Screening for Down syndrome is an integral part of routine antenatal care. The most common screening methods currently in use in the United Kingdom involve the assessment of maternal age, multiple second trimester serum markers, or nuchal translucency measurement. The United Kingdom National Screening Committee has recommended that by April 2007, maternity units should use either the combined or integrated test for Down syndrome screening, both with an expected detection rate of more than 75% for a 3% false-positive rate.1,2 These tests involve the use of nuchal translucency with the addition of either first-trimester (combined) or first and second trimester (integrated) maternal serum biochemistry. The purpose of this recommendation is to optimize Down syndrome detection rates for a relatively low false-positive rate. Similar recommendations are also being supported by the American College of Obstetricians and Gynecologists,3 particularly in reference to first-trimester screening.
At the time that these recommendations were being formulated, there was emerging evidence that ultrasound assessment of ductus venosus Doppler flow4–6 and fetal nasal bones7,8 may improve the screening efficiency of first-trimester nuchal translucency programs. The value of these first-trimester ultrasound markers is that they have been shown in small, highly-selected populations to allow effective first-trimester screening to the required standards without the need for blood letting and the delay of biochemical analysis. However, what is not clear from the existing data is how valuable these markers are in a routine setting and whether these ultrasound features are completely independent when calculating the risk for Down syndrome. The purpose of this study is to evaluate the relative value of nasal bones assessment and ductus venosus Doppler in improving first-trimester nuchal translucency screening for Down syndrome.
This was a prospective observational study carried out over 24 months, from December 2001 to November 2003. All women referred to our unit for first-trimester fetal karyotyping were invited to participate in the study, which had approval from the local research ethics committee. Indications for referral included increased risk for aneuploidy by nuchal translucency, maternal request for fetal karyotyping, fetal abnormality in a previous pregnancy, and suspected fetal abnormality in the current pregnancy.
During the ultrasound examination, a full structural survey was undertaken, the nuchal translucency was measured, and the risk of Down syndrome adjusted by the nuchal translucency was calculated. Ductus venosus Doppler evaluation was performed as previously described.5,9 Briefly, the high-pass filter was set to minimum and the pulse repetitive frequency was 2.5 kHz. The maximal achievable thermal and mechanical indices were 1.2 and 1.0, respectively. The exposure of the scan was limited to a maximum of 3 minutes, and if satisfactory waveforms were not formed within that time, the Doppler investigation was abandoned. The size of the sampling gate was set to 1 mm. Localization of the ductus venosus was facilitated using color Doppler imaging. Flow velocity waveforms from the ductus venosus were obtained in the midsagittal plane of the fetal trunk, with the angle of insonation always being less than 30°, immediately distal to the portal sinus and proximal to the infundibulum of the inferior vena cava. This enabled avoidance of contamination from the intrahepatic portion of the umbilical vein, the left hepatic vein, and inferior vena cava. The blood flow velocity waveforms were classified categorically as being normal (forward flow) or abnormal (absent or reversed flow) with regard to the pattern of blood flow during atrial contraction. The Doppler examination in the ductus venosus was repeated a minimum of 3 times to confirm the assessment of flow in the ductus venosus during atrial contraction.
Assessment of the nasal bones was performed as previously described.8,10 A midsagittal view of the fetus was obtained, with the beam of the ultrasound transducer being parallel to the nasal bones. To avoid misinterpretation of the skin of the nose as the nasal bones, the ultrasound transducer was gently tilted from side to side to ensure that the nasal bones were seen separate from the nasal skin. The sonographer first recorded whether the examination of the fetal profile was technically satisfactory. If the examination was satisfactory, then the visualization of the nasal bones was recorded as “present.” If the nasal bones were not visualized, they were recorded as “absent.” The total examination time for ductus venosus and nasal bones assessment was limited to a maximum of 10 minutes, and only fetuses quiescent at the time of scan were enrolled. Because this was a controlled introduction into clinical practice, no action was taken based on the ultrasound findings. All ultrasound scans were performed by obstetricians and sonographers experienced in late first-trimester examinations. Fetal karyotyping was performed by chorionic villus sampling (CVS).
The agreement between the different markers in trisomy 21 fetuses was assessed using a 2 × 2 frequency table and Cohen's κ coefficient. The sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratio for trisomy 21 were calculated for each marker. Logistic regression analysis was performed to assess the association between trisomy 21 and nuchal translucency, ductus venosus, and nasal bones findings. All calculations were performed using the SPSS 11.5 software package (SPSS Inc., Chicago, IL).
During the study period, CVS was performed in 790 pregnancies. Assessment of ductus venosus flow and nasal bones was not attempted in 4 twin pregnancies and in another 158 pregnancies due to time restrictions or the patient declining to be recruited. Therefore a total of 628 fetuses were evaluated. The median maternal age was 37 years (range 19 to 46 years), median crown–rump length was 68 mm (range 41 to 90 mm), and median gestational age was 13 + 2 weeks (range 11 + 0 to 14 + 1 weeks). In all cases crown-rump length and nuchal translucency were measured before CVS, and a nuchal translucency-adjusted risk for trisomy 21 was calculated.11 The indication for CVS was an increased risk (more than 1:300) for trisomy 21 based on maternal age and nuchal translucency screening in 313 cases (54.7%), increased maternal age in 195 (34.1%), and other in 64 (11.2%). During the time allowed for the ultrasound examination, it was not possible to satisfactorily assess ductus venosus flow in 4 cases (0.6%) and nasal bones in 52 cases (8.3%). Therefore, ductus venosus and nasal bones could both be assessed in 572 fetuses. Demographic characteristics of these cases are shown in Table 1. The karyotypes obtained are shown in Table 2.
