Key Points
Nuchal translucency measurement in the first trimester is the most powerful marker for fetal Down syndrome.
Combination of nuchal translucency with serum markers in the first trimester detects up to 87% of cases of Down syndrome for a 5% false-positive rate.
Septated cystic hygroma, or simple nuchal translucency of 3.0 mm or greater, are indications for chorionic villus sampling (CVS) without need to await serum marker results.
First trimester absence of the nasal bones, reversal of flow in the ductus venosus, and tricuspid regurgitation may have a limited role as second-line screening tests for select high-risk patients by expert sonologists.
These second-line screening tests are unlikely to have any value for routine general population screening.
The single most powerful marker available today for differentiating Down syndrome from euploid pregnancies is the first trimester sonographic measurement of the fetal nuchal translucency space. Nuchal translucency refers to the normal subcutaneous fluid-filled space between the back of the fetal neck and the overlying skin (Figure 2-1). Figure 2-2 demonstrates an increased nuchal translucency observed in a fetus subsequently shown to have Down syndrome. By adhering to a standard ultrasonographic technique, it is possible to obtain accurate measurements of this area in the vast majority of fetuses between 10 and 14 weeks’ gestation. When performing nuchal translucency sonography, it is absolutely essential to ensure optimal technique, which can be attained by focusing on the following criteria (Abuhamad, 2005):
Fetus should be imaged in the midsagittal plane, ideally with the fetal spine down.
The image should be adequately magnified so that only the fetal head, neck, and upper thorax fill the viewable area.
Fetal neck should be neutral, with care being taken to avoid measurements in the hyperflexed or hyperextended positions.
The skin at the fetal back should be clearly differentiated from the underlying amniotic membrane, either by visualizing separate echogenic lines or by noting that the skin line moves with the fetus.
Measurement calipers should be placed on the inner borders of the echolucent space, and should be perpendicular to the long axis of the fetus.
Ultrasound and transducer settings should be optimized to ensure clarity of the image and of the borders of the nuchal space in particular. This may require transvaginal sonography in certain situations.
Figure 2-1
Optimizing the technique for first trimester nuchal translucency sonography: Nuchal translucency measurement in a normal fetus at 12 weeks’ gestation. Components of a good sonographic screening protocol are evident, including adequate image magnification, midsagittal plane, neutral fetal neck position, and correct caliper placement.
There is a direct correlation between increasing nuchal translucency measurement and risk for Down syndrome, other aneuploidies, major structural malformations, and adverse pregnancy outcome (Malone et al., 2000, 2005b; Nicolaides et al., 2002; Wald et al., 2003b). Possible etiologies for the development of this increased fluid-filled space include cardiac failure secondary to structural malformation, abnormalities in the extracellular matrix, and abnormal or delayed development of the lymphatic system (Moscoso, 1995).
Nuchal translucency sonography is the most powerful marker for general population screening for Down syndrome (Malone and D’Alton, 2003). The largest study of this form of screening was performed by the Fetal Medicine Foundation based in London (Snijders et al., 1998). This prospective study of 96,127 unselected patients at 22 centers required nuchal translucency sonography to be performed between 10 and 14 weeks’ gestation by specially trained sonographers who utilized a standardized technique. The overall Down syndrome detection rate was 77%, for a 5% false-positive rate. Another large prospective study from the United Kingdom that evaluated the role of nuchal translucency sonography in general population screening was the SURUSS Trial (Wald et al., 2003b). A total of 39,983 patients had nuchal translucency sonography obtained between 10 and 14 weeks’ gestation, and the Down syndrome detection rate was 63%, for a 5% false-positive rate. The largest prospective trial of all forms of Down syndrome screening yet performed, the FASTER Trial, has also validated the important role of nuchal translucency sonography. This was a multicenter prospective study from 15 centers in the United States in which 36,306 patients from the general population had first trimester nuchal translucency sonography performed (Malone et al., 2005b). The detection rate for nuchal translucency with maternal age ranged from 70% to 64% at 11 and 13 weeks’ gestation respectively, for a 5% false-positive rate. These large studies from varied centers and geographic locations confirm that nuchal translucency sonography must be a key component of first trimester screening programs for fetal Down syndrome.
Together with the clear role of nuchal translucency sonography, research in first trimester screening has consistently shown that pregnancies with fetal Down syndrome are associated with altered levels of certain maternal serum markers, including elevated levels of total human chorionic gonadotropin (hCG) and of the free β subunit of hCG (with a median multiple of the median [MoM] of 1.83 in affected cases) and lower levels of pregnancy-associated plasma protein A (with a median MoM of 0.38 in affected cases) (Canick and Kellner, 1999). Studies of the combination of free β subunit of hCG, pregnancy-associated plasma protein A, and maternal age uniformly demonstrate a sensitivity for Down syndrome of approximately 60% with a 5% false-positive rate.
These first trimester serum markers are largely independent of nuchal translucency, which has resulted in the development of a combined serum and sonographic screening protocol that would be more effective for screening than either component alone. The FASTER study evaluated 38,033 patients and demonstrated very high Down syndrome detection rates, and showed that performance varied significantly by gestational age. For a 5% false-positive rate, the Down syndrome detection rates using combined serum and sonographic screening were 87%, 85%, and 82% at 11, 12, and 13 weeks’ gestation respectively (Malone et al., 2005b). For a 1% false-positive rate, the Down syndrome detection rates were 73%, 72%, and 67% at 11, 12, and 13 weeks’ gestation respectively.
Figure 2-3 summarizes the comparative performance of the various screening options from the FASTER Trial, and demonstrates that first trimester combined screening has very similar performance to second trimester Quad marker serum screening (Malone et al., 2005b). Only when performed at 11 weeks’ gestation does first trimester combined screening have a significantly better performance than second trimester Quad marker serum screening (87% vs. 81% Down syndrome detection, respectively, at a 5% false-positive rate). Additionally, the combined first trimester screening test has the lowest false-positive rate, compared with either first trimester component used alone or compared with second trimester serum screening. It is also important to realize that only the combination of first trimester nuchal translucency sonography with first trimester serum markers comes close to the performance of second trimester Quad marker serum screening. Nuchal translucency alone, without being combined with serum markers, has significantly inferior performance characteristics.
Figure 2-3
A. Comparison of first and second trimester screening for Down syndrome: Detection rates of combined first trimester screening at 11, 12, and 13 weeks’ gestation, compared with second trimester Quad marker serum screening performed at 15 to 18 weeks’ gestation (each at 5% false-positive rate). B. Comparison of first and second trimester screening for Down syndrome: False-positive rates of first trimester nuchal translucency alone, PAPP-A and fβhCG alone, and first trimester combined screening at 12 weeks’ gestation, compared with second trimester Quad marker serum screening performed at 15 to 18 weeks’ gestation (each for 85% detection rate).
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