Review Article

Sonographic Markers
of Fetal Trisomies
Second Trimester
David A. Nyberg, MD, Vivienne L. Souter, MD, MRCOG

Objective. Second-trimester sonographic findings of fetal trisomy may include structural abnormali-
ties or sonographic markers of fetal aneuploidy. Unlike structural anomalies, sonographic markers of
fetal aneuploidy are insignificant by themselves with regard to outcome, are nonspecificmost fre-
quently seen in normal fetuses, and are often transient. Our objective was to review the second-
trimester sonographic findings of the major trisomic conditions, trisomies 13, 18, and 21. Methods.
We reviewed a number of the most commonly accepted markers, including nuchal thickening, hyper-
echoic bowel, echogenic intracardiac focus, renal pyelectasis, shortened extremities, mild cerebral ven-
tricular dilatation, and choroid plexus cysts. Markers associated with trisomy 21 were emphasized.
Results. The sensitivity of sonography for detection of fetal trisomic conditions varies with the type of
chromosome abnormality, gestational age at the time of sonography, reasons for referral, criteria for
positive sonographic findings, and the quality of the sonography. As an estimate, 1 or more sono-
graphic findings can be identified in approximately 90% of fetuses with trisomy 13, 80% of fetuses
with trisomy 18, and 50% to 70% of fetuses with trisomy 21 (Down syndrome). Conclusions. The
presence or absence of sonographic markers can substantially modify the risk of fetal Down syndrome
and is the basis of the so-called genetic sonogram. Because maternal biochemical and sonographic
markers are largely independent, combined risk estimates will result in even higher detection rates
than either alone. Key words: trisomy 21; trisomy 18; trisomy 13; Down syndrome; prenatal sonog-
raphy; nuchal thickening; hyperechoic bowel; echogenic intracardiac foci; pyelectasis; choroid plexus
cyst; ventricular dilatation.

S
Abbreviations
AAURA, age-adjusted ultrasound risk assessment; EIF,
echogenic intracardiac foci; hCG, human chorionic
gonadotropin; IUGR, intrauterine growth restriction;
SMFA, sonographic markers of fetal aneuploidy
Received February 14, 2001, from the Center for
Perinatal Studies, Seattle Medical Center (D.A.N.),
and Departments of Radiology (D.A.N.), Obstetrics
and Gynecology (D.A.N.), and Genetics (V.L.S.),
University of Washington Medical Center, Seattle,
Washington. Revision requested February 20, 2001.
Revised manuscript accepted for publication
February 20, 2001.
Address correspondence to David A Nyberg,
MD, 1229 Madison St, 1150, Seattle, WA 98104.
onography can show abnormalities in many fetus-
es with chromosomal aberrations.1,2 These may
include both major or structural defects and non-
structural findings, also known as sonographic
markers. Unlike structural anomalies, sonographic mark-
ers of fetal aneuploidy (SMFA) are insignificant by them-
selves with regard to outcome, are nonspecificmost
frequently seen in normal fetuses, and are often tran-
sient. The most common SMFA in the second trimester
are nuchal thickening, hyperechoic bowel, shortened
extremities, renal pyelectasis, echogenic intracardiac foci
(EIF), and choroid plexus cysts.
Table 1 summarizes the common structural anomalies
and sonographic markers associated with the 3 common
trisomic conditions (trisomies 13, 18, and 21). Although
each trisomic condition has a typical phenotype, there is
wide variation in phenotypic expression. The sensitivity of
sonography for detecting these abnormalities varies with
a number of factors, including the type of chromosome
abnormality, gestational age at the time of sonography,

2001 by the American Institute of Ultrasound in Medicine J Ultrasound Med 20:655674, 2001 0278-4297/01/$3.50
Sonographic Markers of Fetal Trisomies: Second Trimester

Table 1. Common Structural Anomalies and Sonographic Markers Associated With the 3 Common Trisomic Conditions
Trisomy 21 Trisomy 18 Trisomy 13

Major anomalies Cardiac defects Cardiac defects Cardiac defects

Duodenal atresia Spina bifida Central nervous system abnormalities
Cystic hygroma Cerebellar dysgenesis Facial anomalies
Micrognathia Cleft lip/palate
Omphalocele Urogenital anomalies
Clenched hands/wrists Echogenic kidneys
Radial aplasia Omphalocele
Club feet Polydactyly
Cystic hygroma Rocker-bottom feet
Cystic hygroma
Markers Nuchal thickening* Choroid plexus cysts* EIF*
Hyperechoic bowel* Brachycephaly IUGR
EIF* Shortened limbs Pyelectasis
Shortened limbs* IUGR Single umbilical artery
Pyelectasis* Single umbilical artery
Mild ventriculomegaly*
Clinodactyly
Sandal gap
Widened pelvic angle
Pericardial effusion
Right-left heart disproportion
*Discussed in greater detail in text.

