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First-Trimester Screening
David A. Nyberg, MD*, Jon Hyett, MD,
Jo-Ann Johnson, MD, FRCSC, Vivienne Souter, MD
&First-trimester aneuploidy screening
&Screening strategies
First-trimester combined screen
First-trimester combined screen plus other
ultrasound markers
First-trimester screening followed by
second-trimester biochemistry
First-trimester screening followed by
second-trimester ultrasonography
&Other advantages of first-trimester
screening
Other chromosome abnormalities
Birth defects in euploid fetuses who have
increased nuchal translucency
Twins and multiple gestations
Structural defects detected during the first
trimester
&Summary
&References
All patients have a 2% to 3% risk of birth defects,
regardless of their prior history, family history,
maternal age, or lifestyle [1]. Chromosome abnor-
malities account for approximately 10% of birth
defects, but are important because of their high
mortality and morbidity. Trisomy 21 (Down syn-
drome) is the most common serious chromosome
abnormality at birth, occurring in approximately
1 of 500 pregnancies in the United States. The
actual risk varies with maternal and gestational
age and whether there is a history of previous preg-
nancies affected by chromosomal abnormality, al-
though, as with other birth defects, all patients are
at risk for fetal Down syndrome.
A detailed fetal anatomic survey performed at
18 to 22 weeks remains the primary means for
detecting the majority of serious ‘‘structural’’ birth
defects; however, first-trimester screening at 11 to
14 weeks has developed into the initial screening
test for many patients. A wealth of information can
be obtained at this time, including detection of
many structural defects, as well as screening for
fetal aneuploidy, including Down syndrome. The
major advantage of first-trimester screening is the
earlier gestational age of detection so that diagnos-
tic testing (chorionic villous sampling [CVS] or
genetic amniocentesis) can be made available for
patients considered at highest risk for chromo-
some abnormalities. First-trimester screening can
also help identify patients at increased risk for a
variety of other abnormalities, including cardiac
defects, that may be seen later. In this way, first-
trimester screening can help triage patients for sub-
sequent testing.
Older screening methods relied on clinical risk
factors, particularly maternal age, to determine
which patients might benefit from a diagnostic in-
vasive test for fetal aneuploidy; however, maternal
age alone is a poor screening method for determin-
ing who is at risk for chromosome abnormalities.
First-trimester screening has proved to be very effec-
tive in screening for fetal aneuploidy. The accuracy
of both first-trimester and second-trimester ultra-
sound can be improved by also considering various
ULTRASOUND
CLINICS
Ultrasound Clin 1 (2006) 231–255
Fetal & Womens Center,9440 E Ironwood Square Dr, Scottsdale, AZ 85258, USA
*Corresponding author.
E-mail address: nyberg@fetalcenter.com (D.A. Nyberg).
1556-858X/06/$ –see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cult.2006.01.006
ultrasound.theclinics.com
231
biochemical markers. As a result, there are cur-
rently four main components to screening for
fetal aneuploidy and other birth defects: (1) first-
trimester ultrasound, (2) first-trimester biochemistry,
(3) second-trimester ultrasound, and (4) second-
trimester biochemistry. These four components
of contemporary screening can be used in isola-
tion or can be combined with one another for
greater accuracy.
This article focuses on first-trimester ultrasound
screening, but also describes related screening pro-
tocols that can be used.
First-trimester aneuploidy screening
It is now well-known that increased fluid or thick-
ening beneath the skin at the back of the neck
is associated with a higher risk for fetal aneu-
ploidy and other birth defects. This sonographic
observation mirrors the clinical description of Down
syndrome made more than 100 years ago by
Dr. Langdon Down, who reported that the skin
of affected individuals is ‘‘too large for their bod-
ies’’ [2].
During the 1980s, many ultrasound studies de-
scribed the typical appearance of cystic hygromas
in the second trimester, and their association with
aneuploidy, particularly Turner’s syndrome [2–12].
At the same time, it was observed that cystic hy-
gromas seen during the first trimester may have
different appearances (nonseptated), and different
associations (trisomies) than those seen during the
second trimester. It was also observed that ‘‘cystic
hygromas’’ seen during the first trimester can
resolve to nuchal thickening alone, or even normal
nuchal thickness, and still be associated with aneu-
ploidy [13,14]. In a related observation, Benacerraf
and colleagues [15,16] noted that second-trimester
nuchal thickening was associated with an increased
risk of Down syndrome.
In 1992, Nicolaides and colleagues [17] proposed
the term ‘‘nuchal translucency (NT)’’ for the sono-
graphic appearance of fluid under the skin at the
back of the fetal neck observed in all fetuses during
the first trimester [Fig. 1]. They further reported an
association between the thickness of the translu-
cency and the risk of fetal aneuploidy, especially
trisomies. This concept of measuring NT in all
fetuses formed the basis for first-trimester screening
by ultrasound. By 1995, the first large study of NT
was published [18]. Subsequent studies have con-
firmed that NT thickness can be reliably measured
at 11 to 14 weeks gestation and, combined with
maternal age, can produce an effective means of
screening for trisomy 21 [19].
The mechanism for increased NT may vary with
the underlying condition. The most likely causes
include heart strain or failure [20,21] and abnor-
malities of lymphatic drainage [22]. Evidence for
heart strain includes the finding of increased levels
of atrial and brain natriuretic peptide mRNA in fe-
tal hearts among trisomic fetuses [23]. Also, some
Doppler ultrasound studies of the ductus venosus
at 11 to 14 weeks in fetuses who have increased NT
have reported absent or reversed flow during atrial
contraction in the majority of chromosomally ab-
normal fetuses and in chromosomally normal fe-
tuses who have cardiac defects [24,25].
Abnormal lymphatic drainage may occur because
of developmental delay in the connection with the
venous system, or a primary abnormal dilatation
or proliferation of the lymphatic channels. Fetuses
who have Turner’s syndrome are known to have
hypoplasia of lymphatic vessels [26,27]. Lymphatic
drainage could also be impaired by lack of fetal
movements in various neuromuscular disorders,
such as fetal akinesia deformation sequence [28].
An alternative explanation for increased NT is
abnormal composition of the extracellular matrix.
Many of the component proteins of the extracellu-
lar matrix are encoded on chromosomes 21, 18,
or 13. Immunohistochemical studies of the skin of
chromosomally abnormal fetuses have demon-
strated specific alterations of the extracellular ma-
trix that may be attributed to gene dosage effects
[29,30]. Altered composition of the extracellular
matrix may also be the underlying mechanism for
increased fetal NT in certain genetic syndromes that
are associated with alterations in collagen metabo-
lism (such as achondrogenesis Type II), abnormali-
ties of fibroblast growth factor receptors (such
as achondroplasia and thanatophoric dysplasia),
or disturbed metabolism of peroxisome biogenesis
factor (such as Zellweger syndrome).
All studies indicate that proper training is re-
quired to obtain reproducible, accurate data from
Fig. 1. Normal nuchal translucency measurement (arrows)
at 12 weeks, 5 days.
232 Nyberg et al
NT measurements [31–33]. The Fetal Medicine
Foundation (www.fetalmedicine.org) has outlined
guidelines that have become the standard for mea-
surement of NT throughout the world. These are
listed in Box 1. They also offer a certificate of com-
petency for those sonographers who successfully
show they can adhere to them. Virtually identical
guidelines have now been proposed by the Society
for Maternal Fetal Medicine in the United States,
and they also offer a certificate of competency.
Use of the guidelines proposed by the Fetal Medi-
cine Foundation have resulted in a high consistency
in results [Table 1]. Monni and coworkers [34]
reported that after modifying their technique of
measuring NT, by following the guidelines estab-
lished by The Fetal Medicine Foundation, their
detection rate of trisomy 21 improved from 30%
to 84%.
The ability to measure NT and obtain reproduc-
ible results improves with training; good results are
achieved after 80 and 100 scans for the transab-
dominal and the transvaginal routes, respectively
[35]. The intraobserver and interobserver differ-
ences in measurements are less than 0.5 mm in
95% of cases [36]. NT is usually measured using a
transabdominal approach; transvaginal scanning
may be necessary in 5% to 10% of pregnancies
when transabdominal scans are technically limited.
The normal range for NT measurements is ges-
tational age dependent. Pandya and colleagues
[36] reported that the median NT increases from
1.3 mm at a crown-rump length (CRL) of 38 mm to
1.9 mm at a CRL of 84 mm. The 95th percentile
increases from 2.2 mm at a crown rump length of
38 mm to 2.8 mm at a CRL of 84 mm. Sonogra-
phers should recognize that technical factors influ-
ence NT measurements. For example, extension of
the neck increases NT thickness, whereas flexion
reduces the measurement.
The criteria for a positive NT scan have evolved
since its first description. Initially a categorical cut-
off measurement (usually 2.5 or 3 mm) was used
by most centers; however, as noted above, NT in-
creases with gestational age, and the degree of risk
was found to vary with NT measurements. There-
fore, it is more appropriate to express NT measure-
ments relative to gestational age or CRL as a delta
value or multiple of the median. Use of multiple of
median data and derived likelihood ratios can then
estimate the patient-specific risk. This also permits
integration of risk based on NT with biochemical
data to generate a combined risk. It should be noted
that the median NT measurement for Down syn-
drome is about two multiples of the median. This
is equivalent to about 2.5 mm at 12 weeks.
The effectiveness of NT screening for detection
of fetal Down syndrome has now been confirmed
by a number of studies [see Table 1]. In the largest
multicenter study published [19], 96,127 single-
ton pregnancies were examined, including 326 af-
Box 1: Criteria for what constitutes an
adequate NT measurement include
1. Crown–rump length between 45 mm and
84 mm
2. Sagittal view that shows the nuchal
measurement and face with the fetus in
neutral position
3. Magnification so that only the upper two
thirds of the fetus is included on the image
4. Distinguishing nuchal membrane from
the amnion
5. Measuring maximal subcutaneous
translucency overlying the neck
6. Identifying causes of falsely increased
nuchal translucency measurements, includ-
ing fetal extension, and nuchal cord
Table 1: Studies examining the implementation of fetal nuchal translucency measurement at
10–14 weeks of gestation in screening for trisomy 21
Author N Screening cutoff FPR DR
Pandya et al, 1995 [37] 1763 NT >2.5 mm 3.6% 3 of 4 (75%)
Szabo et al, 1995 [38] 3380 NT >3.0 mm 1.6% 28 of 31 (90%)
Taiplae et al, 1997 [39] 6939 NT >3.0 mm 0.8% 4 of 6 (67%)
Hafner et al, 1998 [40] 4233 NT >2.5 mm 1.7% 3 of 7 (43%)
Pajkrt et al, 1998 [41] 1473 NT >3.0 mm 2.2% 6 of 9 (67%)
Economides et al, 1998 [42] 2281 NT >99th centile 0.4% 6 of 8 (75%)
Zoppi et al, 2000 [43] 5210 Risk >1 in 100 4.2% 33 of 47 (70%)
Thilaganathan et al, 1999 [44] 11,398 Risk >1 in 200 4.7% 16 of 21 (76%)
Schwarzler et al, 1999 [45] 4523 Risk >1 in 270 4.7% 10 of 12 (83%)
Theodoropoulos et al, 1998 [46] 3550 Risk >1 in 300 4.9% 10 of 11 (91%)
Total 44,750 3.0% 119 of 156 (76%)
Abbreviations: DR, detection rate; FPR, false-positive rate; N, number.
233First-Trimester Screening
fected by trisomy 21 and 325 who had other
chromosomal abnormalities. The median gesta-
tion at the time of screening was 12 weeks (range
10–14 weeks), and the median maternal age was
31 years (range 14–45 years). The fetal NT was
above the 95th percentile for crown-rump length
in 72% of the trisomy 21 pregnancies [Figs. 2, 3].
The estimated risk for trisomy 21 based on mater-
nal age and fetal NT was above 1 in 300 in 8.3% of
normal pregnancies and 82% of those affected by
trisomy 21. For a screen positive rate of 5%, the
sensitivity was 77% (95% CI: 72%–82%). The
cumulative data from a number of other studies
demonstrate a sensitivity of 77% for a false positive
rate of 3% [see Table 1][37–46].
The effectiveness of screening for fetal aneu-
ploidy is further increased when nuchal trans-
lucency thickness is combined with biochemical
markers [Table 2]. The two most effective maternal
serum markers currently used in the first trimester
are pregnancy-associated plasma protein A (PAPP-A)
and free B-human chorionic gonadotrophin (B-hCG).
Maternal serum free β-human chorionic gonado-
tropin (β-hCG) normally decreases with gestation
after 10 weeks and maternal serum PAPP-A levels
normally increase. Levels of these two proteins tend
to be increased and decreased, respectively, in preg-
nancies affected by trisomy 21. There does not
appear to any correlation between the rise in free
β-hCG and fall in PAPP-A seen in trisomy 21 preg-
nancies, so these markers may be combined for
screening purposes [47]. Similarly, these biochemi-
cal markers are independent of fetal NT thickness,
allowing combination of biochemical and ultra-
sound tests [48,49].
Some authorities believe it is important to dis-
tinguish cystic hygromas from increased NT [50],
whereas others do not. Malone and coworkers [50]
reported 132 cases of cystic hygroma with follow-
up among 38,167 screened patients (1 in 289).
Chromosomal abnormalities were diagnosed in
67 (51%), including 25 who had Down syndrome,
19 who had Turner’s syndrome, 13 who had tri-
somy 18, and 10 who had other types of chro-
mosome abnormalities. Major structural fetal
malformations, primarily cardiac and skeletal ab-
normalities, were diagnosed in 22 of the remaining
65 cases (34%). Of the remaining cases, 20 resulted
in spontaneous fetal death (n = 5) or elective preg-
nancy termination (15). One of 23 normal survi-
Fig. 2. Mildly increased nuchal translucency measure-
ment associated with trisomy 21 (calibers). The nuchal
measurement was 2.3 mm, which is about twice nor-
mal for gestational age. Biochemical values also indi-
cated an increased risk for trisomy 21.
Fig. 3. Increased nuchal translucency and trisomy 21.
The nuchal translucency measurement (NT ) exceeded
3 mm.
Table 2: Studies examining the implementa-
tion of a combined first-trimester test using
maternal age, fetal nuchal translucency thick-
ness, free β-hCG and PAPP-A to screen for tri-
somy 21
Author N FPR DR
Orlandi et al,
1997 [53]
744 5.0% 6 of 7 (86%)
Biagotti et al,
1998 [54]
232 5.0% 24 of 32 (75%)
Benattar et al,
1999 [55]
1656 5.0% 5 of 5 (100%)
De Biasio et al,
1999 [56]
1467 3.3% 11 of 13 (85%)
De Graff et al,
1999 [57]
300 5.0% 31 of 37 (84%)
Spencer et al,
1999 [47]
1156 5.0% 187 of 210
(89%)
Krantz et al,
2000 [58]
5718 5.0% 30 of 33 (90%)
Total 11,273 4.8% 294 of 337
(87%)
234 Nyberg et al
vors (4%) was diagnosed with cerebral palsy and
developmental delay at birth. Overall, survival with
normal pediatric outcome was confirmed in 17%
of cases (22 of 132). Compared with increased
nuchal translucency (>3 mm), cystic hygromas car-
ried a fivefold, 12 fold, and sixfold increased risk
of aneuploidy, cardiac malformation, and perinatal
death, respectively. On the other hand, cystic hy-
gromas were associated with larger NT measure-
ments than those that had increased NT but did
not have cystic hygromas, so it remains uncertain
whether cystic hygromas are an independent risk
factor. Like patients who have increased NT, the
vast majority of pregnancies that have normal
evaluation at the completion of the second trimes-
ter resulted in a healthy infant and a normal pedi-
atric outcome.
Lateral neck cysts, also termed ‘‘jugular lymphatic
sacs,’’ have been found by Bekker and coworkers
[51] to be associated with larger NT measurements
and thus a higher risk for fetal aneuploidy [Fig. 4].
They found that among 26 fetuses with increased
NT (>95th percentile), 22 had clearly visible jugular
lymphatic sacs and 16 of 26 (62%) had aneu-
ploidy. In comparison, two fetuses in the control
group also showed jugular lymphatic sacs and their
NT measurements were upper normal (2.8 mm and
2.9 mm). Although one might conclude that lateral
neck cysts are associated with a high risk of fetal
aneuploidy, Sharony and colleagues [52] found
that the outcome of lateral neck cysts is associated
with both the presence of other abnormalities and
the NT measurement, but not with the presence of
cysts themselves. On the other hand, these authors
found a relatively high incidence of lateral neck
cysts (2.4%) in the general population, suggesting
that some of these cysts were very small and would
have escaped general detection.
Fig. 4. Distended jugular lymphatic “sacs.”(A) Increased nuchal translucency measurement of 2.5 mm is noted.
(B) Transvaginal scans show small bilateral fluid collections consistent with jugular lymphatic sacs. These are as-
sociated with increased nuchal translucency measurements.
235First-Trimester Screening
Screening strategies
First-trimester combined screen
The first-trimester combined screen uses maternal
age, NT measurement, and biochemical markers
(free β-hCG and PAPP-A) to estimate the risk for
fetal Down syndrome and trisomy 18. This is the
most popular and effective screening strategy dur-
ing the first trimester. A number of studies suggest a
detection rate in the range of 85% to 90% for a
screen positive rate of 5% [see Table 1][52–59].
Two large US studies have also been reported
showing the effectiveness of first-trimester screen-
ing. The First-trimester Maternal Serum Biochemis-
try and Fetal Nuchal Translucency Screening (BUN)
study found a 79% detection rate, for a 5% false-
positive rate [60].
The First- and Second-Trimester Evaluation of
Risk (FASTER) Research Consortium trial [61] is
the largest US-based study, and the only study
that has compared first-trimester screening with
second-trimester screening. The FASTER data [61]
clearly confirm the pioneering work of Nicolaides
and colleagues [17,19], with similar results. The
overall detection rate was 85%, for a false-positive
rate of 5%; however, the results clearly varied
with gestational age, with detection rate of 87% at
11 weeks compared with 82% at 13 weeks.
