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Chapter 31 ■ Chromosomal Abnormalities 1127
A B
FIGURE 31-4. First-trimester nasal bone assessment. A, Midsagittal profile of a fetus shows the correct method of assessing
the nasal bone. Note that the nasal bone and the overlying skin form an “=“ sign (arrow). B, Midsagittal profile of a fetus with trisomy
21 shows the echogenic overlying skin but absent nasal bone.
nasal bone. Overall, 110 fetuses (8.5%) had an NT detection rate of 95% or greater, and 25 (1.9%) had an absent
nasal bone. Of the 31 trisomy 21 fetuses, 28 had NT above
95% and 13 had an absent nasal bone. The detection rate
of trisomy 21 was 90.3% using NT and 41.9% using an
absent nasal bone. All but one fetus with an absent nasal
bone had a thickened NT, and only two normal fetuses
had an absent nasal bone. These authors concluded that
although an absent nasal bone is highly predictive of
trisomy 21, it is less useful as a sonographic marker than
the NT. Malone et al.
48
reported that the nasal bone evalu-
ation was not a useful test for population screening.
It is evident that the issues surrounding nasal bone
(NB) screening in the first trimester are complex. The
identification of the nasal bone as present or absent is
a specialized skill that is attained with experience, even
for competent imagers. It has been recommended that
the nasal bone be considered a contingency marker
in patients whose first-trimester risk based on NT and
biochemistry is in an intermediate-risk category between
1/101 and 1/1000.
46,49,50
Other Markers for Aneuploidy
Flattened Facies
the angle and NT or serum biochemistries, suggesting
that this may ultimately prove to be a useful adjunct in
screening for trisomy 21.
51
Reversed Flow in Ductus Venosus
The ductus venosus directs well-oxygenated blood from
the umbilical vein to the coronary and cerebral circulation. Abnormal blood flow demonstrated as a reversed a
wave in the ductus venosus is seen in 80% of fetuses with
trisomy 21 and in 5% of euploid fetuses
7,52
(Fig. 31-5).
Tricuspid Regurgitation
Tricuspid regurgitation has also been proposed as a
method of risk assessment. Falcon et al.
53
compared 77
fetuses with trisomy 21 and 232 chromosomally normal
fetuses from singleton pregnancies at 11 to 14 weeks of
gestation. Tricuspid regurgitation was identified in 57
(74%) of trisomy 21 fetuses and in 16 (7%) of euploid
fetuses. No relationship between tricuspid regurgitation
and the levels of maternal serum free β-hCG and PAPP-A
was identified. The authors concluded that an integrated
sonographic and biochemical test can identify about
90% of trisomy 21 fetuses for a 2% to 3% FPR.
Individuals with trisomy 21 are known to have flattened
facies. Recently, the frontomaxillofacial angle of the fetus
has been studied to determine whether this might be a
useful marker for trisomy 21. On a midsagittal view of
the face, the angle between the upper surface of the
maxilla and the frontal bone is measured. Early data have
shown that the angle is greater than 85 degrees in 69%
of fetuses with trisomy 21, compared with 5% of euploid
fetuses. Importantly, there was no association between
Thickened Nuchal Translucency
with Normal Karyotype
A thickened NT is associated with an increased risk of
congenital heart defects (CHDs). In a study of 29,154
euploid fetuses at 10 to 14 weeks’ gestation, Hyett
54
identified 50 with CHDs; 56% of the fetuses
et al.
were from a group of 1822 with an NT thickness greater
than 95%. In a meta-analysis evaluating the screening
1128 PART IV ■ Obstetric Sonography
S
D
IVC
A
DV
UV
A B
FIGURE 31-5. Reversed flow in ductus venosus. A, Color Doppler anatomy of vessels at oblique sagittal view of fetal trunk;
UV, umbilical vein; DV, ductus venosus; IVC, inferior vena cava. B, Abnormal ductus venosus sonogram shows a reverse a wave. Absent
or reversed a-wave flow can occur in cardiac failure, with or without cardiac defects, and in chromosomally abnormal fetuses.
performance of increased first-trimester NT for the
detection of major CHDs, eight independent studies
with 58,492 patients were reviewed. An NT above
99% had a sensitivity of 30% for the detection
of CHDs. If an NT above 99% is used as an indication
for a fetal echocardiogram, 1 in 16 referred cases would
have CHDs. If the threshold was lowered to fetuses
with an NT above 95%, 1 in 33 referred cases would
have a major CHD.