reasons for referral, criteria for positive sonograph-
ic findings, and the quality of the sonography.
As an estimate, major or structural abnormali-
ties are seen in 20% of fetuses with trisomy 21
(Down syndrome) during the second trimester,
whereas they are seen in most fetuses with tri-
somies 18 and 13.37 Combined with SMFA,
sonographic findings are identified in approxi-
mately 50% to 70% of fetuses with Down syn-
drome, 80% of fetuses with trisomy 18, and 90%
of fetuses with trisomy 13. This emphasizes the
potential importance of nonstructural markers
in detection of fetal trisomy.
In the following sections, we review the
second-trimester sonographic findings of the
major trisomic conditions, trisomies 13, 18,
and 21. We emphasize fetal Down syndrome
because it is the most common trisomic con-
dition, the most likely to result in a surviving
neonate, and the most likely to show SMFA
without structural anomalies.
Trisomy 13
mon malformations detected are facial abnor-
malities, including cyclopia, hypotelorism, and
cleft lip and palate (Fig. 1A), renal cystic dysplasia
or hydronephrosis, cardiovascular malforma-
tions, cystic hygroma, polydactyly, and club or
rocker-bottom feet.
Markers
Nonspecific markers of trisomy 13 may include
mild dilatation of the lateral cerebral ventricles,
hyperechoic bowel, and EIF. Lehman et al6 report-
ed EIF in 39% of fetuses with trisomy 13 before 20
weeks. Multiple EIF probably increase the risk of
aneuploidy, including trisomy 13 (Fig. 1B). The
combination of EIF and a hypoplastic-appearing
left side of the heart is a characteristic pattern of
trisomy 13 (Fig. 2).6 We have encountered 1 case
of trisomy 13 in which multiple EIF was the only
sonographic finding and several other cases in
which EIF was the initial finding that led to
detection of other subtle anomalies. Because of
its association with trisomy 21, EIF is discussed
further below (see Trisomy 21).

In trisomy 13, malformations of the central ner- Trisomy 18

vous system are common. These may include
holoprosencephaly, agenesis of the corpus callo- A wide diversity of sonographic and pathologic
sum, Dandy-Walker malformation, vermian abnormalities have been associated with trisomy
agenesis, and neural tube defects. Other com- 18 during the second trimester, including cystic

656 J Ultrasound Med 20:655674, 2001

 Nyberg and Souter

A B
Figure 1. Trisomy 13. A, Bilateral cleft lip and plate. Coronal view of the face shows features of bilateral cleft lip and palate, seen as premaxillary pro-
trusion (arrows). O indicates orbits. B, Bilateral EIF. Transverse view of the heart with the apex away from the transducer shows prominent bilateral EIF
(arrows). No other abnormalities were identified in this fetus. LV indicates left ventricle; RV, right ventricle; and Sp, spine.

hygroma, nonimmune hydrops, hydrocephalus,
spina bifida, diaphragmatic hernia, tracheo-
esophageal fistula, genitourinary anomalies,
cardiovascular malformations, and omphalo-
cele. Subtle abnormalities may include ver-
mian agenesis and8,9 small-bowelcontaining
omphalocele (Fig. 3),10,11 Skeletal abnormalities
are common and include clenched hands (Fig.
4),12,13 club feet, and radial aplasia or limb short-
ening. In the third trimester, some fetuses with
trisomy 18 may primarily have intrauterine
growth restriction (IUGR), which is often associ-
ated with polyhydramnios.
Markers
Subtle or nonstructural findings of trisomy 18
may include choroid plexus cysts, brachy-
cephaly or strawberry-shaped head,14 and sin-
gle umbilical artery.15 Of these, choroid plexus
cysts (Fig. 5) have been the most controversial
and the subject of considerable interest.1621 Like
other SMFA, choroid plexus cysts are a relatively
common variant during the second trimester,
are transient, and have no known effect on fetal
development. Unlike some of the other potential
markers (e.g., nuchal thickening and hyper-
echoic bowel), choroid plexus cysts have no
known association with other adverse outcomes
when the karyotype is normal.
Variables that may influence detection of
choroid plexus cysts include gestational age, the
thoroughness of the sonography, the threshold
for calling a finding a choroid plexus cyst, under-
lying risk factors, and reasons for referral. It
should be noted that studies that restrict
patients to those with known karyotypes may be
biased, because sonographic findings influence
patients decisions about invasive testing. High-
risk patients with SMFA are more likely to under-
go invasive testing than low-risk patients with
the same findings. For this reason, a higher risk
will be found among patients who choose inva-
sive testing compared with patients who do not.
Snijders et al22 reported that among 107 fetuses
with isolated choroid plexus cysts who had kary-
otyping, 2 had chromosome defects (1 each of
trisomy 18 and 21), whereas no chromosome
abnormality was found among the 174 fetuses

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Sonographic Markers of Fetal Trisomies: Second Trimester
Figure 2. Trisomy 13 and EIF. Four-chamber view of the heart shows EIF (arrow) in
the left ventricle and the disproportionately smaller size of the left ventricle and left
atrium compared with the right-sided chambers. A ventricular septal defect is also
present. Other anomalies included single umbilical artery and probable cleft lip and
palate. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right
ventricle.
Figure 3. Trisomy 18 and omphalocele. Transverse view of the abdomen at 17
weeks shows small-bowelcontaining omphalocele (arrows). A strawberry-shaped
head was also present. Sp indicates spine.
658
with choroid plexus cysts who did not have
amniocentesis. Similar results can be found with
other SMFA.
The prevalence of choroid plexus cysts in the
general population has been reported as 0.5% to
3.6%, with most studies reporting in the range of
1% to 2%.23,24 At our own center, which has high-
risk patients, we observe choroid plexus cysts in
approximately 3.5% of fetuses at 14 to 20 weeks.
In comparison, choroid plexus cysts are
observed in 30% to 40% of fetuses with trisomy
18 before 20 weeks. This might suggest a high risk
for trisomy 18 when choroid plexus cysts are
identified prenatally. However, because most
fetuses with trisomy 18 have other abnormalities,
the risk from isolated choroid plexus cysts is rela-
tively low.
Snijders et al22 observed choroid plexus cysts in
50% of fetuses with trisomy 18 and 1% of karyo-
typically normal fetuses. They found that isolated
choroid plexus cysts carried only a marginally
increased risk (likelihood ratio <2) for trisomy
18, but the presence of another abnormality
increased the risk approximately 20 times
(Table 2). The authors suggested that maternal
age should be the main factor in deciding
whether to offer fetal karyotyping when isolated
choroid plexus cysts are detected. Similar opin-
ions have been reached by a number of other
authorities, including Chitty et al,25 who evalu-
ated 658 fetuses with choroid plexus cysts.
Two meta-analyses found higher likelihood
ratios for isolated choroid plexus cysts and tri-
somy 18 compared with that of Snijders et al.22
Ghidini and colleagues26 observed that isolated
choroid plexus cysts were detected in 6.7% (13 of
194) of fetuses with trisomy 18 and 0.9% (752 of
79,583) of control fetuses, yielding a likelihood
ratio of 7.1. In another report, Yoder et al27 evalu-
ated 13 prospective studies comprising 246,545
second-trimester scans and found a likelihood
ratio of 13.8 for trisomy 18. Despite this relatively
high likelihood ratio, the authors concluded that
fetal karyotyping should be offered only when
maternal age at delivery is 36 years or older or
when the risk for trisomy 18 detected by serum
multiple-marker screening is more than 1 per
3000.
Among other variables, there is good evidence
to suggest that larger choroid plexus cysts further
increase the risk of trisomy 18 compared with
smaller cysts (Fig. 6).2832 Such large cysts
undoubtedly take longer to resolve, supporting
J Ultrasound Med 20:655674, 2001
 Nyberg and Souter

