Croat Med J 2005;46(5):786-791
CLINICAL SCIENCE
Nuchal Translucency and Nasal Bone for Trisomy 21
Screening: Single Center Experience
Giovanni Monni, Maria A. Zoppi, Rosa M. Ibba, Marcella Floris, Fabiola
Manca, Carolina Axiana
Department of Obstetrics and Gynecology, Prenatal and Preimplantation Genetic Diagnosis, Fetal
Therapy, Ospedale Microcitemico, Cagliari, Italy
To evaluate the feasibility and diagnostic accuracy of fetal nuchal translucency and nasal bone assessment at 11-14 weeks for screening of trisomy 21 at a single center.
Methods
Nuchal translucency measurement and nasal bone evaluation in relation to the fetal karyotype for singleton fetuses were retrospectively assessed at the Ospedale Microcitemico, Cagliari, Italy, in a threeyear period (2001-2004). Nuchal translucency was considered enlarged if greater than or equal to the
95th centile for crown-rump length (CRL) of the reference ranges, and nasal bone was described as
present or absent during the evaluation of the fetal facial profile. Sensitivity and specificity for trisomy
21 were assessed for nuchal translucency and absent nasal bone.
Results
Among 32,000 cases recorded in the database including fetuses from 11 to 14 weeks, 16,654 fetuses
were included in the study with both nuchal translucency measurement and nasal bone evaluation.
Median maternal age was 32 years (range, 14-49). In 854 fetuses (5.1%), nuchal translucency was
greater than the 95th centile, and 744 (87.1%) of them had a normal karyotype. Among 141 (0.8%)
diagnosed cases of chromosomopathies, there were 96 cases of trisomy 21. Nuchal translucency was enlarged in 110 chromosomopathies and in 72 trisomies 21. Sensitivity was 75.0% (95% confidence interval [CI], 65.5-82.6), and specificity 95.5% (95% CI, 95.2-95.8). In fetuses with enlarged nuchal translucency and normal karyotype, there were 30 structural defects (4%), and among these, 15 heart defects
(2%). Measurement of nuchal translucency was possible in all cases where it was attempted. In 13 cases
(0.1%), it was not possible to determine the visibility of the nasal bone. In 16,486 cases, the nasal bone
was defined as visible and in 155 cases (0.9%) the nasal bone was described as absent. The nasal bone
was absent in 56 trisomies 21 and in 23 other chromosomopathies, as well as in 76 normal karyotype
fetuses. The sensitivity was 58.3% (95% CI, 48.3-67.7) and specificity 99.5% (95% CI, 99.4-99.6). The
sensitivity of enlarged nuchal translucency and nasal bone was 80.2% (95% CI, 71.1-86.9).
Conclusions Enlarged nuchal translucency and absent nasal bone are useful markers of trisomy 21 in the first trimester ultrasound screening, increasing the sensitivity of detection of affected fetuses.
Aim
The thickness of nuchal translucency is
an anechoic space behind the fetal neck (1), visible and measurable in all fetuses from 10 to 14
weeks (Fig. 1). Enlarged nuchal translucency has
been shown to identify fetuses at higher risk for
aneuploidies (2,3) and its measurement has been
used as a prenatal ultrasound screening test for
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trisomy 21 (Fig. 2). An enlarged nuchal translucency at 11-14 weeks of gestation has been found
in about 80% of fetuses with trisomy 21 and in 8%
of normal karyotype fetuses (4-6).
Prenatal ultrasound studies in 11-14
weeks fetuses at high risk for aneuploidies have
shown that the nasal bone is not visible in about
Croat Med J
Monni et al: Nuchal Translucency and Nasal Bone for Screening
Figure 1. Normal nuchal translucency thickness in a first
trimester fetus. The measurement of nuchal translucency
comprises the hypo-anechoic space behind the fetal neck.
2005;46(5):786-791
Figure 3. Present nasal bone in a first trimester fetus. The
ultrasound image of the nasal bone is the second white
line in the nasal region, behind the anterior white line that
represents the fetal skin.
