.6%). This group, however, also included 26 fetuses (43%) with an NT measuring 3–4 mm but a normal anatomic scan in the second trimester and that were normal at birth. A total of 11 fetuses were found to have either a structural anomaly or a cystic hygroma (0.6% or 1 of 155). Of the 7 structural anomalies diagnosed, one (pleural effusion and NT of 4.5 mm) resulted in a normal fetus at birth and in 6 the women chose pregnancy termination. Therefore, in this study, following negative cfDNA results, abnormal ultrasound findings were identified in 1 in 28 women, and a fetal anomaly was identified in 1 in 290.
Another large study (n = 5306) evaluated the role of cfDNA screening and first-trimester NT assessment in the detection of chromosomal abnormalities in a high-risk cohort referred for chorionic villus sampling (CVS). The prevalence of chromosome abnormalities was 19% in this cohort, and it was estimated that a cfDNA screen would have detected 88.9% of these. The addition of first-trimester NT assessment would have increased the detection of chromosomal abnormalities to 94.8% if CVS was performed on the 21.7% of cases with an NT ≥3.0 mm ( Table 1 ). In other words, adding the first-trimester NT measurement increased the detection rate of chromosome abnormalities by 6% over the detection rate that would have been achieved with cfDNA screening alone, but this resulted in an increase in the rate of CVS from 2% to 22%.
| Variable | cfDNA only | cfDNA plus NT; CVS for NT ≥3.0 mm |
|---|---|---|
| Detection rate of all chromosomal abnormalities | 88.9% | 94.8% |
| Screen-positive/CVS rate | 2.0% | 21.7% |
| Residual risk of significant chromosome abnormality | 2.5% | 1.00% |
a High risk is defined as any of the following: increased NT with or without biochemistry, structural anomalies, advanced maternal age/anxiety, or family history.
Using cfDNA screening as the primary evaluation strategy, the residual risk of a significant chromosomal abnormality after a negative cfDNA screen result was 2.5%. In contrast, using cfDNA screening alone for those with an NT <3.0 mm and CVS for women with an NT of 3.0 mm or higher resulted in a residual risk of a significant chromosome abnormality of 1% in this high-risk cohort.
The current ACOG and SMFM guidance states that nuchal translucency measurement for aneuploidy risk is not necessary at the time of cfDNA screening in the first trimester. However, ultrasound examination is useful to confirm viability, to confirm the number of fetuses and the presence of an empty gestational sac, to assign gestational age, and to identify some major fetal anomalies for patients who may choose to have cfDNA screening.
Patients who choose serum integrated screening may be offered first-trimester ultrasonography for gestational dating, even if an NT measurement is unavailable or cannot be obtained. If an enlarged NT, an obvious anomaly, or a cystic hygroma is identified on ultrasonography, the woman should be offered genetic counseling and diagnostic testing for aneuploidy as well as follow-up ultrasonography for fetal structural abnormalities.
Therefore, in women who are considering having cfDNA screening, first-trimester NT assessment may provide some benefit in helping them to choose between screening and diagnostic testing. In women who have already had a negative cfDNA screen, first-trimester NT screening may slightly reduce the residual risk of significant chromosome abnormalities. However, further research is needed to determine the optimal approach. In women with a negative cfDNA screen, first-trimester NT measurement is of limited additional benefit as a screening test for aneuploidy or structural abnormalities. This is due to the fact that the detection rate for trisomies 21, 18, and 13 by cfDNA is sufficiently high that if the result is negative/low risk, the NT measurement provides little additional information.
In women who have already received a negative cfDNA screen, ultrasound at 11–14 weeks of gestation solely for the purpose of NT measurement (CPT code 76813) is not recommended (GRADE 1B) . The detection of some anomalies is possible as early as 11–14 weeks of gestation; however, the use of ultrasonography to screen for major structural abnormalities in the first trimester should not replace screening of fetal anatomy in the second trimester.
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.
Because 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. In one study, the negative likelihood ratio was calculated as 1 of 148 for Down syndrome with a negative cfDNA screen. Therefore, for a 38-year-old woman, whose age-based risk of Down syndrome is about 1 in 100, her risk after a negative cfDNA screen is now approximately 1 in 14,800.
Given the low a priori risk, the presence of an isolated soft marker is unlikely to add to the detection of Down syndrome to any measurable degree. Recommending diagnostic testing in women when a soft marker is identified would, however, result in a substantial increased number of diagnostic tests.
Therefore, diagnostic testing should not be recommended to patients solely for the indication of an isolated soft marker in the setting of a negative cfDNA screen (GRADE 2B) ( Table 2 ).
Do not report or report as normal variant
|
Evaluate as per routine clinical indications but do not consider as a soft marker for aneuploidy
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