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Ultrasound Findings After Screening for Down Syndrome Using the Integrated Test

Weisz, Boaz1; Pandya, Pranav P.1; David, Anna L.1; Huttly, Wayne2; Jones, Patricia1; Rodeck, Charles H.1

doi: 10.1097/01.AOG.0000260234.20190.6e
Original Research

OBJECTIVE: To evaluate the incidence and significance of fetal anomalies and “soft markers” after screening for Down syndrome using the integrated test.

METHODS: This study is a retrospective study of 2,332 women at University College London Hospitals, United Kingdom. All women were screened for Down syndrome by the integrated test. Subsequently, a detailed anomaly scan was performed. All scan reports and screening results were analyzed statistically using SPSS 11.0 software.

RESULTS: Sixty-eight (2.9%) patients were categorized as high risk. There were 12 cases affected by Down syndrome, 10 (10 of 68) in the high-risk group and two (two of 2,264) in the low-risk group. Soft markers or structural anomalies were found in 13.0% of the low-risk group, in 29.4% of the high-risk group, and in 50% of the fetuses affected by Down syndrome. Multiplying the likelihood ratio of each marker with the risk of Down syndrome from the integrated test reduced the false-positive rate of the integrated test from 2.5% to 1.8%, but was accompanied by a reduction in the detection rate from 83% to 75%.

CONCLUSION: Absence of structural anomalies or markers should not prevent offering karyotyping to women in the high-risk group, because this would result in a significant reduction in the detection rate of Down syndrome. Women screened as low risk by the integrated test who have isolated soft markers should not be offered an amniocentesis.


Isolated soft markers should not alter screening results obtained by the integrated test.

From the 1Department of Obstetrics and Gynaecology, University College London and 2Wolfson Institute of Preventive Medicine, St. Bartholomew’s and Royal London School of Medicine and Dentistry, London, United Kingdom.

Corresponding author: Dr. Boaz Weisz, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer 52621, Israel; e-mail:

Screening tests for Down syndrome use the maternal age-related risk and also incorporate both ultrasound and maternal serum biochemistry to optimize the detection rate and at the same time reduce the number of invasive procedures performed on unaffected pregnancies (false-positive rate). The integrated test combines first and second trimester markers. It uses nuchal translucency and pregnancy-associated plasma protein-A (PAPP-A) in the late first trimester and the quadruple test: alpha-fetoprotein (AFP), β-hCG, unconjugated estriol (uE3), and inhibin in the early second trimester (15–22 weeks of gestation; ideally, weeks 15–16). The integrated test gives a single risk estimation which is calculated only after the second trimester blood is analyzed. The major advantage of the integrated test is that it offers high detection rates of 94% and 85% with a false-positive rate of 5% and 1%, respectively.1 Thus, fewer women will need to undergo invasive testing with its inherent risk of miscarriage of up to 1%, and equally importantly, fewer women are made anxious about their pregnancy.2 Both the Serum Urine and Ultrasound Screening Study (SURUSS)3 and the First and Second Trimester Evaluation of Risk (FASTER) Trial (FASTER)4 studies have shown that the integrated test has a low false-positive rate (0.8–1.2% for detection rate of 85%).

Pregnancies affected by Down syndrome are associated with an increased risk of major fetal anomalies and specific ultrasound markers. These markers (“soft markers”) are structural changes detected at ultrasound scan which may be transient and in themselves have little or no pathologic significance (unlike fetal anomalies), but are more commonly found in fetuses with Down syndrome.5 Several groups have reported screening for Down syndrome based on the presence of fetal anomalies and specific soft markers on the mid-trimester anomaly scan (“genetic sonogram”).6–18 This method of screening has been mainly used to modify the maternal age-related risk of Down syndrome for women who had not had a prior screening test. Some studies have reported the application of ultrasound markers for modifying risks based on nuchal translucency19 or serum screening.14,20–22 The aim of this study is to report the incidence of ultrasound markers in a population screened by the integrated test and to evaluate the significance and effect of these markers on the risk of Down syndrome.

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This was a retrospective study of 2,332 women booked for antenatal care at University College London Hospitals from January 2003 to September 2004. All women completed screening for Down syndrome by the integrated test.1 Nuchal translucency measurement and plasma PAPP-A analysis were performed at 11–14 weeks and β-hCG, AFP, inhibin-A, and estriol at 15–22 weeks of gestation.

The technique used to measure nuchal translucency was as described by Nicolaides.23 All nuchal translucency measurements were performed in the routine ultrasound department by qualified ultrasound technicians (ultrasonographers or midwives) who were trained by one of the coauthors (P.P.P.). All biochemical analysis was performed at the Wolfson Institute of Preventive Medicine, Bart’s and the London School of Medicine and Dentistry. Fetal nuchal translucency was measured at 11–13 6/7 weeks (crown-rump length 44–84 mm). Patients with a nuchal translucency of 3.5 mm or more were referred to the Fetal Medicine Unit, where they had a repeat scan and counseling. These patients were offered invasive testing and subsequently excluded from the analysis because they did not complete the integrated test.

After the nuchal translucency measurement, blood was taken for routine obstetric care (booking bloods) and for measurement of PAPP-A. Patients returned at or after 15 weeks of gestation for the second component of the integrated test (ie, measurement of maternal serum AFP, β-hCG, uE3, and inhibin-A).

Risks for Down syndrome were calculated and interpreted by αlpha 6 software (Logical Medical Systems, London, United Kingdom). When reporting screening results to the women, absolute risk values were given with an explanation as to whether they fell into the group that would usually be offered karyotyping (“high risk” 1 in 150 or greater) or not (low-risk less than 1 in 150). All high-risk patients were seen within 48 hours of receiving the results for a detailed anomaly scan performed by a specialist in fetal medicine. These women were offered the option of an amniocentesis after performing a scan. Women considered to be at low risk for Down syndrome from the integrated test (risk lower than 1 in 150) were offered a 20-week detailed anomaly scan in the routine ultrasound department by a qualified ultrasonographer. When a structural anomaly was suspected, the scan was repeated by a fetal medicine specialist. All ultrasonographers and fetal medicine specialists reported soft markers (see below).

The definition of “high risk” used in the United Kingdom by the integrated test is risk of 1 in 150 or greater. Because the definition of “high risk” in the United States is defined of risk of 1 in 250 or greater, data will be presented for both cutoffs.

The soft markers that were recorded were echogenic intracardiac focus, defined as a bright discreet echogenic mass in the left or right ventricles of the heart, echogenic bowel was diagnosed when it appeared as bright as bone, renal pelvis dilatation was defined as an anterior–posterior diameter of the renal pelvis of 5 mm or more, increased nuchal fold thickness was defined as a thickness that was equal to or greater than 6 mm in the transcerebellar view, and short femur was defined as femur length below the fifth percentile for gestation. We excluded choroid plexus cysts and single umbilical artery because they are not specific markers for Down syndrome. Nasal bone assessment was not performed routinely during the study period and was not included in this study.

The risk of Down syndrome can be calculated by multiplying the risk of Down syndrome from the integrated test by the likelihood ratio for a specific defect (marker). When the marker is present (seen on scan) the likelihood ratio increases the risk of Down syndrome (positive likelihood ratio). If the marker is absent the risk is reduced (negative likelihood ratio). The likelihood ratio incorporates both the sensitivity and specificity of the test and is calculated by positive likelihood ratio=sensitivity/(1–specificity); negative likelihood ratio=(1–sensitivity)/specificity.24

Details on patients at booking and on pregnancy outcome were entered into the University College London Hospitals patient administration database. Ultrasound scan data were entered into a computer database at the time of the examination (Viewpoint software, General Electric Company, Fairfield CT). Results of the biochemical markers (absolute concentrations and calculated multiples of median, MoM), nuchal translucency MoM, and risk of Down syndrome were supplied by the Wolfson Institute of Preventive Medicine, Bart’s and The London, Queen Mary’s School of Medicine and Dentistry, London (Alpha software, Logical Medical Systems). Because this study was done as part of our institutional performance, it received institutional review board exemption.

Cases of Down syndrome were identified either by invasive prenatal diagnosis or by postnatal ascertainment, including local databases and obstetric and neonatal staff. These cases were additionally confirmed by data retrieved from the Antenatal DS Cytogenetic Register and Audit of Screening for Chromosomal Anomalies.

Statistics were calculated by the SPSS 12.0.1 statistical software (SPSS Inc., Chicago, IL). Significance level was set at P≤.05.

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During the study period, 2,377 women completed the integrated test. The mean maternal age was 31.7 (range 15–47) years. Detailed anomaly scan results were found in our database for 2,332 of 2,377 patients (98%) and included all “high-risk” patients (68 women defined by risk of 1 in 150 or greater or 92 women defined by risk of 1 in 250 or greater) and 2,264 of 2,311 (97.9%) of the “low-risk” patients (Table 1). The results of the integrated test show significantly higher MoM levels for nuchal translucency, inhibin-A, β-hCG (all P<.001) and lower MoM levels of AFP (t test; P<.001), PAPP-A (P=.008) and uE3 (P=.004) in Down syndrome cases (all Wilcoxon rank sum test).

Table 1

Table 1

The expected false-positive rate (for risk 1 in 150) for our study group based on maternal age distribution was 2.2%. The actual false-positive rate of the integrated test was 58 of 2,320 (cutoff 1:150; 2.5%, 95% confidence interval [CI] 1.9–3.2%; cutoff 1:250; 3.6%, 95% CI 2.8–4.3%). The detection rate of the integrated test was 10 of 12 (84%, 95% CI 55–95%); 2 of 2,264 (0.08%) pregnancies that were classified as low risk delivered neonates with Down syndrome.

The mean and standard deviation of PAPP-A, AFP, β-hCG, uE3 and inhibin-A were analyzed for when each marker was present or not seen. A short femur was significantly associated (t test; P<.01) with higher levels of β-hCG (1.70±3.40 compared with 1.27±0.95 MoM), AFP (1.44±1.78 compared with 1.08±0.80), inhibin-A (1.77±4.57 compared with 1.09±0.59), and lower levels of PAPP-A (0.91±0.58 compared with 1.21±0.70). Intracardiac echogenic focus, echogenic bowel, increased nuchal fold thickness, and renal pelvis dilatation were not correlated with altered levels of these biochemical markers.

Anomaly scans were performed at a mean gestational age (±standard deviation) of 16.9±1.4 weeks in the high-risk group and at 19.7±1.3 weeks in the low-risk group (P<.001, t test) (Table 2). The incidence of major structural malformations was significantly increased in the Down syndrome cases. The incidence of echogenic intracardiac focus, echogenic bowel, increased nuchal fold thickness, and a combination of any two or more soft markers were significantly increased in the Down syndrome cases. Overall, an “abnormal” scan (the presence of a structural anomaly or soft marker) occurred in 50% of the Down syndrome cases and in 12.7% of fetuses without Down syndrome (P<.01). Isolated soft markers were found in 10.9% fetuses without Down syndrome and this incidence was not significantly increased in Down syndrome cases (P=.52).

Table 2

Table 2

Three of the ultrasound soft markers (short femur, echogenic intracardiac focus, and echogenic bowel), and a combination of two or more soft markers were found more commonly in patients who had a high-risk screening result in comparison with the low-risk group (Table 3). The incidence of isolated soft markers was significantly increased by almost two-fold (10.6% compared with 19.1%, P=.02) in the high-risk group. However, the only isolated soft marker significantly associated with “high-risk” patients was a short femur.

Table 3

Table 3

Five of 10 of the Down syndrome cases within the “high-risk” group had an abnormal scan (either a structural anomaly or an isolated soft marker). Cases of Down syndrome within the high-risk group were more likely to have major structural anomalies (40% compared with 3.4%, P<.01) or the presence of two or more soft markers (20% compared with 1.7%, P<.01). However, the rate of isolated soft markers was not significantly increased in this group.

The proportion of Down syndrome cases in the low-risk group was too small (1 in 1,132) to assess the implication of ultrasound markers for detection of Down syndrome in this study. In this group, 1.0% had a structural anomaly, 0.61% had two or more soft markers, and 10.6% had an isolated soft marker. One of the two undiagnosed Down syndrome cases in this group had a single intracardiac echogenic focus (risk 1 in 770 by the integrated test), whereas the other one had a normal scan (risk 1 in 7,700).

The positive likelihood ratio and negative likelihood ratio in our cohort are presented in Table 4. In our cohort, echogenic intracardiac focus, echogenic bowel, increased nuchal fold thickness, the presence of two (or more) soft markers, and major structural anomalies had a statistically significant positive likelihood ratio for Down syndrome. Several studies recommend combining results of two separate sequential screening modalities by multiplying the likelihood ratio of the new findings with a previous screening result.26,27 To assess the influence of ultrasound findings on the risk calculation of our cohort of patients, we analyzed the new risk of Down syndrome based on the positive and negative likelihood ratio derived from this cohort. Because our cases of Down syndrome are limited (resulting in wide confidence intervals), we have also analyzed the new risk based on likelihood ratio presented in the literature.26 Table 5 presents the proportion of women considered at high risk for Down syndrome, using two risk cutoffs, less than 1 in 150 and more than 1 in 250, and the detection rate of Down syndrome in each group. The adjustment of the risks and using a cutoff of 1 in 150 resulted in an approximate 28% (19 women) fall in the number of women who screened positive. However, the detection rate decreased as well from 83% to 75% (likelihood ratio derived from this study) or 66% (likelihood ratio derived from the literature). Similar results are obtained using the 1 in 250 cutoff (29 women, ie, 32% reduction in screen positive women but the detection rate decreased from 83% to 75%).

Table 4

Table 4

Table 5

Table 5

Another option is calculating the new risk only for patients within the low-risk group. In our cohort, 13 patients within the low-risk group would have a new risk greater than 1 in 150 based solely on the presence of soft markers. This implies an increase of 0.5% of the false-positive rate without decreasing the detection rate.

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This is the first study to describe the incidence and significance of ultrasound markers in a population screened by the integrated test (PubMed, no language limitations; January 1999 through December 2006; search terms “Down syndrome,” “Down’s syndrome,” “integrated test,” “soft marker,” “sonogram”). The incidence of structural anomalies and soft markers in our study are similar to previous studies.10,13

To date, the three most effective screening strategies for Down syndrome are the first trimester combined test (nuchal translucency, PAPP-A, and β-hCG) with a detection rate of 77–90%,26,27 for a false-positive rate of about 5%, the serum integrated test (PAPP-A in the first trimester and β-hCG, AFP, inhibin, and uE3 in the second trimester), with 83% detection rate for 5% false-positive rate, and the integrated test (addition of nuchal translucency to serum integrated test) with an 83% detection rate for a 0.9% false-positive rate.26 In our hospital we have chosen the integrated test to screen for Down syndrome because it offers the lowest false-positive rate and is most cost-effective.28 Using a cutoff risk of 1 in 150, the expected false-positive rate in our population was 2.2% with an expected detection rate of 90%.

For the individual woman and her clinician, the results of the anomaly scan raise two possible considerations:

  1. Does the absence of an anomaly or soft marker modify the risk of Down syndrome in a woman screened high risk by the integrated test to reduce the false-positive rate and avoiding invasive prenatal diagnosis?
  2. Does an isolated soft marker or combination of markers in women screened as low risk for Down syndrome by the integrated test indicate the need for invasive prenatal diagnosis?

The interpretation and significance of soft makers markers is controversial,29 although in an unscreened population all the soft markers described in this study have been shown to be associated with Down syndrome.14 Half of the Down syndrome cases within the “high-risk” group had a completely normal scan. It should be emphasized that these scans were performed by physicians who were not blinded to the integrated test result and the level of suspicion (for an abnormality) was high. Therefore, in our opinion, a normal ultrasound scan should not be used as an argument for avoiding invasive prenatal testing in cases already screened by the integrated test.

Most authors agree that the main indications for invasive prenatal diagnosis based on the anomaly scan alone are an increased nuchal fold, existence of two soft markers or a major structural anomaly30 and that an isolated soft marker should not be the sole indication for amniocentesis. These indications yielded a 75% detection rate detection rate with 5.7% false-positive rate for Down syndrome,13 and combining this with the maternal age-related risk of Down syndrome increased the detection rate to 86.8%, with false-positive rate of 27.1%.16 In our cohort, using such a scoring system alone would have detected only five of 12 cases of Down syndrome, with a 4.5% false-positive rate. Due to the very small proportion of Down syndrome cases in the low-risk population, applying such a sequential (two-stage) screening policy would significantly increase the false-positive rate (resulting in an additional 99 “high-risk” cases) without improving the detection rate. Therefore, applying these indications sequentially after performing the integrated test (as a two-staged screening) is not beneficial.

The presence or absence of soft markers can be used to alter the risk of Down syndrome by multiplying the result of a previous screening test by a positive or a negative likelihood ratio, respectively.25 In this study, we show that such a method of risk adjustment based on ultrasound markers using the likelihood ratio of each marker (for all patients)10,13,25 decreased the false-positive rate and increased the positive predictive value of the test, but it was accompanied by a decrease in the detection rate (Table 5). We consider that because the false-positive rate is already small after screening by the integrated test, a further decrease in the false-positive rate at the expense of lowering the detection rate would not be clinically beneficial in most cases. A possible implementation of such scheme (which needs to be evaluated in a larger cohort) might be to adjust the risks only of those patients considered low-risk and to offer amniocentesis to those whose risk is increased to 1 in 150 or greater. Alternatively, it is possible that newer markers with a high correlation with Down syndrome which were not included in our study such as nasal bone hypoplasia31,32 might improve the detection provided by the integrated test.

A normal ultrasound scan should not change the recommendation to patients that are screened as “high risk” by the integrated test. Due to the small numbers of Down syndrome cases that occurred in the low-risk group, we would recommend that the ultrasound findings are used to assess the need for amniocentesis in this group. If a major defect is suspected, it is advisable to offer fetal karyotyping, even in the low-risk group. The prevalence of such defects is low (1.0%), and therefore the cost implications are small. If the defects are either lethal or they are associated with severe handicap, such as hydrops or duodenal atresia, fetal karyotyping constitutes one of a series of investigations to determine the possible cause and thus the risk of recurrence. If the defect is potentially correctable by intrauterine or postnatal surgery, such as diaphragmatic hernia, it may be logical to exclude an underlying chromosomal abnormality—especially because, for many of these conditions, the usual abnormality is trisomy 18 or 13. Minor fetal defects or soft markers are very common and they are not usually associated with any handicap, unless there is an underlying chromosomal abnormality. Routine karyotyping of all pregnancies with these markers would have major implications, both in terms of miscarriage and in economic costs. Therefore, in the low-risk group, it is best to counsel on an individual estimated risk for a chromosomal abnormality based on the result of the integrated test.

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© 2007 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.