Figure 2. Enlarged nuchal translucency space in a trisomy
21 fetus.
60-70% of cases of trisomy 21 and in 0.5-1% of
the normal karyotype fetuses (7-8). The ultrasound
sign of absent nasal bone seems to be a promising
marker of trisomy 21 in the first trimester ultrasound
screening (9-10), either alone or in association with
the nuchal translucency test (Figs. 3 and 4).
A validated system of quality certification
has been carried out for nuchal translucency measurement in the last 10 years, and there is a large
body of evidence supporting the reliability of
nuchal translucency test for screening for chromosomopathies, if the quality of measurements is assured (5,11,12).
There are currently some reservations
about the applicability of the nasal bone evaluation for screening, because of problems have been
reported with reproducibility among different operators and relations with enlarged nuchal translucency (13).
In this study, we report the experience at
a single center for fetal nuchal translucency and
nasal bone evaluation at 11-14 weeks gestation for
Figure 4. Absent nasal bone in a trisomy 21 fetus. Only the
white line representing the fetal skin is visible in the fetal
nasal region, but not the second line of the nose.
trisomy 21 screening, focusing on the feasibility of
the assessment of both markers and on the diagnostic accuracy of these signs either separately or
together.
Methods
Sample and Procedure
The First Trimester Database of the
Ospedale Microcitemico, Cagliari, Italy, has been
in use since 1996 for nuchal translucency screening for Down syndrome. First trimester screening
for trisomy 21 has been offered to pregnant
women if they ask for it, according to the current
Italian National Health Ministry Guidelines for
prevention of congenital abnormalities. The software of the Fetal Medicine Foundation (FMF) has
been used since 1996 to calculate the individual
risk for Down syndrome on the basis of maternal
age, previous history, and nuchal translucency
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Monni et al: Nuchal Translucency and Nasal Bone for Screening
Croat Med J
measurement (4). Nuchal translucency measurement was performed according to the guidelines
of the FMF, by 7 certified operators throughout the
period, and the center’s results have been audited
on the annual basis.
Microsoft Excel 2000 software was used
for data storage and calculations.
Since 2001, data have been collected on
the presence and absence of the nasal bone. The
fetal nasal bone was visualized by transabdominal
ultrasound in an adequately magnified midsagittal
view of the fetal profile, as previously described
(14). When nasal bone was visualized, it was recorded in a database as “present,” and when it was
not visualized, as “absent.”
Among 32,000 cases in the database, including fetuses from 11 to 14 weeks for nuchal
translucency screening, 16,654 fetuses underwent
both nuchal translucency measurement and nasal
bone evaluation and met the inclusion criteria,
whereas 15,346 cases were excluded.
Prenatal invasive procedures for fetal
karyotype analysis were offered in the hospital,
providing the case was within the categories eligible under the Italian law (Italian Heath Ministry
Decree 1998, www.ministerosalute.it). Prenatal
karyotype, pregnancy outcome, and neonatal outcomes (neonatal assessment or necropsy), provided by outcome sheets or telephone interviews,
were entered in the database.
For this study, we analyzed the data on
fetuses from singleton pregnancies with no chromosomal abnormalities as assessed prenatally or
postnatally, or presumed by clinical examination
after delivery, and Down syndrome fetuses, diagnosed prenatally or postnatally or other chromosomal abnormalities. The data available in the database in December 2004 were analyzed in this
study. Normal variants, common inversions, balanced translocations, and pseudomosaicism were
classified as normal for this study. Fetuses with unknown outcomes and multiple pregnancies were
excluded.
For the purpose of this study, fetal nuchal translucency was retrospectively considered
“enlarged,” if greater than or equal to 95th centile
of reference range values of the FMF software (4),
and “normal” if lesser than the cut-off. Nasal bone
was recorded as either present or absent.
Statistical Analysis
Data on maternal age, crown-rump
length (CRL), and nuchal translucency measurement were presented as medians and ranges (min
and max). Sensitivity and specificity (95% confidence interval [CI]) for trisomy 21 were evaluated
for nuchal translucency greater than or equal to
95th centile of reference range values of the FMF
software and for absent nasal bone sign.