Figure 4. Trisomy 18 and clenched hand. A typical clenched hand (H) Figure 5. Trisomy 18 and choroid plexus cyst. Image of the head at
is shown. 18 weeks shows a typical choroid plexus cyst (arrow) measuring 5 mm.
Other abnormalities in this case included a diaphragmatic hernia, a car-
diac defect, and probably micrognathia.

observations that delayed resolution of choroid
plexus cysts carries an increased risk for trisomy
18. Whether the cysts are unilateral or bilateral
does not appear to be significant, although it is
probably true that large cysts also tend to be
bilateral.
All of these findings indicate that detection of a
choroid plexus cyst, as with any SMFA, should
initiate a renewed search for other abnormalities.
A choroid plexus cyst can be presumed to be iso-
lated only after a detailed fetal survey fails to
show structural abnormalities or other SMFA. As
an isolated finding after high-quality sonogra-
phy, and assuming the patient is otherwise con-
sidered at low risk for fetal aneuploidy, we think
that detection of choroid plexus cysts should not
alter obstetric management. Additional reassur-
ance can be obtained by correlating sonographic
findings with serum biochemical markers.33,34
Because choroid plexus cysts always resolve,
follow-up sonography is of no value in decision
making unless it is done to detect other abnormal-
ities that were previously missed (e.g., cardiac
defects).
Trisomy 21
Structural or major abnormalities in trisomy 21
include cardiac defects, hydrops, and cystic
hygroma. Rarely, duodenal atresia can also be
seen before 20 weeks, especially when com-
bined with esophageal atresia.3537
Figure 6. Trisomy 18 and large choroid plexus cyst. A large choroid plexus cyst (C)
measuring 16 mm in length is shown in the dependent ventricle. No other sono-
graphic abnormalities were identified in this case.

Table 2. Approximate Risk of Trisomy 18 in Fetuses

With Choroid Plexus Cysts
Gestational Baseline Isolated Other
Age, wk Risk Cyst Abnormalities

2024 1:4500 1:2950 1:225

2529 1:3600 1:2300 1:175
3034 1:2000 1:1300 1:100
3539 1:750 1:470 1:35
4044 1:400 1:100 1:10
Data from Snijders et al.22

