is an Assistant Professor,
is a Clinical Assistant Professor, and
is an Associate Professor and Chief of Ultrasound, Department of
Radiology University of Texas Medical School--Houston, Houston,
The prevalence of Down's syndrome during the second trimester
has risen in the last three decades due to an increasing number of
births in women older than the age of 35. In 1997, the prevalence
had increased to 1 in 504 births,
or approximately 0.2%; it continues to be the most common
chromosomal abnormality among newborns. Screening protocols for
fetal Down's syndrome have advanced simultaneously, improving
detection in both high-risk and low-risk populations. Most recent
advances relate to the first trimester examination, with an
emphasis on nuchal translucency (NT). Second trimester sonographic
screening has also improved with recognition of structural and
nonstructural abnormalities and incorporation of the presence or
absence of such findings to modify the risk of fetal Down's
First trimester sonographic findings
With recent advances in technology, first trimester sonography
can now detect, or at least suggest, many structural abnormalities.
However, structural abnormalities in the first trimester are
identified much more commonly in trisomies 18 and 13 than in
The focus of first trimester screening for Down's syndrome is
rather on fetal NT.
Nicolaides et al
introduced the term "nuchal translucency" to describe the
collection of fluid under the skin behind the neck of fetuses
between 11 and 14 weeks of gestation (Figure 1). An increase in
this fluid is seen in chromosomally abnormal fetuses, most commonly
trisomy 21, and has since been recognized to be a useful
sonographic marker for the detection of fetal Down's syndrome in
the first trimester.
Its relatively low false-positive rate further enhances its
screening potential. The origin of the fluid is unknown, and maybe
multifactorial. It is thought to be possibly linked to cardiac
dysfunction, venous congestion, lymphatic abnormality, altered
extracellular matrix, or other unknown causes.
A reproducible specific method for measurement of NT is very
important, as the variation of measurement between abnormal and
normal is so small. The Fetal Medicine Foundation (FMF) has
established standardized technical guidelines for the correct
measurement of NT (also available online at: http://
It has also developed a training and accreditation program. Using
this protocol, NT can be measured reproducibly in approximately 95%
of cases transabdominally, with transvaginal scanning required in
the remaining 5%. The criteria used to obtain uniform results are
as follows: 1) good sagittal section of the fetus with a crown-rump
length between 45 and 84 mm; 2) gestational age of 11 to 13 6/7
weeks; 3) magnification such that the fetus occupies at least
three-quarters of the image and measurements are accurate to 0.1 to
0.2 mm; 4) measurement performed in neutral position, as flexion
may decrease measurements and hyperextension may increase
measurements; 5) visualization of the amnion separate from the
fetal skin, and 6) correct placement of calipers from the inner to
Multiple studies of NT have been performed. Souter and Nyberg
cite 16 studies, with most early studies using a cut-off of 3.0 mm
and most recent studies using gestational-agespecific thresholds
for a positive result.
The sensitivity rate for the detection of trisomy 21 varied from
28.6% to 90.3%. However, many of these studies did not implement
strict criteria and quality control. A large study of approximately
100,000 cases from the FMF published in 1998 by Snijders and
reported a sensitivity rate for trisomy 21 of 82.2% with a
false-positive rate of 8.3% using their established criteria.
Subsequent studies have obtained similar results.
The normal range for NT measurements is gestational age
dependent. The 95th percentile increases from 2.2 mm at a
crown-rump length of 38 mm to 2.8 mm at 84 mm.
As such, NT measurements are usually expressed relative to
gestational age or crown-rump length and positive results reported
as >95th percentile, multiple of the median, or a delta value.
These values can then be combined with maternal age to calculate a
risk for trisomy 21.
During the second trimester, NT in both karyotypically normal
and abnormal fetuses usually resolves or, in a few cases, evolves
into either nuchal edema or cystic hygromas with or without
Fetuses with abnormally increased NT measurements and normal
chromosomes are still at risk for structural abnormalities,
especially major cardiac defects, and a variety of genetic
conditions. The risk increases with increasing NT and subsequent
fetal echocardiography has been advised.
Second trimester sonographic findings
Although structural abnormalities are common with trisomies,
they are less often seen sonographically in trisomy 21, and are
usually identified in <25% of fetuses with trisomy 21.
Major structural abnormalities associated with second trimester
Down's syndrome include cardiac defects, cystic hygroma (Figure 2),
duodenal atresia (Figure 3), and hydrops (Figure 4).
Cardiac defects such as ventricular septal defect (Figure 5) and
endocardial cushion defect are commonly associated with Down's
syndrome clinically and pathologically. However, these are
particularly difficult to detect sonographically, especially at the
routine screening age of 16 to 20 weeks. Even at 24 weeks, an
optimal gestational age for sonography, with prior knowledge of
karyotype, Paladini et al
detected only approximately one half of cardiac defects. Nyberg
also reports low detection rates of cardiac defects of <10% in
fetuses with Down's syndrome. Using less specific cardiac
findingssuch as right-to-left chamber disproportion, pericardial
effusion and tricuspid regurgitation--Devore
identified cardiac abnormalities in 76% of affected fetuses.
However, in practice, without prior knowledge of karyotype, there
appears to be a low sensitivity for detection of cardiac defects in
trisomy 21 with sonography.