55
Data from the FASTER trial
confirmed that the incidence of major CHD increased
with increasing NT, although the sensitivity for CHD
detection was only 9.6%. These investigators concluded
that NT lacked the qualities of a good screening test
for heart disease; however, an NT of 2.5 MOM
(99%) or greater is considered an indication for fetal
echocardiography.
Fetuses with a thick NT are at increased risk for a
variety of major congenital abnormalities
56
11
(Fig. 31-6).
A major abnormality is one that is defined as requiring
medical or surgical treatment or is associated with developmental delay. These include not only cardiac defects
but also diaphragmatic hernia, body stalk anomalies,
and abdominal wall defects, among a multitude of
other syndromes and anomalies. In combined data of 28
studies of 6153 euploid fetuses with thick NT, the prevalence of major anomalies was 7.3% (range, 3% to 50%).
The prevalence of major anomalies increased from 1.6%
in those with an NT less than 95 percentile to 2.5% for
95 to 99 percentile, 10% with an NT of 3.5 to 4.4 mm,
and increasing dramatically thereafter to 46% in those
with an NT greater than 6.5 mm.11 Similarly, a thickened NT has been associated with a myriad of genetic
disorders.
7,11
In chromosomally normal fetuses, the risk of intrauterine demise increases with increasing NT. In a study
of 6650 pregnancies undergoing NT screening, the prevalence of miscarriage, fetal death, or termination for an
anomaly was 1.5% in euploid fetuses with an NT below
95 percentile compared with 18% in those with an NT
above 99 percentile.
Not all fetuses with a thick NT have an abnormal
outcome. In 2001, Souka et al.
57
58
reported on 1320
euploid singleton pregnancies with an NT of 3.5 mm or
greater. These fetuses underwent sonographic evaluation
at 14 to 16 weeks and 20 to 22 weeks. The chance of a
live birth with no defect was 86% in the group with an
NT of 3.5 to 4.4 mm, 77% for NT of 4.5 to 5.4 mm,
and 67% for NT of 5.5 to 6.4 mm. In fetuses with an
NT of 6.5 mm or greater, the chance of normal outcome
was 31%. In total, there were 200 fetuses (15.5%) with
abnormalities, 80% of which were diagnosed prenatally.
There were 1080 (82%) survivors, 60 (6%) of whom
had abnormalities requiring medical or surgical care or
were developmentally delayed. In a group of 82 fetuses
with persistent nuchal thickening but an otherwise
normal scan, 19% had an adverse outcome. In the group
of 980 euploid fetuses with a normal second-trimester
scan, there were 22 (2%) with adverse outcome. Severe
developmental delay was seen in 1 of 82 (1%) with
isolated persistent nuchal thickening, compared with 4
of 980 (0.4%) with a normal scan.
58
Bilardo et al.59 reviewed the outcome of 675 pregnancies with an increased NT, known karyotype, and known
pregnancy outcome. Of the study group, 451 (67%) had
a normal karyotype, and 19% of these euploid pregnancies had an adverse outcome. The range of abnormal
outcome varied with the degree of NT thickening, from
8% with NT between the 95% and 3.4 mm to 80% with
NT of 6.5 mm or greater. Second-trimester sonography
was performed on 425 euploid fetuses, and an abnormality was identified in 50 fetuses (12%). Of fetuses with
a suspicious or abnormal scan, 86% had an adverse
outcome. A normal second-trimester ultrasound was
reported on 375 (88%) of fetuses, and 96% of those are
Chapter 31 ■ Chromosomal Abnormalities 1129
A
D
FIGURE 31-6. Structural abnormalities seen at nuchal translucency screening. A, Omphalocele; B, anencephaly;
C, holoprosencephaly; D, micrognathia; E, megacystis.
alive and well. Of fetuses with a thickened NT in the
first trimester, normal karyotype, and normal secondtrimester scan, 4% had an adverse outcome, which
included intrauterine demise, structural defects, and
genetic syndromes. The most frequently missed anomalies on ultrasound were cardiac defects, underscoring the
need for detailed fetal echocardiography in fetuses with
a thick NT. Westin et al.
60
reported on 16,260 euploid
fetuses from an unselected population to determine how
B C
E
children had no malformations and normal developmental testing. Eleven percent of children had a structural
abnormality noted after birth. Two children (1.2%) had
neurologic delay. In one child, the delay was isolated,
and in the other it was associated with an unidentified
syndrome. These authors concluded that when the
karyotype is normal and the sonogram is normal with
resolution of the NT, the outcome is not adversely
affected at 2 years of age.
well NT measurements predicted adverse outcome. The
overall rate of adverse outcome was 2.7%. The risk of
adverse outcome increased with thickening NT values.