First-trimester combined screen plus other
ultrasound markers
Although increased NT remains the primary ultra-
sound marker of fetal aneuploidy and other birth
defects during the first trimester, several other ultra-
sound findings have been found to be helpful at
this time. These include hypoplastic or absent nasal
bone, and abnormal Doppler waveforms of the
tricuspid valve and ductus venosus.
Hypoplastic/absent nasal bone
A small nasal bone was first noted to a com-
mon feature of patients who had trisomy 21 by
Dr. Langdon Down [2]. Anthromorphic studies in
patients who have trisomy 21 have shown a small
nasal bone in approximately half of affected cases.
A number of ultrasound studies have now also
shown an association between sonographically ab-
sent nasal bone and trisomy 21 as well as other
chromosome abnormalities [62–69]. In the com-
bined data of 15,822 fetuses, the fetal profile was
successfully examined in 97.4%, and the nasal
bone was absent in 1.4% of normal fetuses and
in 69% of fetuses who had trisomy 21.
A minority of studies have concluded that an
absent nasal bone is not a useful feature to detect
fetal Down syndrome, and that reproducibility is
poor during the first trimester [70,71]. This prob-
ably reflects the technical difficulty in obtaining
accurate nasal bone measurements at this time.
Imaging of the nasal bones requires a near-perfect
midsagittal image and optimal angle of insonation
with the fetal profile, whereas NT measurements
can be obtained with minor variations off-center
and differences in direction of imaging. Demon-
strating the absence of a very small structure is even
more difficult than detecting its presence, because it
can be difficult to know for certain whether the
nasal bones are absent or whether the images are
simply suboptimal. Malone and coworkers [71]
found that factors associated with an increased fail-
ure rate of nasal bone included early gestational
age when the nasal bone is normally small, larger
maternal body habitus, inadequate nuchal translu-
cency sonography, and use of a transvaginal sono-
graphic approach.
Increased impedance of flow of the ductus
venosus
Abnormal Doppler flow patterns of the ductus ve-
nosus have been associated with an increased risk
of fetal Down syndrome [Fig. 5][24,25]. Matias
and colleagues [24] performed ductus venosus
Doppler measurements on 486 singleton fetuses,
including 68 who had chromosomal abnormali-
ties, at 10 to 14 weeks’ gestation. In 90.5% of the
chromosomally abnormal fetuses there was re-
versed or absent flow during atrial contraction,
Fig. 5. Abnormal ductus venosus Doppler and tri-
somy 21 (same fetus as Fig. 4). Duplex Doppler of
the ductus venosus shows retrograde flow during
atrial contractions.
236 Nyberg et al
whereas abnormal ductus flow was only present in
3.1% of the chromosomally normal fetuses. The
height of the A-wave was found to be the only sig-
nificant independent factor in multivariate regres-
sion analysis. Other researchers have also found
that ductus venosus Doppler studies can sub-
stantially improve Down syndrome screening effi-
ciency [72].
Tricuspid regurgitation has also been associated
with an increased risk of fetal Down syndrome. In
the largest study reported, Faiola and coworkers
[73] reported that the tricuspid valve was success-
fully examined in 718 (96.8%) cases. Tricuspid
regurgitation was found in 39 (8.5%) of the 458
chromosomally normal fetuses, in 82 (65.1%) of
the 126 who had trisomy 21, in 44 (53%) of the 83
who had trisomy 18 or 13, and in 11 (21.6%) of
the 51 who had other chromosomal defects. In
chromosomally normal fetuses, tricuspid regurgita-
tion was associated with increased NT measure-
ments, suggesting that Doppler studies may be
particularly useful in this group of patients.
Fetuses who have abnormal flow patterns of the
ductus venosus and tricuspid valve also appear to
have a higher risk of cardiac defects. Among 142
chromosomally normal fetuses who had increased
NT, 11 fetuses had reversed or absent flow on duc-
tus venosus Doppler during atrial contraction, and
7 of these had major cardiac defects at subsequent
echocardiography [25]. Similarly, Faiola and col-
leagues [73] found that in the chromosomally nor-
mal fetuses, tricuspid regurgitation was found in
nearly half (46.9%) of fetuses who had cardiac
defects and in 5.6% of those who did not have
cardiac defects (likelihood ratio of 8.4).
Nicolaides and coworkers [74] suggest that sec-
ondary findings of absent nasal bone or abnormal
Doppler studies could be particularly useful in pa-
tients found to be in the intermediate risk group by
the first-trimester screen. Using these secondary
signs in patients with an intermediate risk group
(risk of 1 in 100 to 1 in 1000) for fetal Down
syndrome, the researchers reported detection rates
of 92% for absent nasal bone, 94% for increased
impedance of the ductus venosus, and 91.7% for
tricuspid regurgitation, with each method showing
an overall false-positive rate of less than 3% [74].
First-trimester screening followed by
second-trimester biochemistry
Second-trimester biochemical screening can detect
70% to 80% of affected fetuses who had Down
syndrome (at a false positive rate of 7%–8%). The
effectiveness appears to be clearly higher for the
‘‘quad’’ screen (HCG, alpha-fetoprotein, estriol, and
inhibit-A), than the older ‘‘triple’’ screen that did
not include inhibin-A [50]; however, the effective-
ness of second-trimester biochemical screening is
more limited in a population that has already been
screened, and in the authors’ experience, most pa-
tients who have undergone first-trimester screening
will choose not to undergo second-trimester bio-
chemical screening.
For those patients who would like additional
reassurance by way of a second-trimester biochemi-
cal screen, it should be done in a way that accounts
for the first-trimester screening results rather than
treating them as independent tests. One method is
the so-called ‘‘integrated screen,’’ which combines
the elements of the first-trimester combined screen
with the elements of the second-trimester ‘‘quad’’
screen, providing a single, low false-positive result
in the second trimester [75]. This is the most accu-
rate screening method currently available, with
detection rate of 92% in the FASTER study [76];
however, a major disadvantage of integrated screen-
ing is that patients do not receive results until
after completion of the second-trimester biochem-
istry. Thus screen-positive women do not have
the option of CVS for early definitive diagnosis
[77]. In addition, it is considered unethical to sup-
press ultrasound information obtained in the
first trimester.
‘‘Stepwise sequential’’ screening is an alternative
approach that has been proposed; it interprets
second-trimester results based on first-trimester risk
assessment. A clear advantage of stepwise sequen-
tial screening is that it provides some women an
earlier diagnosis while maintaining an extremely
high detection rate. This method has gained rapid
acceptance and it is expected to be widely adapted
into clinical practice in the near future [78]. When
patients in the FASTER trial underwent first-
trimester combined screening at 11 weeks and the
false-positive rate of each component was set at
2.5%, stepwise sequential screening provided a
95% detection of Down syndrome, for a 4.9%
false-positive rate. This compares to a 4.0% false-
positive rate for fully integrated screening.
Incorporation of second-trimester biochemical
as part of a stepwise sequential screen would be
most effective for patients considered in an inter-
mediate risk group (risk between 1 in 100 and 1 in
1000) [79]. The intermediate group includes 15%
of affected fetuses who had Down syndrome and
approximately 15% of normal fetuses. In compari-
son, high risk patients (risk >1 in 100) should
probably consider diagnostic invasive testing with-
out additional screening; this group includes
80% of affected fetuses who have Down syndrome
but only 5% of normal fetuses. Also, low-risk pa-
tients (risk <1 in 1000) probably do not require
additional screening in most cases; this group of
patients includes less than 5% of affected fetuses
237First-Trimester Screening
who have Down syndrome, but 80% of nor-
mal fetuses.
First-trimester screening followed by
second-trimester ultrasonography
A second-trimester fetal survey remains the primary
method of detecting the majority of birth defects
that can be detected prenatally [80]. Because of the
wide range of anomalies that can be detected at this
time, this examination is unlikely to be replaced
by any other screening test in the future. In addi-
tion to detection of structural defects, the presence
or absence of various sonographic markers can
further modify the risk for fetal aneuploidy, includ-
ing Down syndrome. The estimated risk can be
derived by multiplying the background risk (based
on maternal age, gestational age, history of previ-
ously affected pregnancies, and, where appropriate,
the results of previous screening by NT or biochem-
istry in the current pregnancy) by the likelihood
ratio of the specific defect [81]. The most common
second-trimester ultrasound markers that are sys-
tematically evaluated include nuchal thickening,
echogenic intracardiac foci, absent or hypoplastic
nasal bone, hyperechoic bowel, renal pyelectasis,
and shortened femur and humerus lengths relative
to the biparietal diameter. Nyberg and coworkers
[82] and others have calculated likelihood ratios for
many of these markers and have refined this for
single markers [83].
In the vast majority of cases, second-trimester
ultrasound markers such as echogenic intracar-
diac foci will be found in normal fetuses, especially
when the marker is isolated. In this situation, a
prior normal first-trimester screening result can be
very reassuring. Because a normal first-trimester
screening results permits significant reduction of
risk for fetal Down syndrome, and because isolated
findings such as echogenic intracardiac foci only
slightly increase the risk, most patients will remain
at very low risk and do not require further testing.
Ultrasound findings, however, can also improve
the detection rate of fetuses who have Down syn-
drome in patients who have borderline normal
results from first-trimester screening, or fetuses
who show multiple markers or major defects. At
the same time, a normal second-trimester ultra-
sound can reduce the risk of fetal Down syndrome
approximately threefold, and this can normalize
patients who have borderline positive results form
first-trimester screening (risk 1 in 100 to 1 in 300).
Results of the FASTER trial show that use of a
second-trimester genetic sonogram can both im-
prove the detection rate and lower the false positive
rate in patients who have undergone first-trimester
screening [84].
Other advantages of first-trimester screening
Other chromosome abnormalities
Nuchal translucency is also increased with other
chromosome abnormalities, including trisomies 13
and 18, Turner’s syndrome, triploidy, and unbal-
anced translocations [Fig. 6][85]; however, first-
trimester biochemical markers may differ from
those typically associated with trisomy 21. In triso-
mies 18 and 13, maternal serum free β-hCG and
PAPP-A are decreased [86,87]. In cases of sex chro-
mosomal anomalies, maternal serum free β-hCG is
normal and PAPP-A is low [88]. Triploidy of pater-
nal origin, which is associated with a partial molar
placenta, has greatly increased levels of free β-hCG,
whereas PAPP-A is mildly decreased [89]. In con-
Fig. 6. Increased nuchal translucency and trisomy 18. Large nuchal translucency measurement was noted and
cytogenetic testing revealed trisomy 18.
238 Nyberg et al
trast, digynic triploidy, characterized by severe
asymmetrical fetal growth restriction, is associated
with markedly decreased maternal serum free
β-hCG and PAPP-A. Screening by a combination
of fetal NT, free β-hCG, and PAPP-A can identify
Table 3: Abnormalities and genetic syndromes
reported in association with increased nuchal
translucency and normal karyotype
Central nervous
sytem defect Anencephaly
Craniosynostosis
Dandy-Walker
malformation
Diastematomyelia
Encephalocele
Holoprosencephaly
Hydrolethalus syndrome
Joubert syndrome
Microcephaly
Macrocephaly
Spina bifida
Iniencephaly
Trigoncephaly C
Ventriculomegaly
Facial defect Agnathia/micrognathia
Facial cleft
Treacher-Collins syndrome
Nuchal defect Cystic hygroma
Neck lipoma
Cardiac defect Di George syndrome
Pulmonary
defect
Cystic adenomatoid
malformation
Diaphragmatic hernia
Fryn syndrome
Abdominal
wall defect
Cloacal exstrophy
Omphalocele
Gastroschisis
Gastrointestinal
defect
Crohn´s disease
Duodenal atresia
Esophageal atresia
Small bowel obstruction
Genitourinary
defect
Ambiguous genitalia
Congenital nephrotic
syndrome
Hydronephrosis
Hypospadius
Infantile polycystic kidney
disease
Meckel-Gruber syndrome
Megacystis
Multicystic dysplastic
kidney disease
Renal agenesis
Skeletal
defect
Achondrogenesis
Achondroplasia
Asphyxiating thoracic
dystrophy
Blomstrand
osteochondrodysplasia
Campomelic dwarfism
Jarcho-Levin syndrome
Kyphoscoliosis
Limb reduction defect
Noonan-Sweeney syndrome
Osteogenesis imperfecta
Roberts syndrome
Table 3: (continued )
Central nervous
sytem defect Anencephaly
Robinow syndrome
Short rib polydactyly
Sirenomelia
Talipes equinovarus
Split hand/foot
malformation
Thanatophoric dwarfism
VACTER association
Fetal anemia Blackfan-Diamond anemia
Dyserthropoietic anemia
Fanconi anemia
Parovirus 19 infection
Alpha thalassemia
Neuromuscular
defect
Fetal akinesia
deformation sequence
Myotonic dystrophy
Spina muscular atrophy
Metabolic defect Beckwith-Wiedemann
syndrome
GM1 gangliosidosis
Long-chain 3-hydroyacyl-
coenzyme A dehydrogenase
deficiency
Mucopolysaccharisosis
Type VII
Smith-Lemli-Opitz syndrome
Vitamin D-resistant rickets
Zellweger syndrome
Other Body stalk anomaly
(limb body wall complex)
Brachmann-de Lange
syndrome
CHARGE association
Deficiency of the immune
system
Congenital lymphedema
EEC syndrome
Neonatal myoclonic
encephalopathy
Noonan syndrome
Perlman syndrome
Stickler syndrome
Unspecified syndrome
Severe developmental delay
Abbreviation: EEC syndrome, ectrodactyly-ectodermal
dysplasia-cleft palate syndrome.
Adapted from Souka AP, Krampl E, Bakalis S, et al. Out-
come of pregnancy in chromosomally normal fetuses
with increased nuchal translucency in the first-trimester.
Ultrasound Obstet Gynecol 2001;18(1):13, 14.
239First-Trimester Screening
about 90% of these anomalies for a screen positive
rate of 1%.
Birth defects in euploid fetuses who have
increased nuchal translucency
Extensive studies have now established that, in
chromosomally normal fetuses, increased NT is as-
sociated with a wide range of fetal defects and
genetic syndromes [Table 3].
The prevalence of birth defects and adverse
outcome also increases with increasing NT mea-
surements [Table 4]. Souka and colleagues [90]
reported that the overall risk of adverse outcome,
including miscarriage and intrauterine death, was
32% for those who had NT of 3.5 to 4.4 mm, 49%
for NT of 4.5 to 5.4 mm, 67% for NT 5.5 to 6.4 mm,
and 89% for those who had NT of 6.5 mm or
more. Among 1080 surviving fetuses who had NT
of 3.5 mm or more, 5.6% had abnormalities requir-
ing medical or surgical treatment or leading to
mental handicap. The chance of no defect among
live births was 86% for those who had NT of 3.5 to
4.4 mm, 77% for those who had NT of 4.5 to
5.4 mm, 67% for those who had NT of 5.5 to 6.4,
and 31% for those who had NT of 6.5 mm or more.
An association between increased NT and cardiac
defects was first noted by Hyett and coworkers [20]
in both chromosomally abnormal and normal fe-
tuses. This has subsequently been confirmed by a
number of studies [91–100]. A retrospective study
of 29,154 chromosomally normal singleton preg-
nancies identified major defects of the heart and
great arteries in 50 cases, and 56% of these had NT
measurement translucency above the 95th percen-
tile [101]. In chromosomally normal fetuses, the
prevalence of major cardiac defects increases expo-
nentially from 1.6 per 1000 for NT less than 95th
percentile, 1% for NT between 2.5 and 34 mm, 3%
for NT 3.5% to 4.4%, 7% for NT 4.5% to 5.4%,
20% for NT 5.5 to 6.4 mm, 30% for NT 6.5 mm
or more.
The clinical implication of these observations is
that patients found to have increased NT should
undergo formal fetal echocardiography. Certainly,
Table 4: Nuchal translucency measurements and adverse outcomes
Nuchal translucency
measurement Aneuploidy Death Major anomaly Alive and well
<95th percentile .2% 1.3% 1.6% 97%
95th–99th 3.7% 1.3% 2.5% 93%
3.5–4.4 mm 21.1% 2.7% 10% 70%
4.5–5.4 mm 33.3% 3.4% 18.5% 50%
5.5–6.4% 50.5% 10.1% 24.2% 30%
6.5 mm 64.5% 19% 46.2% 15%
Data from Refs. [19,42,90,103].
Fig. 7. Discrepant nuchal translucency measurements in monochorionic twins. (A) This fetus shows nuchal trans-
lucency measurement (NT ) of 2 mm at 12 weeks. The co-twin showed nuchal translucency measurement of
1.1 mm. (B) Velemenous cord insertion is also apparent. This monochorionic twin pregnancy showed signs of
severe twin-twin transfusion syndrome by 18 weeks.
240 Nyberg et al
the overall prevalence of major cardiac defects in
such a group of fetuses (about 2%) is similar to that
found in pregnancies affected by maternal diabetes
mellitus or who have a history of a previously
affected offspring, which are well-accepted indica-
tions for fetal echocardiography. Improvements in
the resolution of ultrasound machines have now
made it possible to undertake detailed cardiac scan-
ning as early as 14 weeks [87,102].
It should be emphasized to the parents that
increased NT per se does not constitute a fetal
abnormality, and that, once chromosomal defects
have been excluded, nearly 90% of liveborns who
have fetal translucency below 4.5 mm have healthy
live births. If the fetus survives until midgestation,
and if a targeted ultrasound at 20 to 22 weeks fails
to reveal any abnormality, the risk of adverse out-
come is not statistically increased [103]. The rate of
Fig. 9. Normal brain at 12 weeks. (A) Transabdominal scans show that the normal choroid plexus dominates
the cerebral hemispheres. (B) Transvaginal scan on the same patient better shows normal anatomy.
Fig. 8. Normal face at 13 weeks. (A) Sagittal view shows normal facial profile including nasal bone. (B) 3D multi-
planar ultrasound with surface rendering shows normal facial features.
241First-Trimester Screening
development delay is also not statistically increased
among fetuses who have increased NT [104].
Twins and multiple gestations
First-trimester screening can be effectively used for
twin pregnancies [105]. Detection rates for Down
syndrome are in the range of 75% to 85%, with a
5% false-positive rate [106]. Therefore, effective
screening and diagnosis of major chromosomal
abnormalities can be achieved in the first-trimester,
allowing the possibility of earlier and therefore
safer selective feticide for those parents that choose
this option.