In addition to structural abnormalities, nonstructural findings,
or sonographic markers, are important findings in trisomy 21. These
sonographic markers are seen most often in normal fetuses, are
nonspecific, are often transient, and by themselves do not alter
fetal outcome. Their significance varies with the specific marker,
increases with multiplicity of markers identified, and is
interpreted most accurately with maternal age and other clinical
variables. The most commonly recognized sonographic markers
associated with trisomy 21 are nuchal thickening, hyperechoic
bowel, echogenic intracardiac focus, short femur or humerus, and
renal pyelectasis. Other proposed markers include widened pelvic
angle, small ears, clinodactyly, shortened frontal lobes, small
cerebellum, pericardial effusion, and others.
Of these, nuchal thickening has the highest association with
Down's syndrome. Benacerraf et al
first described this important second trimester marker as abnormal
thickening of the soft tissues in the back of the fetal occiput.
This is measured in the transverse plane at the level of the
cerebellum with the view including the cerebellum, posterior fossa,
and the occipital bone (Figure 6). It is measured from the outer
edge of the occipital bone to the outer edge of the fetal skin.
A measurement >5 mm is considered abnormal.
This measurement appears to vary with gestational age, however, and
age-specific criteria may be used to establish relative risk in the
This finding generally resolves with time, but its transient nature
does not deter from its initial significance.
Echogenic bowel is another nonspecific marker that has been
found in fetuses with aneuploidy (Figure 7). However, it is also
seen in multiple other conditions, including bowel atresia,
meconium ileus, thalassemia, intra-amniotic bleed, congenital
infection, and intrauterine growth retardation.
A grading classification has been established for echogenic bowel:
grade 1--mildly echogenic and often diffuse; grade 2--moderately
echogenic and often focal; and grade 3--very echogenic, equivalent
to bone. Both grade 2 and grade 3 have been associated with
aneuploidy, with a higher risk associated with grade 3.
Care must be taken in grading the echogenicity of bowel, as the
echogenicity of normal bowel increases with increasing transducer
Echogenic intracardiac foci are a much-debated soft sonographic
marker. They represent calcification of the papillary muscle and
are seen best when the cardiac apex is pointed toward the
They are observed in 3% to 4% of normal fetuses.
Multiple studies yield conflicting conclusions as to the
association of echogenic intracardiac foci with trisomy 21.
However, multiple, large, or unusually conspicuous foci appear to
carry a greater risk.
Skeletal abnormalities associated with trisomy 21 include short
proximal long bones. However, there is a large overlap between
trisomy 21 and normal fetuses, and variations may be related to
gestational age and ethnicity. A shortened humerus appears to be a
more specific indicator for trisomy 21 than a shortened femur.
Abnormalities are recognized from expected measurement based on the
biparietal diameter at the time of the examination rather than the
gestational age. The ratio of the measured femur/humerus length to
the expected length is calculated. A measure:expected ratio of
<0.90 for humerus length was found in 50% of afflicted fetuses
Commonly utilized cutoffs included ratios of <0.90 for a short
humerus and <0.91 for a short femur. These numbers may also
change as investigators further establish likelihood ratios.
Renal pyelectasis is a measure of the fluid-filled fetal renal
pelvis in the anteroposterior dimension on a transverse image of
the kidneys (Figure 8). The commonly used cutoffs are 3 or 4 mm.
Pyelectasis is also seen commonly in normal fetuses and may be
related to the degree of maternal hydration, other genitourinary
abnormalities, or fetal bladder distention.
Nyberg et al
observed pyelectasis in 3% of normal fetuses. Corteville et al
reported an incidence of pyelectasis in 17.4% of fetuses with
Down's syndrome and 2% in the normal population.
The importance of each of these findings lies not in isolation,
but in interpretation with all the sonographic findings, the
maternal age, and biochemical markers, to yield a more accurate
risk assessment for trisomy 21. The genetic sonogram is such an
assessment of sonographic abnormalities used to modify the risk of
Down's syndrome, either up or down for each fetus. Multiple scoring
systems for sonographic findings have been proposed. Benacerraf and
derived an excellent scoring index assigning 1 or 2 points for
certain ultrasound findings, with a structural anomaly or nuchal
thickening assigned 2 points; and with short humerus, short femur,
hyperechoic bowel (grade 3), echogenic intracardiac focus, and
pyelectasis each assigned 1 point. Maternal age >= 35 years also
can be assigned 1 point. A score of 2 or more can result in a
sensitivity of 75.5% and a false-positive rate of 5.7% for the
detection of Down's syndrome.
Amniocentesis is usually offered with a score of 2 or more. Nyberg
have also derived an excellent method of integrating sonographic
findings into prior maternal risk by an age-adjusted ultrasound
risk assessment. Sonographic markers are expressed as likelihood
ratios weighted by their individual importance, and the mother's
prior risk based on age is modified by these likelihood ratios to
obtain a post-ultrasound risk, or post prior risk. This system
helps minimize false-positive rates while providing a
patient-specific risk estimate.
Both first and second trimester ultrasound screening for Down's
syndrome has made dramatic advances in recent years. It remains to
be seen if one will prove more effective than the other, or a
combination of the two will become the future standard in trisomy