Fetal Nasal Bone in the First Trimester
The inclusion of absence of the nasal bone during the first trimester as a marker for trisomy 21 was first examined in a large prospective trial of high-risk patients undergoing chorionic villus sampling.36 The nasal bone was absent in 73% of trisomy 21 fetuses and in only 0.5% of euploid pregnancies. These authors therefore asserted that nasal bone assessment would significantly improve the performance of first trimester ultrasound screening for trisomy 21. At false-positive rates of 1% and 4%, they reported detection rates for trisomy 21 of 85% and 93%, respectively. The same group of investigators conducted a retrospective analysis that suggested a 97% detection rate for trisomy 21 could be achieved for a false-positive rate of 5% by incorporating nasal bone measurements into existing combined (NT and serum biochemistry) screening protocols.37
When applied as a screening tool in the general population studied by the FASTER group, the performance of this marker was, however, disappointing,38 as 9 of 11 fetuses with trisomy 21 were identified as having nasal bones present. The disparity in reported detection rates relating to nasal bone assessment as a screening tool may be attributed to variability between centers in the nature of the nasal bone assessment that is conducted. For example, Cicero et al39 included not only cases in which the nasal bone was completely absent, but also those in which the nasal bone was reportedly hypoplastic. Other authors40 have strictly considered the nasal bone absent if there is no evidence whatsoever of its presence.
Nasal bone assessment is conducted when the fetal CRL measures between 45 and 84 mm, to coincide with the timing of NT assessment. The fetus should be imaged in a mid-sagittal plane with the fetal spine down. The angle of insonation of the ultrasound beam with the fetal profile should be close to 45 degrees. The image should be magnified until 2 parallel echogenic lines are visualized in the region of the fetal nose (Figure 22-7). The transducer should be tilted from side to side to distinguish fetal skin from underlying nasal bones, and the deeper echogenic line, corresponding to the nasal bone, should become more echolucent at its distal end.
A: Nasal bone visualized in mid-sagittal plane at 11 weeks' gestation. B: Parallel echogenic lines 3 (nasal tip), 2 (skin), 1 (nasal bone).
Nasal bone hypoplasia was considered by Cicero et al36 where the nasal bone appeared as a thin line, less echogenic than the overlying skin. The policy of including such cases may make nasal bone assessment more difficult as evaluating the degree of echogenicity of the nasal bone line is somewhat subjective. Other investigators38,40 therefore consider it technically easier and practically more meaningful to classify the nasal bone as being either present or absent.
The conflicting reports of the utility of this marker are such that the application of nasal bone evaluation as a screening tool in unselected populations remains unjustified.
First Trimester Doppler Assessment of the Ductus Venosus
The ductus venosus is a fetal vessel that carries oxygenated blood from the umbilical vein to the inferior vena cava and hence to the fetal heart. It is characterized by a high-velocity jet, which generates arterial-like peak velocities. Blood flow within the ductus venosus has been shown to be directed preferentially toward the foramen ovale and hence the left atrium, thereby essentially bypassing the right atrium41,42 and ultimately perfusing the coronary arteries and fetal brain via the ascending aorta. During conditions of fetal stress (eg, hypoxia or hypovolemia), the ductus venosus is capable of adapting the volume of blood shunted along this path, through modification of its vessel diameter.
The technique for obtaining a ductus venosus waveform in the first trimester is as follows: A mid-sagittal view of the fetus is required, and color Doppler sonography is used to enhance visualization of the ductus (Figure 22-8). With the gate for a pulsed Doppler study positioned at the inlet, immediately distal to the portal sinus and proximal to the infundibulum of the inferior vena cava, a waveform can be obtained after 9 weeks' gestation. The angle of insonation should always be less than 30 degrees. The characteristic normal ductus venosus waveform is biphasic, with peak velocities observed at ventricular systole (S) and early diastole (D). Corresponding to atrial contraction, the end of diastole (ED) coincides with the lowest velocities observed in the ductus venosus. The pulsatility index for veins (PIV), calculated as S – ED/time-averaged maximum velocity, is a parameter that is seen to decrease with advancing gestation as velocities increase.
Color-flow Doppler of ductus venosus at 11 weeks' gestation.
Under normal physiologic conditions, blood flow should be directed toward the heart throughout the cardiac cycle. Reversal of blood flow during atrial contraction was first described in association with congenital heart disease and was thought to indicate that this point in the fetal cardiac cycle, the end of diastole, represented the most vulnerable phase of ductus venosus flow and was thus a sensitive indicator of altered fetal hemodynamics.41
The significance of decreased or reversed flow in the ductus venosus was soon recognized as being indicative, not just of congenital heart disease, but also of fetal aneuploidy.43,44 The same cardiac strain thought to be responsible for increased nuchal translucency thickness in aneuploid fetuses provides a plausible explanation for the observation of reversal of flow in the ductus venosus. In a multicenter review that pooled the results of 6 studies assessing the relationship between ductus venosus flow and aneuploidy, the utility of this marker was investigated by Nicolaides et al.35 Abnormal ductus venosus flow was identified in 82% of aneuploid fetuses with a false-positive rate of 5%.
Although these results are promising, acquisition of the ductus venosus waveform can prove technically challenging, thus limiting its applicability to general population screening. The acquisition of ductus venosus velocities is dependent on both the sampling site and the angle of insonation. Venous contamination from adjacent veins (inferior vena cava, umbilical and intrahepatic veins) presents the greatest challenge in acquiring an accurate waveform from the ductus venosus, especially in early pregnancy. Repeated assessment may overcome this problem to some extent.45
Theoretical concerns have been raised over the safety of Doppler insonation in early pregnancy. However, the majority of ductus venosus assessments are performed in the 12th and 13th weeks of pregnancy, by which time embryogenesis is complete. Nonetheless, the role of first trimester Doppler assessment of the ductus venosus may, like that of nasal bone assessment, be restricted to high-risk pregnancies in specialist centers.
First Trimester Tricuspid Regurgitation
Regurgitation across the tricuspid valve in the first trimester, even in the absence of structural cardiac defects, was demonstrated as having a link with fetal aneuploidy by Huggon et al.46 The mechanism whereby tricuspid regurgitation is associated with chromosomal abnormalities is postulated to be related to increased cardiac preload or afterload.47 Tricuspid regurgitation has been demonstrated in a range of conditions that are characterized by increased cardiac preload, such as nonimmune hydrops,48 or feto-fetal transfusion syndrome (recipient fetus)49 and also in the setting of increased cardiac afterload, such as severe fetal growth restriction.50
In the study by Huggon et al,46 increased nuchal translucency was a feature in the majority of the 262 high-risk patients, 70 of whom were found to have tricuspid regurgitation. The prevalence of aneuploidy in those who screened positive for tricuspid regurgitation was 83%, whereas 35% of those without tricuspid regurgitation were aneuploid, thus underpinning the high-risk nature of this cohort. This observation was further studied by Faiola et al,51 whose cohort of 742 high-risk pregnancies was scanned by pediatric cardiologists at 11 to 13+6 weeks' gestation.
An apical 4-chamber view is required for the detection of tricuspid regurgitation. Using pulsed-wave Doppler, the sample volume is positioned across the tricuspid valve such that the angle to the direction of flow is less than 30 degrees. The group led by Faiola applied a strict definition for tricuspid regurgitation, in that it had to occupy at least half of systole and reach a velocity of over 80 cm/s. Tricuspid regurgitation was thus identified in 65% of fetuses with trisomy 21 and in 8.5% of chromosomally normal cases, with a likelihood ratio of tricuspid regurgitation for cardiac defects of 8.4.
Importantly, in both of these studies investigators chose to use pulsed-wave Doppler rather than color-flow mapping to identify tricuspid regurgitation between 11 and 14 weeks' gestation. Although in postnatal life color-flow mapping is the most reliable way of identifying valvular regurgitation, it appears that the small size of the tricuspid orifice (mean 2 mm) in the late first and early second trimester, combined with a mean fetal heart rate exceeding 160 beats per minute, render color-flow mapping unreliable at this gestation. The detection of tricuspid regurgitation by color-flow mapping has also been shown to be highly variable between ultrasound machines.46
Whether the fetal karyotype is normal or not, the prevalence of tricuspid regurgitation is seen to increase with increasing nuchal translucency and to decrease with advancing gestation. This marker has not been evaluated in unselected populations, and therefore its utility is currently restricted to high-risk populations in specialized centers.