Discrepant NT measurements also appear to be a
nonspecific early marker of twin-twin transfusion
syndrome among monochorionc twins [Fig. 7]. In
a study of 132 monochorionic twin pregnancies,
including 16 that developed severe twin-to-twin
transfusion syndrome at 15–22 weeks of gesta-
tion, increased NT (above the 95th percentile of
the normal range) at the 11 to 14 week scan was
associated with a fourfold increase in risk for
the subsequent development of severe twin-to-twin
transfusion syndrome [107]. It is possible that in-
creased NT thickness in the recipient fetus may be
a manifestation of heart failure caused by hyper-
volemic congestion. With advancing gestation and
the development of diuresis that would tend to cor-
rect the hypervolemia and reduce heart strain, both
the congestive heart failure and NT resolve.
Severe complications unique to monochorionic
pregnancies, such as reversed arterial perfusion syn-
drome or acardiac twin, and conjoined twins, can
be diagnosed during the first trimester. Twin re-
versed arterial perfusion (TRAP) has been reported
at 10 to 12 weeks using both TVS and color Dopp-
ler [108,109]. Conjoined twins have also been
frequently diagnosed during the first trimester,
Fig. 10. Normal anatomy. (A) Transvaginal scan at 13 weeks shows normal four-chamber view of the heart.
(B) Transabdominal scan at 13 weeks shows normal fluid-filled stomach. (C) Transabdominal scan of the pelvis at
12 weeks shows a normal urinary bladder between the two umbilical arteries, seen with color flow Doppler.
A normal urinary bladder is less frequently seen than the stomach.
242 Nyberg et al
and have been detected as early as 8 to 9 weeks
[110–118].
Structural defects detected during the first
trimester
Use of a systematic survey can demonstrate normal
anatomic development in the first trimester, similar
to the fetal survey performed during the second
trimester. Normal structures that can be visualized
include the brain, choroid plexi, posterior fossa,
face, heart, thorax, abdomen, stomach, urinary blad-
der, and all four extremities, including both feet and
hands [Figs. 8–10]. In addition, the individual digits
of each hand can usually be counted by 12 weeks.
Fetal gender can be reliably determined by 13 weeks,
and by 12 weeks in most cases [Fig. 11][119].When
deviation from normal anatomy is recognized, a
number of birth defects can be detected during the
first trimester. Detection varies significantly between
centers, with increasing detection by a thorough
systematic survey and greater use of transvaginal
ultrasound and three-dimensional (3D) multipla-
nar ultrasound.
Fig. 11. Normal genitalia. (A) Male genitalia at 13 weeks. (B) Female genitalia at 12 weeks.
Fig. 12. Anencephaly/acrania at 12 weeks. The normal
calvarium is not visualized and the shape of the brain
is slightly abnormal. Anencephaly/acrania can be easily
missed at this gestational age.
243First-Trimester Screening
244 Nyberg et al
Ossification of the fetal cranium begins and accel-
erates after 9 weeks [120,121],so that anencephaly
can be diagnosed as early as 9 to 10 weeks [122].
Ancephaly can also be easily overlooked during the
first trimester, however, because it initially is seen
as acrania with absent calvarium but relatively nor-
mal amount of brain. Careful scrutiny will show
an abnormal shape and appearance of the brain
caused by the lack of the supporting calvarium
[Fig. 12]. The sagging appearance of the brain
may show ‘‘Mickey Mouse’’ ears.
Posterior cephaloceles have been diagnosed as
early as 12 weeks [123], and alobar holoprosen-
cephaly has been diagnosed as early as 10 weeks
[124,125], but other brain abnormalities cannot
reliably detected until later.
Spina bifida can occasionally be detected before
the 12th postmenstrual week by noting irregulari-
ties of the bony spine or a bulging within the
posterior contour of the fetal back [126]. There
are also well-established additional sonographic
findings that can enhance the detection of spina
bifida, namely ‘‘the lemon sign’’ or ‘‘the banana
sign’’ [127,128], and these may be evident as early
as 12 weeks, although they can be initially subtle
[129–131]. With high quality imaging, which may
include tansvaginal scans, a normal posterior cere-
bellum and cisterna magna should be apparent,
and this finding excludes all but the mildest
forms of spina bifida.
Cleft lip and palate have been diagnosed in utero
as early as the 13 to 14 weeks [132]. Bilateral cleft
lip and palate may appear initially only as a an
echogenic median mass, which actually is the pre-
maxillary protrusion, made up of soft tissue, and at
times of osseous and dental structures [Fig. 13]
[133]. Because bilateral cleft lip and palate is asso-
ciated with a high rate of aneuploidy and other
birth defects, close follow-up, genetic counseling,
and amniocentesis should be offered.
Ocular abnormalities such as hyper- and hypo-
telorism, anophthalmia and microphthalmia, have
been diagnosed from 12 to 16 weeks [134–136].
Congenital cataracts has been diagnosed as early as
12 to 14 weeks [137,138].
By 12 to 14 weeks, a four-chamber view of the
heart can be consistently imaged [139–142]. The
great arteries can also be imaged by 11 to 12 weeks
in many cases. As with normal anatomy later in
the second trimester, the right and left ventri-
cles should be of approximately the same size, the
heart should not occupy more than one third of
the thoracic cavity, and the heart apex should
be oriented obliquely to the left anterior thorax.
Fig. 14. (A,B) Omphalocele associated with trisomy 18 at 10.5 weeks. Chorionic villus sampling showed trisomy 18.
Fig. 13. Bilateral cleft lip associated with trisomy 13 at 13 weeks. (A) Sagittal view shows abnormal soft tissue
protruding just below the nose (arrow). (B) Transverse view confirms this finding. Bilateral cleft lip and palate was
diagnosed (arrow). (C) Umbilical cord cyst (arrow, C ) was also noted. (D) Follow-up 3D rendered image at
17 weeks confirms bilateral cleft lip and palate with premaxially protrusion. Other findings identified on the
follow-up ultrasound, but not seen on the first-trimester scan, included echogenic intracardiac focus in the left
ventricle, mildly hypoplastic left ventricle and atrium, micro-opthalmia, echogenic kidneys, and polydactyly.