An NT of 3 mm or greater was associated with a 6-fold
SECOND-TRIMESTER SCREENING
FOR TRISOMY 21
increase in adverse outcome, 3.5 mm or greater with a
15-fold increased risk, and 4.5 mm or greater with a
30-fold increased risk. These authors concluded that
likelihood ratios could be used to calculate an individual’s risk of adverse outcome but could not reliably diatinguish between normal and adverse outcome.
Senat et al.
61
prospectively evaluated long-term
outcome in children with a normal karyotype and a
nuchal translucency at or greater than the 99%. An
external control group was utilized for comparison. The
study population consisted of 179 fetuses that underwent midtrimester sonography as well as fetal echocardiography. There were 17 fetal losses, including 10
malformations, 5 intrauterine demises, 1 miscarriage,
and 1 termination. One hundred and sixty two liveborns
were evaluated with serial pediatric examinations and
formal developmental testing. At 2 years of age, 89% of
Although first-trimester risk assessment allows a patient
the benefit of time in using the information to make
decisions regarding pregnancy, not all women present for
prenatal care early enough in gestation to take advantage
of this benefit. In addition, first-trimester screening may
not be readily available in all areas. Until about the last
decade, the only method of prenatal risk assessment
for aneuploidy was multiple marker serum screening and
midtrimester genetic sonography. Serum screening,
which now includes four biochemical markers and is
known as the quad screen, is performed in the second
trimester and has a sensitivity of approximately 80% for
the detection of trisomy 21 with an FPR of 5%.
Ultrasound is an integral part of risk assessment for
aneuploidy in the middle trimester.
62-70
Approximately
1
25% of fetuses with trisomy 21 have a major congenital
1130 PART IV ■ Obstetric Sonography
A
B
C D
FIGURE 31-7. Major congenital anomalies in trisomy 21. A, Ventriculoseptal defect (VSD). Four chamber view of the
heart with a ventriculoseptal defect (arrow) demonstrated with color flow Doppler. B, Atrioventricular (A-V) canal. Four-chamber view
of the fetal heart demonstrates a complete A-V canal. Note the abnormal “flattening” of the mitral and tricuspid valves into a common
A-V valve (arrows). C, Duodenal atresia. Axial scan through the fetal abdomen shows a double bubble. D, Ventriculomegaly. Axial scan
through the cranium of a fetus with trisomy 21 shows dangling choroid in fetus with ventriculomegaly.
anomaly, such as cardiac defect, duodenal atresia, or
ventriculomegaly
66,67
(Fig. 31-7). The cornerstone to
identifying fetuses with trisomy 21 has been the recognition of sonographic “markers.” Some of these markers
are well known physical entities that were first described
by Dr. Down in 1866, such as the thickened nuchal fold
and the small nasal bone.
8
Others are findings specific to
prenatal sonography, such as echogenic bowel, echogenic
intracardiac focus, pyelectasis, and short femoral and
humeral length.
Nuchal Fold
Early studies showed that the presence of a thickened
nuchal fold identified 40% of fetuses with trisomy 21
with FPR of 0.1%.
71-74
This measurement is obtained
using an axial view through the fetal head, across the
thalami and angled posteriorly to include the cerebral
peduncles, cerebellar hemispheres, and cisterna magna as
well as the occipital bone. The measurement is made
from the surface of the occipital bone to the surface
Chapter 31 ■ Chromosomal Abnormalities 1131
TRISOMY 21:
SONOGRAPHIC MARKERS
Nuchal fold
Absent/hypoplastic nasal bone
Short femur
Short humerus
Echogenic bowel
Echogenic intracardiac focus
Pyelectasis
Heart defect
Mild ventriculomegaly
Hypoplasia of fifth digit
Wide iliac angle
Ear length
Frontothalamic distance
of the skin edge (Fig. 31-8). Care must be taken not to
angle below the occiput because this will lead to spuriously large measurements. Initially, a measurement of
6 mm or greater was considered abnormal; however,
5 mm was later determined to be a more sensitive threshold, with little change in the specificity.
75
Interobserver
variability for this measurement is small (1 mm), establishing the nuchal fold as a highly reproducible measure-
76
Many investigators have subsequently reported
ment.
that a thickened nuchal skin fold is an important marker
for detecting trisomy 21, and after more than 20 years,
it remains one of the most specific second-trimester
markers.
77-82
More recently, some have suggested that
because the nuchal fold measurement fits a log gaussian
distribution, it should be evaluated as a continuous
variable and interpreted in the context of gestationspecific norms, to allow a more refined method of risk
analysis.
