American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 145C:45 – 61 (2007)

A R T I C L E

First Trimester Ultrasonography in

Screening and Detection of
Fetal Anomalies
JIRI SONEK*

An obstetrical ultrasound examination provides invaluable information regarding the fetus. Until the mid-1980s,
ultrasound in the first trimester was limited to localization of the pregnancy, establishing viability, and accurate
dating. With the advent of high-resolution ultrasound and transvaginal scanning, a significant amount of
information about the fetus can be gained and provided to the patient at a very early stage in gestation. This article
provides an overview of the role of first trimester (11–13 þ 6 weeks’ gestation) ultrasound in screening and
diagnosis of fetal anomalies. The first trimester is an ideal time for screening for aneuploidy, primarily due to the
advantages that nuchal translucency (NT) measurement provides. NT measurement is also useful in establishing
the risk of congenital cardiac disorders and a number of genetic and non-genetic syndromes. Significant NT
thickening is associated with an increase in perinatal morbidity and mortality. Potential mechanisms resulting in
increased NT are discussed. A number of new ultrasound markers for fetal aneuploidy have been investigated over
the past several years, some of which appear to improve the screening efficacy of early ultrasonography. The role
of these is reviewed. A number of fetal anomalies can now be consistently diagnosed in the first trimester. Their
appearance at this early gestational age is discussed as well. It is clear that, data obtained by first trimester
ultrasound are useful in counseling expectant parents and in planning the appropriate follow-up.
ß 2007 Wiley-Liss, Inc.

KEY WORDS: first trimester obstetrical ultrasound; fetal markers; fetal anomalies

How to cite this article: Sonek J. 2007. First trimester ultrasonography in screening and detection of fetal
anomalies. Am J Med Genet Part C Semin Med Genet 145C:45–61.

INTRODUCTION
Obstetric ultrasound examination at any
stage in pregnancy serves two important
functions: diagnostic and screening.
While many major fetal defects can be
diagnosed in the first trimester, the diag-
Jiri D. Sonek, MD RDMS specializes in
Maternal-Fetal Medicine and Ultrasound in
Obstetrics, Gynecology, and Neonatology.
He is a Clinical Professor at Wright State
University and is the Medical Director of
Maternal-Fetal Medicine, Ultrasound, and
Genetics Center at the Miami Valley Hospital
in Dayton, Ohio. He is also the President of
the Fetal Medicine Foundation/USA. His
research focuses on prenatal screening and
diagnosis of fetal anomalies.
*Correspondence to: Jiri Sonek, Maternal-
Fetal Medicine/Ultrasound and Genetics,
Miami Valley Hospital, 1 Wyoming Street,
Dayton, OH 45409.
E-mail: JDSonek@mvh.org
DOI 10.1002/ajmg.c.30120
nostic accuracy of an ultrasound scan is
significantly greater in the mid-second
trimester due to the larger size and more
advanced development of the fetus. On
the other hand, the performance of a
second trimester scan as a screening tool
is generally considered less reliable.
The first trimester is an ideal time
for screening for fetal aneuploidy
[Cuckle et al., 2005]. This is primarily
due to the availability of the first
trimester-combined screen, with the
nuchal translucency (NT) measurement
being the most important component.
Moreover, the NT measurement is not
only useful for detection of aneuploidy,
but a thickened NTalso raises a suspicion
of a wide range of fetal defects, genetic
syndromes, and an overall increase in
morbidity and mortality.
Common sense, supported by
objective studies, tells us that parents
want to know about any fetal problems
as early in pregnancy as possible
[Mulvey and Wallace, 2000; de Graaf
et al., 2002]. This review looks at the
screening and diagnostic capabilities of
first trimester ultrasound. For the pur-
pose of this review, this is defined as
11–13 þ 6 weeks’ gestation since this
is when NT screening is done. Markers
of fetal aneuploidy other than NT
will also be discussed. Out of these,
the most promising ones are nasal
bone (NB) evaluation, Doppler evalua-
tion of blood flow across the tricuspid
valve (TCV), Doppler evaluation of
blood flow through the ductus venosus
(DV), and measurement of the fronto-
maxillary facial (FMF) angle. The diag-
nostic capabilities of first trimester
ultrasound will be discussed both in
connection with screening and inde-
pendently.

ß 2007 Wiley-Liss, Inc.