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Sonographic Markers of Fetal Trisomies: Second Trimester
Compared with fetuses with trisomies 18 and
13, fetuses with trisomy 21 are unlikely to have
structural abnormalities before 20 weeks. Sohl et
al38 found major abnormalities in 16.4% of fetus-
es with trisomy 21, and we found major abnor-
malities in 16.7% before 20 weeks, after exclusion
of patients referred for sonographically detected
abnormalities.39 A slightly higher frequency
(21.8%) of structural abnormalities was found in
a previous study at our center, but that study
included referred patients and also categorized
mild ventricular dilatation as a major abnormal-
ity for consistency with previous studies.40,41
Studies that include patients referred for sono-
graphically detected abnormalities will have a
higher rate of major abnormalities.
The low detection rate of structural abnormali-
ties reflects the low sensitivity of sonography for
detection of cardiac defects among fetuses with
trisomy 21 before 20 weeks. We consistently
detect cardiac defects in less than 10% of fetuses
with trisomy 21, although the mean gestational
age at the time of scanning is 16.9 weeks for these
pregnancies. Improved detection of cardiac
defects would be expected even a few weeks
later. Using nonspecific cardiac findings, such as
right-left disproportion, pericardial effusion, and
tricuspid regurgitation, DeVore et al42 reported
cardiac findings in 76% of fetuses with trisomy
21, but just 9% had an endocardial cushion
defect. The mean gestational age for sonography
in that study was also 18 weeks.
A study by Paladini and colleagues43 suggested
what is possible under ideal conditions. Scanning
at an optimal gestational age (24 weeks), under
optimal conditions (in a dedicated fetal echo-
cardiographic center), with inclusion of subtle
ventricular septal defects, and with previous
knowledge of fetal karyotype, they were able to
detect heart defects in just more than half of
fetuses with Down syndrome.
Markers
A large number of potential SMFA have been
described in association with trisomy 21 during
the second trimester (Table 1).40,41,4447 Among
these, we routinely evaluate nuchal thickening,
hyperechoic bowel, EIF, shortened limbs, and
pyelectasis, because they can be easily sought
during the course of routine second-trimester
sonography. Other potential markers include a
widened pelvic angle,4851 shortened frontal
lobes,52,53 small ears,54 clinodactyly,55 pericardial
660
effusion, and right-left disproportion of the
heart, among others. Another potential marker
for trisomy 21, although not related to fetal
anatomy, is unfused amnion and chorion after 14
weeks.56
The sensitivities of most sonographic markers
are low, particularly compared with that of
nuchal translucency in the first trimester (Table 3).
However, the incremental value of each marker
improves the overall sensitivity of second-
trimester sonography so that 1 or more markers
are observed in more than 50% of fetuses with
trisomy 21 at our center. When SMFA are com-
bined with major abnormalities, our overall sen-
sitivity of second-trimester sonography is 69%.
The use of sonographic markers, usually a
panel of markers, to modify the risk of fetal Down
syndrome is widely referred to as a genetic sono-
gram. The actual sensitivity of a genetic sono-
gram will depend on various factors, including
the markers sought, gestational age, reasons for
referral,56A and, of course, the quality of the
sonography. Considering these variables and dif-
ferences in the types of sonographic markers
used (Table 4), the results for genetic sonograms
from different centers are surprisingly similar
(Table 5). Reported detection rates have ranged
from 59% to 82%. Detection rates exceeding 90%
have even been reported, including a high detec-
tion rate for cardiac abnormalities.42
The risk of fetal trisomy 21 increases dramati-
cally with the number of markers present (Table
6). Two or more markers are detected in nearly
one third of fetuses with trisomy 21 at our center,
compared with less than 2% in normal fetuses. In
comparison, a single marker is observed in more
than 11% of normal fetuses compared with
22.6% of fetuses with trisomy 21. Similarly, Sohl
et al38 observed a single marker in 14.6% of nor-
mal fetuses. On the basis of these data, a single
Table 3. Frequency of Sonographic Markers
(Without Structural or Major Abnormalities) in
Fetuses With Trisomy 21
Sonographic Marker Trisomy 21 (n = 186), %
Nuchal thickening 32.3
Hyperechoic bowel 17.2
Short humerus 18.3
Short femur 26.3
EIF 23.1
Pyelectasis 11.3
Data from Swedish Medical Center (Seattle, WA).
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 Nyberg and Souter

Table 4. Components of the Second-Trimester Genetic Sonogram Reported in Various Studies for Detection
of Fetal Down Syndrome
Report Nuchal Humerus Femur Renal HB EIF CC Other
41
Benacerraf et al + + + + + +
DeVore134 + + + + + +
Nyberg et al45 + + + + + +
Bahado-Singh et al71 + + + +
Vergani et al47 +
Sohl et al38 + + + + +
Vintzileos56A + + + + + + + +++
CC indicates choroid plexus cysts; HB, hyperechoic bowel; and +++, multiple other findings.

marker increases the risk 2-fold; 2 markers
increase the risk nearly 10-fold; and 3 or more
markers increase the risk more than 100-fold.
The actual risk will depend on the type as well as
the number of markers present.
The use of multiple sonographic markers will
improve the sensitivity of sonography for detec-
tion of fetal Down syndrome but at the cost of a
higher false-positive rate if the presence of any sin-
gle marker is considered a positive finding. This
high false-positive rate can understandably lead to
considerable anxiety57 and inconsistent manage-
ment58 among low-risk patients. Sonologists
should attempt to minimize these false-positive
results among low-risk patients but should maxi-
mize the sensitivity in high-risk patients.
To optimize clinical management of sono-
graphic markers, Benacerraf and colleagues40,41
devised a scoring index in which 2 points are
given for structural abnormalities or nuchal
thickening and 1 point is given for the other
markers. Amniocentesis is offered to those with
a score of 2 or greater. This approach avoids the
false-positive rates from a single marker, except
for nuchal thickening, which is appropriately
considered a high-risk marker. The scoring
index system can be modified to incorporate
maternal age by giving 1 point for women 35
years of age or older and 2 points for women 40
years of age or older (Table 7).59 With this modi-
fication, a single sonographic marker would be
considered a positive result for higher-risk
women 35 to 39 years of age, and advanced
maternal age alone would be sufficient criteria
for women 40 years of age or older. A primary
advantage of the scoring index method is that it
is easy to use and understand.
Another method of optimizing sonographic
findings is to integrate the risk of sonographic
markers with the a priori risk based on maternal
age. This has been termed age-adjusted ultra-
sound risk assessment (AAURA) for Down syn-
drome.45 The sonographic markers are weighted
by the strength of individual findings, expressed
as likelihood ratios (Table 7). The post priori risk
is estimated by the likelihood ratios, and the a
priori risk is based on maternal age (Table 8).
When AAURA is used, both the sensitivity of
fetal Down syndrome and the false-positive rate
increase with maternal age. This is appropriate

Table 5. Sensitivities and False-Positive Rates Reported for Genetic Sonograms From Different Centers
Report n Sensitivity, % FP rate, % LR LR Negative
41
Benacerraf et al 45 73 4.4 16.5 0.28
DeVore134 15 73 7.4 9.9 0.29
Bromley et al59 53 75 5.7 13.1 0.27
Nyberg et al45 142 74 14.7 5 0.30
Bahado-Singh et al71 24 60 4.5 13.3 0.41
Bahado-Singh et al73 31 73.5 15 4.9 0.31
Vergani et al47 22 59 5.3 11.1 0.43
Sohl et al38 55 67 19.4 3.5 0.41
Vintzileos56A 34 82 9 9.1 0.20
Nyberg et al39 186 69.9 13.3 5.3 0.36
FP indicates false-positive; and LR, likelihood ratio. LR = sensitivity/FP rate; and LR negative = false negative rate/speci-
ficity = (1 sensitivity)/(1 FP rate).

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Sonographic Markers of Fetal Trisomies: Second Trimester

Table 6. Comparison of Number of Markers in Fetuses With Down Nuchal Thickening

Syndrome and Controls
Redundant skin at the back of the neck is a
No. of Markers Down Control characteristic clinical feature of infants with
or Major Syndrome (N = 8712),
trisomy 21 and was first reported by Down in
Abnormality (n = 186), % (n) % (n) LR
1866.64 Benacerraf and coworkers6567 first
0 31 (58) 86.7 (7541) 0.36 reported the sonographic correlate of this clin-
1 22.6 (42) 11.3 (987) 2.0
ical feature in terms of nuchal thickening dur-
2 15.1 (28) 1.5 (136) 9.6
3+ 14.5 (27) 0.1 (11) 115 ing the second trimester (Fig. 7), and thus
Major abnormality 16.7 (31) 0.4 (37) 39.2 began the search for other sonographic mark-
LR indicates likelihood ratio; LR = percent Down syndrome cases/control
ers. Nuchal thickening remains one of the
cases. most sensitive and important markers of tri-
somy 21 during the second trimester. Indeed,
although other criteria vary among centers,
because older women desire high sensitivity, and nuchal thickening is universally used as a
the clinical alternative is amniocentesis for all marker for trisomy 21. Although the sensitivity
women 35 years of age or older (100% false-pos- and false-positive rates will vary with gesta-
itive rate). At the same time, AAURA minimizes tional age and the exact criteria for a positive
the false-positive rate for younger women (4% finding, sensitivities in the range of 20% to 40%
false-positive rate) but still has satisfactory sen- are most common.
sitivity (61.5%). Very similar results can be On the basis of early experience, Benacerraf et
obtained with the modified scoring index al65 suggested that a threshold of 6 mm or
method, which incorporates maternal age, greater after 15 weeks indicated a high risk of
although AAURA has the advantage of providing trisomy 21. However, in a subsequent study
a patient-specific risk estimate.60 Because sono- they observed that none of 303 normal fetuses
graphic findings appear to be largely indepen- showed nuchal thickening of greater than 5
dent of both maternal age and biochemical mm up to 20 weeks.66 Several prospective stud-
analytes,6163 we think that the risk from bio- ies have since suggested that 5 mm is a better
chemical screening (serum markers plus mater- threshold, which results in improved sensitivity
nal age risk) can be substituted for maternal age and only a slight increase in the false-positive
risk alone when known. rate. We have used a 5-mm cutoff for the last 10
AAURA, or any method of risk assessment, years.6870
requires knowledge of the risks associated with A number of studies have shown that normal
individual sonographic markers. In the follow- nuchal thickness varies with gestational age,
ing sections, individual markers are discussed which should not be surprising. This suggests
in greater detail. that, as a further refinement, gestational age-
specific criteria should be used for increased
nuchal thickness rather than a single cutoff.7173
Table 7. Comparison of 2 Methods for Assessing the Risk of Fetal Gestational age-specific criteria may include
Down Syndrome Based on Sonographic Findings: AAURA and the observed-to-expected or observed-minus-
Index Scoring System expected nuchal thickness or a comparison of
Sonographic Finding LR (AAURA) Index Score nuchal thickness with other biometric mea-
surements, such as biparietal diameter and
Structural defect 25 2
Nuchal thickening 11 2 femur and humerus length. The use of multi-
Hyperechoic bowel 6.7 1 ple-of-the-median data, comparing the actual
Short humerus 5 1 nuchal measurement with the expected mea-
EIF 1.8 1 surement, would permit calculation of likeli-
Short femur 1.5 1
hood ratios and would also permit integration
Pyelectasis 1.5 1
Age 3539 y Risk based on age (Table 8) 1 with maternal serum biochemical markers for
Age 40+ y Risk based on age (Table 8) 2 a combined risk. Bahado-Singh and coworkers
If normal 0.4 0 have reported multiples of the median and esti-
Likelihood ratios (LR) reported are those calculated as isolated markers, mated likelihood ratios.7173
from Nyberg et al.39 Slightly different likelihood ratios were assumed pre-
viously in the description of AAURA.45

662 J Ultrasound Med 20:655674, 2001

 Nyberg and Souter

Hyperechoic Bowel
Like other nonstructural markers, hyperechoic
bowel is nonspecific and is most commonly
observed in normal fetuses. However, it is
observed with increased frequency in fetuses
with aneuploidy, including trisomy 21 (Fig. 8).7478
Hyperechoic bowel has also been reported in
association with bowel atresia, congenital infec-
tion, and, rarely, meconium ileus secondary to
cystic fibrosis.79,80 An increased risk of IUGR,
fetal death, and placenta-related complications
is also recognized as being associated with
hyperechoic bowel.81
Despite its subjectivity, the prevalence of
hyperechoic bowel among normal fetuses
(0.5%) has been remarkably consistent at our
center in the last decade and is also similar to Figure 7. Trisomy 21 and nuchal thickening. Mild nuchal thickening is shown
that in other reports, suggesting that different (6 mm), delineated by calipers.
centers can agree on the presence of hyper-
echoic bowel. We use a grading system for
hyperechoic bowel, with grade 1 being mildly
echogenic and typically diffuse, grade 2 being cy,83 although this effect is uniform, whereas true
moderately echogenic and typically focal, and hyperechoic bowel tends to be focal. To mini-
grade 3 being very echogenic, similar to that of mize subjectivity, some authors consider only
bone structures.82 The echogenicity of normal bowel that is markedly hyperechoic, whereas we
bowel also increases with transducer frequen- and others84,85 recognize both moderate and
markedly hyperechoic bowel (grades 2 and 3) as
Table 8. A Priori Risk of Down Syndrome, Expressed a risk factor for fetal aneuploidy (Fig. 8). If only
as Odds Ratio, Based on Maternal Age During the grade 3 hyperechoic bowel were recognized, the
Second Trimester sensitivity would be decreased, but the risk (like-
Age, y Odds Ratio lihood ratio) would be increased.
20 1:1176
21 1:1160
22 1:1136 Figure 8. Trisomy 21 and hyperechoic bowel (HB). Moderately echogenic bowel is
23 1:1114 shown; it is not quite as echogenic as the adjacent bone. H indicates heart; and
24 1:1087 IW, iliac wing.
25 1:1040
26 1:990
27 1:928
28 1:855
29 1:760
30 1:690
31 1:597
32 1:508
33 1:421
34 1:342
35 1:274
36 1:216
37 1:168
38 1:129
39 1:98
40 1:74
41 1:56
42 1:42
43 1:31
44 1:23

J Ultrasound Med 20:655674, 2001 663

Sonographic Markers of Fetal Trisomies: Second Trimester

Skeletal Abnormalities the anteroposterior renal pelvic diameter

increased with maternal hydration in both nor-
Short stature is a characteristic feature of children
mal fetuses and those with pyelectasis and was
with trisomy 21, associated with disproportion-
independent of the state of the fetal bladder,
ately short proximal long bones (femur and
whereas Petrikovsky et al98 found that the degree
humerus). Limb shortening can also be detected
of fetal bladder distention was important.
in some fetuses with trisomy 21 during the sec-
Renal pyelectasis is measured as the fluid-filled
ond trimester.8691 However, there is considerable
renal pelvis in an anteroposterior dimension. We
overlap in bone measurements between affected
prefer measurement when the kidneys and spine
and unaffected fetuses. A shortened humerus
are oriented toward or away from the transducer
appears to be a slightly more specific indicator
rather than to the side. The threshold for a posi-
than a shortened femur. Results probably vary
tive finding varies among centers, but the most
with gestational age, ethnic group, possibly fetal
common criteria are greater than 3 to 4 mm.
gender, and criteria used, as well as systematic
Ideally, gestational age-dependent criteria might
differences in long-bone measurements.92
be used in the future.
Despite these variables, this marker is commonly
Using a cutoff of greater than 3 mm, we observe
used at screening centers. The most common
pyelectasis in about 3% of normal fetuses at our
method for determination of shortened humerus
center. Snijders and Nicolaides101 estimate that
and femur is comparing the actual measurement
mild pyelectasis increases the risk of trisomy 21
with the expected measurement, typically based
by 1.6-fold over the baseline risk. Our own analy-
on biparietal diameter or another dating parame-
sis is consistent with this risk, although this risk
ter rather than gestational age. Until now, we have
may not be increased when pyelectasis is isolat-
used a single cutoff of 0.91 multiples of the medi-
ed. The lack of association as an isolated finding
an for a short femur and 0.89 for a short humerus.
has also been suggested by other studies,102,103
However, like nuchal measurements, optimal
although one center has shown an association as
results would be expected by multiple-of-the-
an isolated finding.104
median data and corresponding likelihood ratios
rather than a single cutoff.71 These methods are
Echogenic Intracardiac Foci (or Papillary Muscle
best performed by computer calculations. Other
Calcification)
skeletal abnormalities associated with trisomy 21
are clinodactyly (shortened middle phalanx of the
Echogenic intracardiac foci as SMFA are the most
fifth finger) and a widened pelvic angle. Although
recent, and probably the most controversial, of the
both are well-known clinical features of trisomy
sonographic markers that have been described. It
21, these can be difficult to assess on second-
is a common finding during the second trimester,
trimester sonography and therefore are not typi-
observed in 3% to 4% of normal fetuses.105,106 The
cally included in most screening programs.
prevalence appears to be significantly higher
among Asian populations; Shipp et al107 found EIF
Renal Pyelectasis 3 times more often among Asian patients com-
pared with white patients. That finding is impor-
Mild pyelectasis (hydronephrosis) has been asso- tant, because an estimation of risk derived from
ciated with an increased risk of aneuploidy,9396 white populations may not apply to Asian women.
primarily for trisomy 21. However, it is most Because EIF is a subjective finding, its detection
commonly seen as a normal variant and appears depends on a variety of factors, including resolu-
more commonly in male fetuses.95 The preva- tion of the sonographic equipment, technique,
lence of pyelectasis undoubtedly varies with thoroughness of the examination, and the sono-
gestational age even during the time of second- graphers experience. Fetal position is also
trimester scans (1422 weeks). A mild degree of important, because intracardiac foci are best
renal pyelectasis may fluctuate during the course visualized when the cardiac apex is oriented
of a single examination. toward the transducer.108 Despite these variable
Studies are conflicting regarding the possible factors, similar detection rates of EIF from differ-
influence of pyelectasis from maternal hydration ent studies suggest that experienced sonogra-
as well as the degree of fetal bladder disten- phers can largely agree on its presence or
tion.97100 Robinson and colleagues100 found that absence. Like many sonographic markers, it typ-

664 J Ultrasound Med 20:655674, 2001


ically resolves by the third trimester despite the
outcome.109
Roberts and Genest110 were the first to suggest
an association between aneuploidy and miner-
alization of the papillary muscle in a pathologic
study. Mineralization of the papillary muscle
was observed in 2% of normal fetuses compared
with 16% (20 of 126) of those with trisomy 21 and
39% (9 of 23) of those with trisomy 13. Similar
but slightly higher rates of EIF have been
observed in sonographic studies during the
second trimester, possibly because small foci
may have escaped pathologic detection.
Comparison of these data, as well as direct corre-
lation by Brown et al,111 suggests that EIF corre-
lates with papillary muscle mineralization that
can be seen histologically.
In 2 sonographic studies of EIF and aneu-
ploidy, Bromley et al112 detected EIF in 4.7% (62
of 1312) of control fetuses compared with 18% (4
of 22) of those with trisomy 21, and Lehman et
al6 reported EIF in 39% of fetuses with trisomy 13
before 20 weeks. A number of studies have con-
firmed an association between EIF and trisomy
21 (Fig. 9)113118 with few exceptions.119121 The
likelihood ratio of EIF in trisomy 21 has been
estimated in the range of 1.8 to 4.2.
The risk of aneuploidy from isolated EIF, as well
as other SMFA, may be underestimated among
low-risk patients because of incomplete ascer-
tainment. Few patients with an isolated marker
undergo chromosome analysis unless they are
already considered at high risk. In one of the few
studies to address this issue, Simpson and col-
leagues114 evaluated 205 fetuses with isolated
EIF from low-risk patients. Clinical follow-up
was obtained by way of a standard questionnaire
completed by the parents when the infants were
6 weeks old. Two infants (1%) proved to have
aneuploidy (1 trisomy 21 and 1 unbalanced
translocation).
On the other hand, the risk of EIF and other
markers is probably overestimated in studies in
which the fetal karyotype is known for all patients,
because sonographic findings influence patient
decision making. Many high-risk patients now
wait for the results from the second-trimester
sonogram before deciding to undergo genetic
amniocentesis, and high-risk patients are appro-
priately more likely to undergo genetic amnio-
centesis than low-risk patients on the basis of the
same sonographic findings. We observed EIF in
5.4% of fetuses with known normal karyotypes
J Ultrasound Med 20:655674, 2001
Nyberg and Souter
Figure 9. Trisomy 21 and EIF. Apical 4-chamber view of the heart at 17 weeks
shows EIF (arrow) in the left ventricle of the heart. It was the only sonographic
abnormality in this case.
compared with 3.9% of all consecutive patients
who had normal or presumed normal fetal kary-
otypes. Previous studies confined to known kary-
otypes have also shown a higher prevalence of
EIF. This emphasizes the potential for bias in
studies of sonographic markers that restrict
patients to those with known fetal karyotypes.
Multiple or large EIF may be important vari-
ables when considering genetic amniocente-
sis.122125 Bettelheim et al122 found EIF located in
the left ventricle in 96% of cases, in combined left
and right ventricles in 4.3%, and isolated to the
right ventricle in just 0.7% (1 of 150). Bromley et
al116 concluded that right-sided and bilateral EIF
combined together had an approximately 2-fold
greater risk of aneuploidy compared with left-
sided foci, and others have also found that
echogenic foci involving both ventricles are more
associated with aneuploidy. Wax and Philput123
reported that aneuploidy was more common
when echogenic foci involved both ventricles
compared with either ventricle alone. Vibhakar
et al117 found that of 15 fetuses with multiple EIF,
10 (67%) had abnormal karyotypes, and only 2 of
those had other sonographically detected abnor-
malities besides EIF. More recently, Wax and
colleagues125 correlated an increased risk of ane-
uploidy with the conspicuity of EIF. Our own
observations agree that multiple or unusually
prominent EIF appear to carry a greater risk.
665
Sonographic Markers of Fetal Trisomies: Second Trimester