83,84
Nasal Bone
The fetal nasal bone is a recent sonographic marker
included in second-trimester genetic sonography
85
(Fig.
31-9). The technique for visualizing the nasal bone in
the midtrimester involves obtaining a midsagittal fetal
profile. The angle of insonation should be 90 degrees to
the longitudinal axis of nasal bone. If the nasal bone is
viewed “on end” (0 or 180 degrees), it will appear erroneously as absent. A slightly oblique angle (45 or 135
degrees) helps to define the edges of the nasal bone more
sharply.
to a risk of trisomy 21 of 1/270 or greater, Bromley
et al.
86
In 239 fetuses referred for amniocentesis due
87
reported that 6/16 (37%) fetuses with trisomy
21 did not have a detectable nasal bone. Of the fetuses
with a detectable nasal bone, the mean length was shorter
in those with trisomy 21 than in euploid fetuses. A
FIGURE 31-8. Nuchal fold. Axial scan through the fetal
head of a midtrimester fetus shows a thickened nuchal fold, measuring 6 mm.
A B C
FIGURE 31-9. Second-trimester nasal bone assessment. A, Midsagittal profile of an 18-week fetus shows a normal nasal
bone (arrow). B, Midsagittal profile of a second-trimester fetus demonstrates an absent nasal bone. C, 3-D image of a midtrimester fetus
with trisomy 21 shows a flat profile.
1132 PART IV ■ Obstetric Sonography
receiver-operator characteristic curve for the prediction
of trisomy 21 based on biparietal diameter (BPD)/nasal
bone length reveals that a cutoff of 11 or greater identifies 69% of trisomy 21 fetuses with a 5% FPR.
Vintzileos et al.
88
retrospectively evaluated the significance of the nasal bone ossification in fetuses referred for
genetic sonogram; 29 fetuses with trisomy 21 were compared to 102 euploid fetuses. Absence of the nasal bone
was seen in 41% of fetuses with trisomy 21 and none of
the euploid fetuses. Other authors recommend measurement of less than 5 percentile or an absolute measurement as thresholds to predict aneuploidy.
89-92
More recently, several groups have suggested that
evaluating the nasal bone length as a multiple of the
median is the optimal method of using this marker.
Odibo et al.
93
evaluated 3634 women at increased risk
for aneuploidy. Nasal bone assessment was possible
in 3197 women (88%), of whom 23 had fetuses with
trisomy 21. A nasal bone length of less than 0.75 MOM
provided the best definition of nasal bone hypoplasia
and had a sensitivity and specificity of 49% and 92%,
respectively, compared with 61% and 84% for BPD/
nasal bone length greater than 11. These investigators
favor the incorporation of absent nasal bone as a major
marker for trisomy 21 in the second-trimester genetic
sonographic screening because of its ease of identification and better specificity compared with MOM of less
than 0.75. The absence of the fetal nasal bone can be
as powerful a marker for trisomy 21 as the thickened
nuchal fold.
94
Of note, there is variation in the prevalence of a hypoplastic or absent nasal bone depending on ethnicity.
Cicero et al.
91
reported that 8.8% of patients of AfricanCaribbean ancestry had an absent or hypoplastic nasal
bone, compared with 0.5% of Caucasian fetuses, thus
limiting the utility of this marker in patients of AfricanCaribbean heritage.
Three-dimensional (3-D) ultrasound has been used to
evaluate the presence or absence of the fetal nasal bone.
In 20 fetuses with trisomy 21, Benoit and Chaoui
95
found nine had either an absent or a hypoplastic nasal
bone on 2-D ultrasound. The 3-D evaluation showed
bilateral nasal bone absence in six fetuses and unilateral
nasal bone absence in three.
length varies among fetuses of different ethnicity. Asian
fetuses tend to have shorter femurs and black fetuses
longer femurs compared with white fetuses.
ferences may be sufficient to question the usefulness of
the femur as a marker in many populations.
Humeral Length
The length of the humerus is a more sensitive and specific marker for trisomy 21 than the femoral length.
Benacerraf et al.
102
found that the measured humeral
length was shorter than the expected humeral length
in fetuses with trisomy 21, with a measured/expected
humeral length ratio of less than 0.90 the optimal criterion for detecting affected fetuses (expected humeral
length = −7.9404 + 0.8492 × BPD). The use of this ratio
identified 50% of the fetuses with trisomy 21, with a
6.2% FPR.
102
Mild Pyelectasis
In the second trimester, mild pyelectasis is considered
present if the anteroposterior diameter of the renal pelvis
4 mm or greater
trisomy 21, 17% to 25% have mild pyelectasis, compared with 2% to 3% of euploid fetuses.