46 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

NUCHAL TRANSLUCENCY PATHOPHYSIOLOGY OF ATPase in the heart) have not been

Overview
Between 11 and 13 þ 6 weeks’ gesta-
tion, a layer of fluid is present beneath
the nuchal skin extending for variable
distance over the fetal head and back
[Nicolaides et al., 1992a]. For reasons
that are not entirely clear, at this point in
gestation, the amount of this fluid is
highly sensitive to fetal problems. An
antero-posterior measurement of this
layer of fluid with the fetus in a long-
itudinal view gives an accurate estimate
of the amount of fluid present, provided
that it is done in a strictly standardized
fashion (Table I and Fig. 1) [Snijders
et al., 1998]. Since an increase in the
amount of this fluid is associated with a
number of apparently unrelated fetal
problems, it is safe to assume that there
are a number of mechanisms which
cause its increase. It is also likely that in
some circumstances, more than one
mechanism is at play. In order to under-
stand the versatility of NT as a marker, it
is important to review the variety of
mechanisms, which may increase its
thickness. These include cardiac dys-
function, abnormalities of the heart and
great arteries, venous congestion of the
head and neck, altered composition
of the extracellular matrix, failure of
lymphatic drainage due to abnormal or
delayed development of the lymphatic
system or impaired fetal movements,
fetal anemia or hypoproteinemia and
congenital infection.
TABLE I. Requirements for a Standardized NT Measurement
1. Gestational age: 11 þ 0 to 13 þ 6 weeks (CRL 45–84 mm)
2. View: mid-sagittal (the fetus can be either facing toward or away from the transducer)
3. Image size: the upper thorax and the fetal head should occupy 75% of the image
(measurement accuracy of 0.1 mm)
4. Caliper placement: on-to-on fashion (see Figure 1)
5. The maximum NT measurement should be used for risk calculation
6. If a nuchal cord is present, NT should be measured above and below the nuchal cord
and the average of the two measurements should be used for risk calculation
7. The fetus should be away from the amnion
8. The fetus should be in a neutral position
NT, nuchal translucency.
INCREASED NUCHAL
TRANSLUCENCY
Cardiac Dysfunction
Cardiac dysfunction (failure) is an attrac-
tive explanation for NT thickening.
Fluid accumulation within bodily cav-
ities is a well-recognized clinical feature
of this condition. Direct evaluation of
cardiac performance in the first trimester
is very difficult. For example, there does
not appear to be a direct correlation
between cardiac size or left ventricular
ejection fraction and NT thickening in
fetuses with cardiac defects [Simpson
and Sharland, 2000]. However, chro-
mosomally normal fetuses with a history
of increased NT do show reduced
diastolic function in the second trimester
[Rizzo et al., 2003], suggesting that
perhaps our ability to evaluate the
cardiac function directly in the first
trimester is not sensitive enough.
Indirect evidence of cardiac strain in
fetuses with increased NT measurement
comes from molecular biology studies.
Trisomic fetuses with an increased NT
have been shown to have increased levels
of atrial and brain natriuretic peptide
mRNA [Hyett et al., 1996b]. It is known
that during the postnatal period, con-
gestive heart failure is associated with
upregulation of these peptides [Tsuchi-
mochi et al., 1988]. However, changes in
some other biochemical markers of
cardiac failure (e.g., increased expression
of sarcoplasmic reticulum calcium
found [von Kaisenberg et al., 1997].
Evidence of altered cardiac perfor-
mance and myocardial compliance also
come from Doppler studies. Both aneu-
ploidy and cardiac defects are associated
with the absence or reversal of the
A-wave in the DV [Matias et al., 1998,
1999; Bilardo et al., 2001]. A possible
explanation for this finding is decreased
compliance of the ventricular walls.
Similarly, the association between aneu-
ploidy and cardiac defects with tricuspid
regurgitation [Huggon et al., 2003] may
reflect a certain degree of ventricular
dilation, which may act as the cause of
the TCV incompetence.
the association between
aneuploidy and cardiac defects
with tricuspid regurgitation
may reflect a certain degree of
ventricular dilation, which
may act as the cause of the
TCV incompetence.
However, these Doppler abnormalities
can be seen in association with cardiac
problems that are not generally asso-
ciated with overt heart failure such as
ventricular septal defects [Hyett et al.,
1996], suggesting that myocardial
dysfunction may be only a partial
explanation.
There are physiological reasons why
the heart of a first trimester fetus does not
require a severe impairment for its
hemodynamics to be altered. Fetal ven-
tricles are limited in their elasticity and, as
such, develop much greater tension
when stretched. Also, the placental
resistance in the first trimester (the
afterload) is significantly higher than it
will become later in pregnancy causing
the heart to operate at the upper end of
the Starling’s curve, therefore being
closer to the point of failure. Further-
more, the lack of any significant intrinsic
renal function at this point in pregnancy
takes away from the fetus an extremely
important tool to combat fluid retention.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Figure 1. A: Standardized view of a fetus for NT measurement. (The nasal bone is seen on this particular image. However, visualization
of the nasal bone is not a requirement for the standardized view for NT measurement). B: Standardized placement of calipers for nuchal
translucency measurement.
Abnormalities of the Great Vessels
The aortic isthmus is the portion of
the aorta that extends between the left
subcalvian artery and the ductus arter-
iosus. It is known to be narrowed in
certain fetal conditions, notably Turner
syndrome and Down syndrome [Hyett
et al., 1996]. Increased blood flow to
the head and neck region is a natural
consequence of this narrowing. Other
abnormalities of the great vessels have
also been associated with nuchal thick-
ening (Hyett et al., 1996).
Venous Congestion in the
Head and Neck
Compression of intrathoracic organs,
whether due to a mass effect of a lesion
within the thorax such as a diaphrag-
mantic hernia [Sebire et al., 1997] or the
constrictive effect of short rib skeletal
dysplasias [Ben Ami et al., 1997] can lead
to an increase in intrathoracic pressure
and to venous congestion of the fetal
head and neck. Evaluation of NT helps
in establishing the prognosis in the case
of diaphragmatic hernias: those fetuses
that have an increased NT have a
significantly higher chance of dying
during the neonatal period as compared
to those with a normal NT [Sebire et al.,
1997].
Evaluation of NT helps in
establishing the prognosis in the
case of diaphragmatic hernias:
those fetuses that have an
increased NT have a
significantly higher chance of
dying during the neonatal
period as compared to those
with a normal NT.
Altered Composition of
the Extracellular Matrix
Many of the protein components of the
extracellular matrix are encoded on
chromosomes 21 (collagen type VI),
18 (laminin), and 13 (collagen type IV)
[von Kaisenberg et al., 1998b]. Immu-
nohistochemical studies of the skin
of chromosomally abnormal fetuses
demonstrated specific alterations of
the extracellular matrix which may
be attributed to gene dosage effects
[von Kaisenberg et al., 1998a,b]. Chro-
mosome 21 also encodes superoxide
dismutase. This enzyme protects hyluro-
nic acid from free radical-mediated
47
degradation [Aliakbar et al., 1993].
Hyluronic acid, a component of the
extracellular matrix, can entrap a large
amount of water. The over-production
of superoxide dismutase in trisomy
21 fetuses leads to an increase in
hyaluronic acid, which in turn may lead
to an increase in subcutaneous fluid and
thick NT [Bohlandt et al., 2000]. One
may speculate that altered composition
of the extracellular matrix may also be
the underlying mechanism for increased
fetal NT seen in a number of skeletal
dysplasias that are thought to be asso-
ciated with alterations in collagen meta-
bolism (e.g., achondrogenesis type II
[Soothill et al., 1993]), Nance–Sweeney
syndrome [Brady et al., 1998], osteogen-
esis imperfecta type II [Makrydimas
et al., 2001], abnormalities of fibroblast
receptors for growth factors (e.g.,
achondroplasia [Hernadi and Torocsik,
1997], thanatophoric dysplasia [Hernadi
and Torocsik, 1997; Mangione et al.,
2001; Souka et al., 2001]), and disturbed
metabolism of peroxisome biogenesis
factor (e.g., Zellweger syndrome
[Bilardo et al., 1998; de Graaf et al.,
1999; Christiaens et al., 2000; Johnson
et al., 2001]). However, as mentioned,
earlier, constriction of the thorax also
contributes to nuchal thickening in
many cases of skeletal dysplasia and may
48 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
be the primary underlying pathology
leading to increased NT measurements.
Failure of Lymphatic Drainage
Accumulation of lymphatic fluid within
the nuchal area may result from either an
intrinsic problem with the lymphatic
development or due to a decrease in
lymphatic drainage secondary to
impaired fetal movements. The lympha-
tic system primarily develops indepen-
dently of the venous system with
subsequent formation of anastomoses
[van der Putte and van Limborogh,
1980; Rodriguez-Niedenfuhr et al.,
2001]. A delay in the development of
the lymphatic system or aplasia and
hypoplasia of the lymphatic vessels can
occur in both chromosomally abnormal
and euploid fetuses. These phenomena
can be identified to a varying degree in
most fetuses with aneuploidy. Examples
of chromosomally normal fetuses where
deficient lymphatic drainage is found
include Noonan syndrome [van Zalen-
Sprock et al., 1992b; Johnson et al.,
1993; Trauffer et al., 1994; Reynders
et al., 1997; Bilardo et al., 1998;
Adekunle et al., 1999; Achiron et al.,
2000; