Ultrasound Markers for Aneuploidy in the Second Trimester

Introduction

Soft ultrasound markers were initially described as a screening method for trisomy 21 to improve the detection rate over that based on age-related risk alone. Soft markers are not structural abnormalities; rather, they are minor ultrasound findings identified in the midtrimester that may be a variant of normal but are noteworthy because they have been associated with an increased risk of fetal aneuploidy. Commonly identified soft markers addressed in this chapter include echogenic intracardiac focus (EIF), choroid plexus cyst (CPC), single umbilical artery (SUA), echogenic bowel, urinary tract dilation (UTD) (previously known as pyelectasis or pelviectasis), short humerus and/or femur, and thickened nuchal fold.

Contemporaneous with the advancement in aneuploidy detection using soft markers was the development of improved screening methods to predict aneuploidy risk, including first-trimester screening with maternal serum analytes and nuchal translucency measurement. In 2011, the introduction of cell-free DNA (cfDNA) techniques greatly improved the ability to screen for common aneuploidies. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend that cfDNA screening be offered to patients with a higher risk for common aneuploidies, although any patient who desires aneuploidy screening may elect to pursue cfDNA screening.

Given the high sensitivity of maternal serum screening algorithms and cfDNA for trisomy 21, 18, and 13, the role of ultrasound-based screening for aneuploidy is in evolution. The purpose of this chapter is to focus on the evaluation and management of isolated ultrasound soft markers diagnosed in the second trimester.

What Is the Initial Approach After a Soft Marker Is Identified?

Once a soft marker is identified, a detailed ultrasound examination is recommended to ensure the finding is isolated (i.e., there is only a single soft marker that does not co-occur with any structural abnormality or other soft marker), as the presence of multiple soft markers increases the risk of aneuploidy. In the case of multiple soft markers or a structural abnormality, the approach to evaluation should be individualized. If an isolated soft marker is confirmed, subsequent evaluation and counseling depends on the nature of the soft marker and associations with nonaneuploid conditions.

The presence or absence of specific soft markers has been used to modify the probability of trisomy 21, and secondarily that of trisomy 18, using positive and negative likelihood ratios (LRs). This approach requires an accurate assessment of (1) the a priori, or pretest, risk (age-related risk at the time of delivery or age-related risk in the midtrimester) of the aneuploidy of interest; (2) the posttest risk based on a screening test, if performed; (3) validated and reproducible sonographic definitions for the identification of each soft marker; and (4) accurate estimates of sensitivity and specificity to generate the positive and negative LRs of an isolated soft marker for a particular aneuploidy. Once the risk estimates and LRs are determined, then a final risk estimate incorporating the presence or absence of an ultrasound soft marker for the aneuploidy of interest can be calculated.

In general, positive LRs from approximately 1.5–5 confer a small increase in the likelihood of the outcome, LRs between 5 and 10 confer a moderate increase in the likelihood of the outcome, and LRs greater than 10 confer a significant increase in the likelihood of the outcome. The absence of structural anomalies or additional soft markers likely decreases this risk, although formulas to assess the interaction of these risks are not readily available. Regardless of the screening strategy used, there is no one threshold value of posttest probability above which additional aneuploidy evaluation is routinely recommended, as risk estimates represent a continuum.

The approach to calculating posttest probability was particularly useful when patients desired aneuploidy screening and soft markers helped shape the “genetic sonogram” as another tool to further refine risk prediction. As data on soft markers have accumulated, variability in positive and negative LR estimates has been noted because of differences in patient populations studied, variability in the definition of a specific finding, and subjectivity in the detection rate as well as other causes.

When reviewed in aggregate, the current data suggest that the positive likelihood ratios for the common soft markers, with the exception of a thickened nuchal fold, are all exceedingly low (ranging from less than 1 to 6, in general). This low range suggests that if a positive likelihood ratio were to be incorporated into a patient’s individual risk for aneuploidy, based on the available results from cfDNA or serum/integrated screening, there would not be a meaningful change in the estimate of absolute aneuploidy risk and thus would not warrant additional counseling or testing based solely on the identification of the isolated soft marker. National recommendations from the Royal College of Obstetrics & Gynecology in the United Kingdom and from the Society of Obstetricians and Gynaecologists of Canada (SOGC) Genetics Committee and the Canadian College of Medical Geneticists (CCMG) suggest not adjusting a patient’s a priori risk for trisomy 21 with the presence of any one soft marker, with the exception of a thickened nuchal fold.

Moreover, if a woman has undergone diagnostic testing and the results indicate a normal karyotype, identification of a soft marker for the purposes of aneuploidy screening is insignificant and should be reported as such.

What Is the Significance of an Echogenic Intracardiac Focus?

An EIF is defined as a small (<6 mm) echogenic area in either cardiac ventricle that is as bright as surrounding bone and visualized in at least two separate planes ( Fig. 10.1 ). EIFs may appear in either cardiac ventricle, although left-sided EIFs are more common, and are thought to represent microcalcifications of papillary muscles. The pathogenesis of this finding is unclear.

EIFs are identified in 3%–5% of karyotypically normal fetuses, and significant ethnic variation exists. In the largest analysis of 7480 ethnically diverse women having amniocentesis, the prevalence of EIF was 8.3% among Middle-Eastern women, 6.9% among Asian-American women, 6.7% among African-American women, 3.4% among Hispanic women, and 3.3% among Caucasian women, with lower prevalence among Asian-Indian and Native-American women. Smaller studies have demonstrated a higher prevalence of EIF among women of Asian descent, with estimates up to 30%.

EIFs do not represent a structural or functional cardiac abnormality, and they have not been associated with cardiac malformations in the fetus or newborn. Fetal echocardiography and additional ultrasound imaging solely to serially follow an EIF are not recommended, and no postnatal follow-up is indicated. When isolated, an EIF should be considered a variant of normal.

Since the first descriptions of EIFs as a soft marker for trisomy 21, a subsequent large body of literature has demonstrated varying positive likelihood ratios for trisomy 21, depending on the population studied and whether the EIF was isolated or in combination with other soft markers. Overall, however, the association between the presence of an EIF and trisomy 21 is weak. In the presence of an isolated EIF, the risk of trisomy 21 is not meaningfully altered, and therefore, an isolated EIF can be considered a variant of normal and additional aneuploidy evaluation is not indicated in women previously screened for aneuploidy. In the absence of any prior aneuploidy screening, the positive likelihood ratio for an EIF ranges between 1.4 and 1.8, with lower confidence bounds extending to or beyond 1, suggesting little to no increased risk.