103
(Fig. 31-10, A). Among fetuses with
103,104
Echogenic Bowel
Echogenic bowel is seen in 0.2% to 0.8% of midtrimester fetuses.
105-107
To be considered echogenic, the bowel
must appear as a well-delineated homogeneous area that
is as bright as the adjacent bone using a transducer with
a frequency of 5 MHz or less (Fig. 31-10, B; Video
31-3). The incidence of chromosomal abnormalities in
the setting of echogenic bowel ranges from 3% to
105-110
27%.
The etiology of echogenic bowel seen in association with aneuploidy may be related to poor bowel
motility and decreased water content of meconium.
addition to aneuploidy, echogenic bowel is associated
with cystic fibrosis, infectious etiologies such as cytomegalovirus, primary bowel abnormalities, and severe
growth restriction. It has also been associated with fetal
ingestion of blood and impending fetal demise.
100
Such dif-
105-110
110
101
In
Femur Length
A short femur was one of the earliest recognized features
in the sonographic detection of trisomy 21.
expected femoral length (FL = −9.645 + 0.9338 × BPD)
accounts for 94% of variation in normal length.
96
The
97
Based
on BPD, a measured-to-expected femur length ratio of
0.91 or less identifies 40% of fetuses with trisomy 21,
with a 5% FPR.
98
Although all agree that fetuses with
trisomy 21 have shorter femurs than euploid fetuses,
the difference is quite small, and the clinical utility of
this finding remains controversial.
99
Additionally, femur
Echogenic Intracardiac Focus
An echogenic intracardiac focus (EIF) is a discrete, bright
white dot, seen in the region of the papillary muscle of
the heart (Fig. 31-10, C). Echogenic intracardiac foci are
usually located within the left ventricle but can be seen
in both sides of the heart. Most also are seen as a single
focus but may occur as multiple foci. This sonographic
finding is caused by mineralization of the papillary
muscle and is seen in 16% of fetuses with trisomy 21.
However, EIF is also present in up to 5% of fetuses
without trisomy 21.
112
111
Chapter 31 ■ Chromosomal Abnormalities 1133
1
2
A
FIGURE 31-10. Markers for trisomy 21. A, Pyelectasis. Transverse scan through the fetal abdomen at 18 weeks shows bilateral
pyelectasis. B, Echogenic bowel. Sagittal scan through the fetal abdomen in the midtrimester reveals echogenic bowel (arrow). Note that
the bowel is as bright as bone. C, Echogenic intracardiac focus (EIF). Axial scan through the fetal chest showing the four chamber view
of the heart demonstrates an EIF in the left ventricle.
An EIF is the most common marker to occur as an
isolated entity both in fetuses with trisomy 21 and in
euploid fetuses.
66,67
This finding carries a twofold to
fourfold increased risk of trisomy 21.
tantly, this marker cannot be used reliably in patients of
Asian ancestry because of the high prevalence of the EIF
in the euploid Asian population.
The identification of an EIF is confounded by technical considerations such as cardiac position. When the
interventricular septum is pointing directly toward or
away from the transducer beam in an apical or basal
view, an EIF is detected more often than when the
septum is imaged perpendicular to the transducer beam
in a lateral view. To be convinced that an EIF is present,
it must be as bright as bone and seen in several planes.
Other normal specular reflectors in the fetal heart,
such as the moderator band in the right ventricle, can
be mistaken for an EIF. Winn et al.
patients scanned between 18 and 22 weeks’ gestation.
The rate of “true” echogenic intracardiac foci was 11/200
(5.5%). The rate of “false” echogenic foci was 34/200
(17%). The most common locations for a false EIF were
the moderator band, endocardial cushion, and tricuspid
valve annulus.
B
114
66,67,70,112,113
115
evaluated 200
Impor-
Adjunct Features of Trisomy 21
Adjunctive features of trisomy 21 that can be sought
sonographically include iliac angle measurements, ear
length, clinodactyly, hypoplasia of the middle phalanx
of the fifth digit, and frontothalamic distance. Many
of these features are difficult to standardize, and there
is substantial overlap between those with and without
trisomy 21. This limits the utility or these adjunct characteristics in identifying fetuses with trisomy 21.
The fetal iliac length and angle measurements have
been addressed as a potential sonographic marker for
trisomy 21. Abuhamad et al.
length measurement is increased in fetuses with trisomy
21. These investigators derived a linear regression of iliac
length measurement (cm) = −0.2723 +
(mm) and found that a ratio of observed/expected iliac
length measurement of 1.21 or greater had a sensitivity
of 40% and specificity of 98% for the detection of
trisomy 21. The angle between the two iliac bones measured on a cross section of the fetal pelvis is wider in
fetuses with trisomy 21. Using an iliac angle of 90
degrees or greater as abnormal, Shipp et al.
37% of fetuses with trisomy 21 with FPR of 4.3%. The
C
118-124
118
reported that the iliac
0.0333 BPD
119
identified
angle measurement varies considerably depending on the
Structural Anomalies
Approximately 25% of fetuses with trisomy 21 are
identified as having a structural anomaly, including
cardiac defects, duodenal atresia, ventriculomegaly, and
hydrops.
66,67,105,116
Cardiac defects are seen in approximately 50% of newborns with trisomy 21 and include
atrioventricular septal defects and ventriculoseptal
defects. With meticulous technique, these can be found
prenatally in 80% to 90% of fetuses with trisomy 21.
117
However, the detection rate of most practitioners is not
this high.
level at which the image is obtained, and the ideal level
of angle determination has not been established.
Frontal lobe dimensions are smaller in fetuses with
trisomy 21. Bahado-Singh et al.
120
reported that 52% of
trisomy 21 fetuses between 16-21 weeks’ gestation had
a frontothalamic distance of less than the 10th percentile. These investigators found that an observed/expected
frontothalamic distance ratio of 0.84 or less had a sensitivity and specificity of 21.2% and 95.2%, respectively,
for the detection of trisomy 21.
About 60% of neonates with trisomy 21 have
hypoplasia of the middle phalanx of the fifth digit.
1134 PART IV ■ Obstetric Sonography
121
Benacerraf et al.
reported that the ratio of the middle
phalanx of the fifth digit over the middle phalanx of the
fourth digit differed between euploid and trisomy 21
fetuses. The median ratio for normal fetuses was 0.85
and for trisomy 21 fetuses, 0.59. Using a cutoff of 0.70,
75% of trisomy 21 fetuses were identified; however, this
finding was also present in 18% of normal fetuses. The
sonographic appearance of the fetal digits was not suggested as a screening tool for trisomy 21, but rather as
an adjunct to other signs.
Short fetal ear length has been reported as a potential
marker for trisomy 21.
122,123
Gill et al.
124
demonstrated a
significant difference between the ear sizes of normal and
trisomy 21 abortuses, but the wide range seen within
each gestational age window makes this finding not diagnostically useful.
Cases of trisomy 21 have been reported in fetuses
with choroid plexus cysts.
result from the population incidence of choroid plexus
cysts rather than from trisomy 21.
125
However, this is believed to
126
TRISOMY 21: REVISED RISK RATIO
Revised risk A priori risk Likelihood ratio LR= ×
Example 1
A 25-year-old woman with a priori risk of trisomy
21 of 1/500 based on quad screen.
Detailed ultrasound shows an isolated EIF (LR ~2).
Revised risk = × =1 500 2 1 250
Example 2
A 39-year-old woman with a priori risk of trisomy
21 of 1/1000 based on quad screen.
Detailed ultrasound shows EIF and mild pyelectasis
(LR ≈ 6 from two markers).
Revised risk = × =1 1000 6 1166
EIF, Echogenic intracardiac focus.
( )
Combined Markers
The finding of individual sonographic markers can be
used to estimate a risk of aneuploidy.
127-133
In 1992, our
laboratory developed a scoring index that rated the
markers previously described as “major” (score of 2 for
thickened nuchal fold or major anomaly) and “minor”
(score of 1 for each finding, such as short femur, short
humerus, pyelectasis, echogenic bowel, and EIF).
cumulative score of 2 or more identified 73% of fetuses
with trisomy 21, with an FPR of 4%. Nyberg et al.
127,128
A
66,132
suggested integrating these markers into risk assessment
by using Bayes theorem and likelihood ratios. He showed
that likelihood ratios could be calculated for each isolated marker, then applied to the patient’s a priori (presumptive) risk using Bayes theorem. This resulted in a
revised risk of aneuploidy based on the presence or
absence of specific markers. Table 31-4 shows a compari-
son of four studies that computed likelihood ratios for
trisomy 21 using isolated markers.
Clusters of markers, even minor ones, confer more
risk than individual markers alone
66,67,70,132
66,67
(Table 31-5).
Winter et al.65 demonstrated that the genetic sonogram
scoring index and the method of ultrasound risk assessment using likelihood ratios were essentially equivalent
in the detection rate of trisomy 21. The advantage of
using likelihood ratios is that a patient’s specific risk
of aneuploidy can be calculated and balanced against
the risk of pregnancy loss associated with an invasive
procedure.