The agreement among nuchal translucency, nasal bones, and ductus venosus Doppler flow in trisomy 21 fetuses is shown in Tables 3, 4, and 5. The sensitivity, specificity, positive and negative predictive value of nuchal translucency–adjusted risk, ductus venosus, and nasal bones for trisomy 21 are shown in Table 6 for the whole study population, and in Tables 7 and 8 for the subgroups of cases positive and negative at nuchal translucency screening, respectively. Tables 9, 10, and 11 display the likelihood ratio for trisomy 21 with different combinations of nuchal translucency–adjusted risk, ductus venosus and nasal bones findings in the same groups. The positive likelihood ratio indicates the increase in the individual risk of trisomy 21 in the case of abnormal ultrasound findings, whereas the negative likelihood ratio expresses the decrease in the individual risk of trisomy 21 in the case of normal ultrasound findings. A logistic regression model including nuchal translucency, ductus venosus, and nasal bones findings as independent variables for the prediction of trisomy 21 was calculated (Table 12). All three measures were shown to be independent predictors of outcome, but the interaction between ductus venosus and nasal bones was not statistically significant. Similar results were obtained when the model was restricted to cases positive at nuchal translucency screening (Table 13).
The data of this study demonstrate that in addition to increased fetal nuchal translucency, Down syndrome is significantly associated with first-trimester abnormal flow velocity patterns in the ductus venosus and hypoplasia of the nasal bones. Statistical assessment of their independence shows that nuchal translucency may be used together with ductus venosus Doppler or assessment of nasal bones, but that there is not a significant additional advantage in using the latter two markers in conjunction for Down syndrome screening. A recent meta-analysis of prospective, interventional screening studies of nuchal translucency involving more than 180,000 patients has shown detection rates of 85% for a false-positive rate of 8%.12 The present study data suggest that, depending on how they are used, the addition of first-trimester ductus venosus Doppler or nasal bones assessment has the potential to improve Down syndrome screening sensitivity by 2–4% or to reduce false-positive rates by half.
Our study population consisted in a group of pregnancies at high risk for chromosomal abnormalities. Therefore, the results presented here cannot be directly translated to low-risk cases. Previous studies in low-risk populations suggested a role for ductus venosus in combination with nuchal translucency.13,14 The recent results from the Malone et al15 study, suggesting a poor sensitivity for Down syndrome with nasal bones assessment in the general population, should be interpreted with caution. The design of the study included nasal bones assessment only during the terminal 8 months of the trial, and the very high failure rate (24%) in obtaining acceptable images of the nasal bones should prompt a careful review of the technique employed. A well-designed, prospective observational study in low-risk women is required to establish whether nuchal translucency with ductus venosus Doppler or assessment of nasal bones or both will achieve an improvement in screening performance. A possible alternative is to assess these very specific ultrasound markers only in cases considered to be at increased risk after nuchal translucency screening, implementing a 2-tier screening strategy.5,16
The importance of the present study findings is highlighted when put in the context of national strategies, clinical priority, the availability of resources, and patient choice. In the United Kingdom, the development of national recommendations for Down syndrome screening has been long awaited to define a minimal standard of care for women choosing to undertake Down syndrome screening in pregnancy. However, within a cost-restricted national health system, the resources required for supporting the development of an ultrasound and biochemistry-based screening program are difficult to rationalize. Furthermore, good communication, the main advantage of undertaking an ultrasound-only screening test in the presence of a health-care worker, is lost when women have to return home to await serum biochemical analysis and test results by telephone. These factors are further amplified by the effect of patient preference when undertaken over 2 visits, as in the integrated test. First, there is the issue of concealing potentially important information from the pregnant mother after an abnormal nuchal scan, and second the likelihood of poor compliance with the second trimester visits. For example, in the only large-scale prospective study of integrated testing of 47,053 women, more than 20% of women recruited failed to attend for the second-trimester biochemical test, and another 20% failed to complete all the screening test measures.17 It would seem that the ideal scenario for patients and health care providers is to offer a cheap single modality (ultrasonography or biochemistry) first-trimester test.
This study demonstrates that first-trimester screening for Down syndrome with single-modality ultrasound-based screening technique using nuchal translucency with either ductus venosus Doppler or nasal bones assessment has the potential to meet the expectations of parents and health care providers. The likely cost-effectiveness of such a technique, patient preference for a first-trimester test, and the practicalities of communicating test results directly to the patient justify the further evaluation of these ultrasound markers in a prospective setting.
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© 2005 The American College of Obstetricians and Gynecologists
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