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2005;46(5):786-791
Results
The median maternal age was 32 years
(range, 14-49), median CRL length 53.4 mm (range,
45.0-82.0), and median nuchal translucency 1.4
mm (range, 0.5-11.0). In 854 cases (5.1%), nuchal
translucency was greater than the 95th centile, and
744 of them (87.1%) had a normal karyotype.
Among 141 diagnosed cases of chromosomopathies (0.8%), there were 96 cases of trisomy 21.
Nuchal translucency was enlarged in 110 chromosomopathies (78.0%), 72 of which were trisomies
21 (75.0%). The sensitivity of the measurement
was 75.0% (95% CI, 65.5-82.6), specificity 95.5%
(95% CI, 95.2-95.8). The flow diagram of nuchal
translucency is shown in Figure 5.
Among fetuses with enlarged nuchal
translucency and normal karyotype, there were 30
structural defects, including 15 heart defects (2%).
Nuchal translucency was measured in all cases in
which it was attempted, and performed by transabdominal ultrasound.
In 13 cases (0.1%), it was not possible to
ascertain if the nasal bone was visible or not. In
16,486 cases, the nasal bone was defined as visible and in 155 cases (0.9%) as absent. The nasal
bone was absent in 56 (58.3%) cases of trisomy 21
and in 23 (51.1%) cases of other chromosomopathies (1 case of partial trisomy 9, 3 cases of
trisomy 13, 14 cases of trisomy 18, 5 cases of 45,
X0) and 76 (0.5%) were normal karyotype fetuses.
The sensitivity was 58.3% (95% CI 48.3-67.7) and
specificity 99.5% (95% CI 99.4-99.6).
Nuchal translucency was enlarged in
145 cases (93.5%) with absent nasal bone and in
51 out of 56 cases with trisomy 21 with absent nasal bone. It was also enlarged in 71 out of 76 normal karyotype fetuses with absent nasal bone. No
abnormalities of the face development at birth
have been reported in these cases. Flow diagram
of nasal bone results is shown in Figure 6.
Croat Med J
2005;46(5):786-791
Cases present in the database
n=32,000
Other chromosomopathies
n=45
Enlarged nuchal translucency
n=72
Monni et al: Nuchal Translucency and Nasal Bone for Screening
Nuchal translucency and nasal bone
assesses, outcome available
n=16,654 singleton fetuses
Excluded (only nuchal translucency,
multiples, no outcome available)
n=15,346
Normal
n=16,513
Trisomies 21
n=96
Normal nuchal translucency
n=24
Enlarged nuchal translucency
n=744
Normal nuchal translucency
n=15,769
Figure 5. Flow diagram of nuchal translucency results in respect to fetal karyotype.
The sensitivity for trisomy 21 of enlarged
nuchal translucency and absent nasal bone was
80.2% (95% CI, 71.1-86.9), because 77 out of 96
trisomy 21 fetuses showed either enlarged nuchal
translucency or absent nasal bone. Among 744
normal fetuses with enlarged nuchal translucency,
673 showed present nasal bone (90.5%).
Discussion
This study confirmed that enlarged
nuchal translucency and absent nasal bone were
more frequent in trisomy 21 fetuses than in normal
karyotype fetuses (75% sensitivity for nuchal translucency and 58% for nasal bone, with a screen
positive rate of 0.9% for absent nasal bone and 5%
for enlarged nuchal translucency). Another evident finding was that nasal bone assessment was
more difficult than that of nuchal translucency. In
this series from a single center with experience in
the first trimester pregnancy screening, and in a
setting where seven operators are involved in the
screening, the measurement of nuchal translucency by transabdominal ultrasound was successful in all cases, whereas in 0.1% of the fetal profile
assessments it was not possible to define the presence or absence of the nasal bone.
Therefore, it seems easier to perform
nuchal translucency, than nasal bone measurement, which is not so specific as it can be defined
as “present,” “visible,” or “absent.” Similar criticism has been presented by other studies on the
nasal bone sign (13). A tested system of certifica-
tion of training in the nuchal translucency measurement used in our center with a periodical audit of the results for the last 10 years showed the
quality of this measurement for trisomy 21 screening (5). An equivalent system has not yet been introduced for the nasal bone, and some of the problems with this assessment may reflect the need of
standardization and training.
In our series, fetuses with absent nasal
bone frequently had enlarged nuchal translucency, either with trisomy or with normal karyotype. In trisomy 21, alteration in the ossification of
the nasal bone can depend on the failure in the migration of the neural crest cells, because of the abnormal composition of the connective tissue (15).
In these fetuses, the same cause involved in the
pathogenesis of the enlarged nuchal translucency
could be involved in the absence of the nasal
bone, and therefore the two signs may be inter-dependent.
On the other hand, in 5 out of 56 cases of
trisomy 21 with absent nasal bone, the finding of absent nasal bone was the only ultrasound marker for
trisomy 21 because the finding of nuchal translucency was normal. Therefore, the importance of absent nasal bone as the first level marker should not
be ignored. Whereas the performance of nasal bone
evaluation alone was modest (58.3% sensitivity in
this series), absent nasal bone improved the sensitivity of the nuchal translucency screening for trisomy
21, which can mean a decrease in the rate of normal
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Croat Med J
2005;46(5):786-791
Monni et al: Nuchal Translucency and Nasal Bone for Screening
Cases present in the database
n=32,000
Excluded (only nuchal translucency,
multiples, no outcome available)
n=15,346
Nuchal translucency and nasal bone
assessed, outcome available
n=16,554 singleton fetuses
Possible to define
nasal bone
n=16,641
Not possible to define if
present or absent nasal bone
n=13
Present nasal bone
n=16,486
Absent nasal bone
n=155
Other chromosomopathies
n=23
Enlarged nuchal
translucency
n=51
Trisomies 21
n=56
Normal nuchal
translucency
n=5
Normal
n=76
Other chromosomopathies
n=22
Enlarged nuchal
translucency
n=71
Trisomies 21
n=40
Normal
n=16,424
Normal nuchal
translucency
n=5
Figure 6. Flow diagram of the nasal bone results in respect to fetal karyotype.
fetuses considered at high risk because of enlarged
nuchal translucency.
A possible explanation for enlarged
nuchal translucency and absent nasal bone in normal karyotype fetuses is an evaluation bias by the
operator, who was not necessarily blinded to the
results.
Enlarged nuchal translucency can identify fetuses at risk for chromosomopathies other
than trisomy 21 and the fact that some cases with
chromosomopathies other than trisomy 21 showed
an absent nasal bone confirms both the results from
our center and from multicenter studies (4,12).
Enlarged nuchal translucency can identify fetuses at risk for structural defects (16). In our
series, heart defects were more frequent in fetuses
with nuchal translucency greater than or equal to
95th centile (about 2% of normal karyotype fetuses) than expected in general population, as reported by others (17,18).
Absent nasal bone was found in chromosomal abnormalities other than trisomy 21.
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This confirms previous reports (10,19). As far as
enlarged nuchal translucency is concerned, it is
suspected that it has different background in different chromosomopathies. Therefore, further
studies are needed to resolve this issue.
In conclusion, our experience with a
large number of fetal screening tests and comprehensive database shows that nuchal translucency
and nasal bone evaluation are useful markers on
first trimester ultrasound screening for trisomy 21,
increasing the sensitivity of detection. Further
studies to explain the relationship between absent nasal bone and enlarged nuchal translucency
should be addressed in order to promote the use of
both markers.
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2005;46(5):786-791
Received: January 17, 2005
Accepted: May 16, 2005
Correspondence to:
Giovanni Monni
Department of Obstetrics and Gynecology
Prenatal and Preimplantation Genetic Diagnosis
Fetal Therapy, Ospedale Microcitemico
via Jenner, 09121 Cagliari, Italy
[email protected]
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