Genetic sonography is best used in conjunction with
a priori risk estimates based on serum screening.
Souter et al.
136
demonstrated that serum biochemical
marker analytes and sonography are independent and
therefore can be used in conjunction with each other to
modify the risk of aneuploidy. Several investigators have
shown that patients of advanced maternal age who had
a normal genetic sonogram and reassuring serum screen
are at low risk for trisomy 21.
66,67,135,138
The use of genetic sonography in risk assessment after
a variety of screening protocols has recently been assessed.
Adding the genetic sonogram to the results of the screening tests within the FASTER trial substantially increased
133-138
TABLE 31-4. LIKELIHOOD RATIOS (LR) OF MARKERS FOR TRISOMY 21
MARKER ISOLATED LR
Nuchal fold 11 — 17
Short humerus 5.1 5.8 7.5
Short femur 1.5 1.2 2.7
Echogenic bowel 6.7 — 6.1
EIF* 1.8 1.4 2.8
Pyelectasis 1.5 1.5 1.9
Structural anomaly — 3.3 —
* Echogenic intracardiac focus.
66
ISOLATED LR
67
ISOLATED LR
70
TABLE 31-5. TRISOMY 21: LIKELIHOOD
RATIOS (LR) OF CLUSTER OF MARKERS
MARKERS (#) LR
0 0.36 0.2
1 2 1.9
2 9.7 6.2
3 115.2 80
66
LR
67
the detection rate of Down syndrome for some protocols. At an FPR of 5%, adding genetic sonography
increased the detection rate of Down syndrome from
81% to 90% for the combined test and the quad screen.
Furthermore, adding genetic sonography to the integrated test increased the detection from 93% to 98%. A
smaller increase in detection rate from 97% to 98% was
observed for the stepwise test, and detection rate for the
contingent protocol increased from 95% to 97%.
Rozenberg et al.
140
performed a multicenter interven-
139
tional study in an unselected population to evaluate the
performance of first-trimester combined screening followed by second-trimester ultrasound. First-trimester
combined screening identified 80% of fetuses with
trisomy 21 at a screen-positive rate of 2.7%. Using a
thickened nuchal fold or the presence of a major anomaly
on a second-trimester ultrasound increased the detection
rate to 90%, with a screen-positive rate of 4.2%.
Krantz et al.
141
performed a simulation study to assess
genetic sonography as a sequential screen for trisomy 21
after first-trimester risk assessment. First-trimester combined screening resulted in a detection rate of 88.5%
with a 4.2% FPR. A follow-up with genetic sonography
using individual marker likelihood ratios to modify the
first-trimester risk for screen-negative patients detected
an additional 6.1% of trisomy 21 cases for an additional
1.2% FPR, giving a total detection rate of 94.6% and a
total FPR of 5.4%. If a contingent protocol were adopted
in which only patients with a first-trimester risk between
1/300 and 1/2500 were evaluated, the additional detection rate would be 4.8% with FPR of 0.7%, giving a
total detection rate of 93% and a total FPR of 4.9%.
These authors concluded that second-trimester genetic
sonography, if used properly, can be an effective sequential screen after first-trimester risk assessment.
TRISOMY 18 (EDWARDS
SYNDROME)
Trisomy 18 is the second most common multiple-malformation syndrome after trisomy 21, with an incidence
of 6.4 per 10,000 in the second trimester and 1.6 per
10,000 live births.
a limited capacity for survival, with 44% of those identi-
142
Individuals with this disorder have
Chapter 31 ■ Chromosomal Abnormalities 1135
143
fied in utero dying before birth.
About 50% of affected
newborns die within the first week, and only 5% to 10%
survive beyond the first year of life. Those who survive
are severely mentally and physically handicapped.
144
Fetuses with trisomy 18 have a plethora of anomalies.
Sonographically, 77% to 97% of fetuses with trisomy 18
can be identified by the presence of these structural malformations.
145-149
The more common structural anomalies in fetuses with trisomy 18 include congenital heart
defects, neural tube defects, hydrocephalus, diaphragmatic hernia, omphalocele, and abnormally clenched and
fisted hands
145-149
(Fig. 31-11). In our experience, cases
of trisomy 18 not identified by prenatal ultrasound have
been scanned early in the second trimester, when a complete structural survey was not feasible or when other
factors such as surgical scarring or maternal body habitus
precluded optimal visualization of the fetus.