245First-Trimester Screening
Achiron and colleagues [143] reported eight cases
of heart defects among approximately 1000 fetuses
scanned by transvaginal ultrasound between 10 and
12 weeks. Only one fetus had an abnormal karyo-
type (45XO), but all fetuses showed other anoma-
lies. Based on this experience, detection of isolated
heart abnormalities is likely to remain difficult be-
fore 14 weeks.
Abdominal and truncal defects may be diag-
nosed during the first trimester, and these include
omphalocele, gastroschisis [144,145], ectopia cordis
[146,147], and body-stalk anomaly [148,149].
Omphaloceles may be categorized as those contain-
ing both bowel and liver (extracorporeal liver) and
those containing only bowel (intracorporeal liver).
Intracorporeal omphalocele can only be reliably di-
agnosed after 12 postmenstrual weeks, because of
the difficulty in distinguishing it from physiologic
midgut herniation [150,151]. Such omphaloceles
have a high rate of fetal aneuploidy [152,153].
Extracorporeal omphalocele can be diagnosed as
early as 9 to 10 weeks [154–156], and these may
Fig. 16. Normal limbs. (A) 3D surface rendering image shows poor visualization of extremities. (B) Transvaginal
scans better shows normal extremities.
Fig. 15. Normal hands. (A) 2D ultrasound at 12 weeks, 3 days shows normal hand with four fingers and one
thumb. (B) Another fetus at 13 weeks shows normal hand and extremities with 3D surface rendering.
246 Nyberg et al
also be associated with fetal aneuploidy and other
birth defects, including cardiac defects [Fig. 14].
The kidneys assume their final position within
the renal fossa by 11 weeks [157]. Using transvagi-
nal ultrasound, the kidneys can be consistently
imaged by 12 to 13 weeks [158–160]. Cystic kid-
neys can sometimes be diagnosed during the first
trimester. Multicystic dysplastic kidney disease has
been diagnosed as early as 12 to 15 weeks [160].
Infantile polycystic kidney disease has also been
diagnosed by 13 to 16 weeks by demonstration
of enlarged, echogenic kidney. [161,162], although
oligohydramnios may not develop until after
16 weeks.
The urinary bladder becomes apparent at 10 to
12 weeks, but like the kidney, it does not become
consistently imaged until the 13th week [162],at
which time cyclical filling and emptying of the fetal
bladder should be apparent. Obstructive uropathy
at the level of the urethra results in an enlarged
urinary bladder (megacystis), which has been diag-
nosed as early as the 11th week [163,164]. It has
been suggested that the diagnosis of megacystis can
be reliably diagnosed when the urinary bladder
measures more than 15 mm during the first trimes-
ter [165]. Affected fetuses seen during the first tri-
mester have a high rate of associated anomalies and
aneuploidy [166].
Fig. 17. Normal extremity movements at 13 weeks. Three images obtained within a few seconds of one another
(A,B,C) show normal extremities with active normal movement.
247First-Trimester Screening
The limbs begin to develop toward the end of the
sixth week with development of the upper limbs
before the lower limbs [167], and they can be
imaged by the eighth week [168]. By 12 weeks
the hands, fingers, feet, and toes can be consistently
imaged [Fig. 15]. Use of transvaginal sonography
and 3D ultrasound with surface rending can aid in
visualization of the extremities [Fig. 16]. By the
12th week, the long bones, phalanges, ilium, and
scapula begin to ossify; the metacarpals and meta-
tarsals ossify by 12 to 16 weeks [169]. Active fetal
movements can be observed after 10 weeks [170].
Normal fetal activity is particularly apparent using
real-time 3D (‘‘4D’’) ultrasound with surface ren-
dering [Fig. 17].
A variety of skeletal abnormalities can be detected
during the first trimester, including amputation de-
fects and certain lethal skeletal dysplasias [Fig. 18];
however, their detection clearly varies with gesta-
tional age. In one of the largest reported series of
prenatally diagnosed skeletal abnormalities in the
first and early second trimesters, Bronshtein and
coworkers [171] were able to detect 96% of the
anomalies between 14 to 16 weeks, 3% between
12 to 14 weeks, and 1% at 10 to 12 weeks. Osteo-
genesis imperfecta (OI) is one of the lethal skele-
Fig. 18. Clubfeet at 12 weeks. (A) Transabdominal scan at 12 weeks, 4 days shows clubbed foot (arrow, F ). (B)3D
surface rendered image confirms severe bilateral clubfeet (arrow). This was also confirmed on follow-up scans
at 18 weeks.
248 Nyberg et al
tal dysplasias that has been diagnosed as early as
13 to 15 weeks [172–175]. Sirenomelia has been
diagnosed as early as 11 to 14 weeks using transva-
ginal ultrasound [176–179]. It is expected that
akensia can be detected during the first trimester.
Polydactyly can also be detected during the first tri-
mester, and this can be aided by use of 3D multi-
planar ultrasound.
Summary
Screening for fetal chromosome abnormalities, par-
ticularly for trisomy 21, has made dramatic ad-
vances in the last 15 years. These advances have
both complicated screening and provided couples
with more effective screening options. More effec-
tive screening has demonstrated that patients who
traditionally were considered ‘‘high risk’’—particu-
larly patients aged 35 or older—can be at lower risk
for aneuploidy and other birth defects than a
20-year-old woman who does not undergo screen-
ing. This has resulted in a clear trend in the reduc-
tion of amniocentesis for these patients, and at
the same time has made screening available for
younger patients who share the 2% to 3% risk of
birth defects that all pregnancies carry. More effec-
tive screening translates into lower procedural-
related losses of normal fetuses, and better use
of resources.
The trend toward earlier detection of structural
defects during the first trimester will undoubtedly
continue as ultrasound resolution and 3D multi-
planar ultrasound continue to improve. Con-
versely, a normal systematic survey at this time
can be reassuring and can help to exclude a variety
of major defects. Based on the presence or absence
of findings, patients can then be triaged into early
follow-up and possible amniocentesis at 14 to
16 weeks, or a later detailed anatomic survey at
18 to 20 weeks.
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255First-Trimester Screening