Mild Ventricular Dilatation Choroid Plexus Cysts

The size of the lateral ventricles remains rela-
Although an association between choroid plexus
tively constant throughout gestation, with a
cysts and trisomy 18 has been clearly estab-
mean diameter of 6.1 1.3 mm and slightly
lished, a possible link with trisomy 21 has been
larger ventricles in male than in female fetuses
controversial.133 Among 1346 fetuses with isolat-
(6.4 versus 5.8 mm).126 Ventriculomegaly is sus-
ed choroid plexus cysts reviewed by Yoder et al,27
pected when the atrial diameter reaches 10
5 had trisomy 21. The calculated likelihood ratio
mm, although separation of the dependent
for trisomy 21 was 1.87, but this did not reach
choroid from the medial ventricular wall may
statistical significance (P = .16). Our own analy-
be visible evidence of early ventricular dilata-
sis suggests that choroid plexus cysts are statisti-
tion.127
cally more likely in fetuses with trisomy 21 but
Mild ventricular dilatation deserves comment
not as isolated findings. We think that as an iso-
because it has been associated with trisomy 21
lated finding after high-quality sonography, and
as well as other aneuploidies.128130 Although
assuming the patient is otherwise considered at
some authors40,41 have categorized it as a major
low risk for fetal aneuploidy, detection of
abnormality, we think it shares similar charac-
choroid plexus cysts should not alter obstetric
teristics (nonspecific, common in normal
management.
fetuses, and often transient)131 with other
minor markers. It is more likely to be seen as a
Reduction of Risk in Women Otherwise
normal variant later in the second trimester
Considered at High Risk
(after 20 weeks) and in male fetuses.
In a series by Bromley et al,129 12% (5 of 43) of
Increasingly, normal sonographic findings are
fetuses with mild ventriculomegaly (ventricular
used to help reduce the risk of Down syndrome
diameter, 1012 mm) had abnormal karyotypes
for women who otherwise would be considered
(3 trisomy 21 and 2 trisomy 18), although all of
at risk for fetal trisomy 21.73,102,134 Reduction of
these had other findings. Similarly, in our most
risk is most useful for women in an intermediate
recent series of trisomy 21, mild cerebral ven-
age group, 34 to 40 years, and for women with
tricular dilatation was observed in 4.3% (8 of
intermediate risk based on biochemical screen-
186) of affected fetuses, but all had other find-
ing (risk 1:100). To what degree the risk is reduced
ings, including structural defects (n = 3), 3 or
depends on a variety of factors, including the
more minor markers (n = 3), or nuchal thicken-
number and type of criteria used, individual
ing alone (n = 2).
thresholds, and, undoubtedly, the gestational age
On the other hand, Pilu et al130 evaluated 31
at the time of scanning. Despite differences
fetuses with isolated borderline ventricular
among centers, most recent studies (Table 5)
dilatation (1015 mm) and found 3 with aneu-
suggest that a likelihood ratio in the range of 0.3
ploidy (2 with trisomy 21 and 1 with trisomy
to 0.4 can be assigned to a normal sonographic
13). In a review of the literature including their
finding. These likelihood ratios correspond to a
own cases (n = 234), chromosomal aberrations,
60% to 70% reduction of risk. With the use of a
mostly trisomy 21, were observed in 3.8%.
larger number of criteria or a higher threshold,
Vergani et al132 evaluated 82 cases of mild ven-
sensitivity of sonography approaching 90% has
triculomegaly (1015 mm) and found aneu-
been reported. Vintzileos and colleagues102 used
ploidy in 2 cases, both of which were associated
a large number of SMFA but applied them only to
with advanced maternal age. Seven additional
reduce the risk among low-risk patients.
cases of aneuploidy were associated with other
anomalies. Current experience suggests that
Comparison of Sonography and Biochemical
mild cerebral ventricular dilatation increases
Analysis
the risk for fetal aneuploidy, although this risk
remains difficult to determine. Further studies
How does second-trimester sonography com-
are needed, including studies comparing ven-
pare with second-trimester biochemical screen-
tricular measurements of fetuses with trisomy
ing? Surprisingly little data are currently available
21 and normal fetuses.
regarding this.62,135 It appears that the reported

666 J Ultrasound Med 20:655674, 2001


sensitivity for sonography in detecting Down
syndrome at centers that have high-risk patients
is similar to that of second-trimester biochemi-
cal screening. Considering the maternal age dis-
tribution at the centers with high-risk patients
that have reported results, the false-positive
results of sonography are also similar to those of
biochemical screening. One difference is that
negative serum biochemical test results can
reduce the risk much more than can normal
sonographic findings. Also, biochemical testing
is more widely available than high-quality
sonography.
It now seems clear that a combined risk esti-
mate using both sonography and biochemical
testing will be more effective than either alone. A
combined risk would also be less confusing than
competing results from each. To date, however,
few studies have evaluated the effectiveness of
combining sonography and biochemical
screening in the second trimester,136,137 even
though a large number of reports have
addressed this combined risk for the first
trimester. Roberts and colleagues138 found that
sonography improved detection over that of
second-trimester biochemical screening alone
from 65% to 80%. Bahado-Singh et al139 have
also shown that incorporation of humerus
length and nuchal thickness significantly
improves the receiver operator curves of bio-
chemical risk assessment alone. Addition of
inhibin to the standard triple-marker test would
further increase second-trimester detection of
trisomy 21 to 75% on the basis of biochemical
screening alone.140,141 Optimal sonographic risk
assessment will require computer calculations
using risk estimates from multiple-of-the-median
data from specific measurements (e.g., nuchal
thickening and limb length).
In another development, urinary biochemical
markers may also prove to be effective in the
detection of trisomy 21. Bahado-Singh and col-
leagues142 have reported that urinary hypergly-
cosylated human chorionic gonadotropin (hCG)
is superior to the 3 analytes of the triple-marker
screen. In 1 study, urine hyperglycosylated hCG
was combined with urine -core fragment
serum -fetoprotein and maternal age to yield a
detection rate of 96% with a 5% false-positive
rate or 94% sensitivity with a 3% false-positive
rate.143 Incorporation of sonographic biometric
measurements with urinary analytes further
J Ultrasound Med 20:655674, 2001
Nyberg and Souter
improves screening performance. Using sono-
graphic measurements of humeral length and
nuchal thickness combined with hyperglycosy-
lated hCG, Bahado-Singh et al144 found a 91.3%
detection rate with a 3.2% false-positive rate.
The area under the receiver operator curve was
0.986 (P < .001), and that combination was supe-
rior to hyperglycosylated hCG plus age alone or
any other second-trimester screening protocol.
The Future
First-trimester nuchal translucency screening
and biochemical markers have proved to be
effective for detection of fetal aneuploidy.145 At
this time, it remains uncertain whether first-
trimester screening is more effective than sec-
ond-trimester screening and what the ultimate
role of second-trimester screening will be. Wald
et al146 have proposed that the combination of
first-trimester nuchal translucency screening
with both first- and second-trimester biochemi-
cal screening might be able to achieve 85% sen-
sitivity for trisomy 21 with only a 1%
false-positive rate. If validated clinically, this
approach would significantly lower the predic-
tive value of second-trimester sonographic
markers.147,148 On the other hand, Bahado-Singh
and coworkers139,144 have shown that sono-
graphic markers can also be correlated with
second-trimester biochemical markers to pro-
vide similar high detection rates. Only time will
tell whether sonographic markers associated
with aneuploidy during the second trimester
will ultimately have the same interest they do
today.
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