127,128
TRISOMY 18: COMMON
SONOGRAPHIC ABNORMALITIES
Choroid plexus cyst
Strawberry-shaped skull
Abnormal cerebellum
Abnormal cisterna magna
Neural tube defects
Cystic hygroma
Micrognathia
Cardiac defects
Omphalocele
Diaphragmatic hernia
Clenched hands
Radial ray anomalies
Clubfeet
Rocker-bottom feet
Intrauterine growth restriction (especially with
polyhydramnios)
The sonographic findings observed in fetuses with
trisomy 18 vary with gestational age. As expected, anomalies such as cystic hygromas are seen more frequently
in the early midtrimester, whereas cardiac defects and
growth restriction tend to be later findings. In a review
of 47 fetuses with trisomy 18, Nyberg et al.
148
identified
cardiac defects in 14% before 24 weeks’ gestation and in
78% scanned after 24 weeks. Intrauterine growth
restriction (IUGR) was seen in 28% of affected fetuses
scanned at less than 24 weeks and in 89% of those evaluated in the third trimester. IUGR, in combination with
polyhydramnios, is an ominous observation highly predictive of Edwards syndrome.
system (CNS) anomalies are reported in 34% of affected
146,149
fetuses.
Fetuses with trisomy 18 often have ompha-
loceles, 70% of which only contain bowel.
148,150
Central nervous
151
Abnormalities of the extremities, such as clenched hands with
overlapping index fingers, are characteristic of trisomy
18. Other findings, such as radial ray defects, rocker-
1136 PART IV ■ Obstetric Sonography
B CA
D E F
FIGURE 31-11. Sonographic findings in trisomy 18. A, Choroid plexus cyst. Scan through the fetal head at 18 weeks
shows bilateral choroid plexus cysts. B, Omphalocele. Scan of the fetal lower abdomen shows a bowel-containing omphalocele (arrow)
as well as an umbilical cord cyst. C, Clenched fists. 3-D scan of a midtrimester fetus shows characteristic clenching of the hands and
overlapping fingers. D, Radial ray anomaly. 3-D scan demonstrates a radial ray anomaly. Note the micrognathia as well. E, Strawberry-
shaped skull. F, 3D scan of the fetal spine at 18 weeks demonstrating a neural tube defect (arrow).
bottom feet, clubfeet, strawberry-shaped skull (flattening
of occiput with pointing of frontal bones), and abnormal-appearing cerebellum and cisterna magna, have been
reported.
144-155
risk assessment based on an accepted screening protocol
is recommended,
sarily warranted.
125,161
but invasive testing is not neces-
150,158,159,162-166
Cheng et al.
167
reported
on the significance of isolated CPCs in a population
previously screened with NT and found that the likeli-
Choroid Plexus Cysts
hood ratio for trisomy 18 was not increased in those with
normal NT measurements.
Choroid plexus cysts (CPCs) are discrete echolucencies
within the choroid plexus that result from the folding of
the neuroepithelium, trapping secretory products and
desquamated cells
156
(Fig. 31-11, A). CPCs are seen in
TRISOMY 13 (PATAU
SYNDROME)
1% to 2% of the normal fetuses and are most common
in the second trimester, usually resolving by 28 weeks’
gestation.
have CPCs.
145-147
About 30% of fetuses with trisomy 18
147,148
The majority of fetuses with trisomy
18 also have other structural anomalies to suggest
aneuploidy; therefore, karyotyping is recommended for
the fetus with a CPC and another finding.
number, size, and laterality are not useful in distinguishing affected fetuses from normals.
resolution of CPCs does not necessarily reflect a normal
karyotype.
160
157-159
The predictive value of isolated CPCs for aneuploidy
is low when no other abnormalities are seen.
145-148
Cyst
Additionally,
125,147
Therefore, after a CPC is seen, there should be a detailed
ultrasound assessment, as well as correlation with a priori
The incidence of trisomy 13 in live-born infants is
approximately 1 : 12,000.
168
Individuals with trisomy 13
have numerous structural abnormalities and are severely
malformed and retarded. Anomalies often seen include
forebrain defects, ocular malformations, facial clefts, and
heart defects, as well abnormal extremities. About 45%
of those born alive die in the first month, and 90% do
not survive beyond 6 months of age. Rarely, survival is
more long term.
trisomy 13 is 90% to 100% (Fig. 31-12).
169
Sonographic detection of fetuses with
127,128,170-174
Cardiac and CNS defects are the most frequently
identified anomalies. The most common CNS malformations identified in trisomy 13 are holoprosencephaly,
ventriculomegaly, microcephaly, Dandy-Walker malfor-
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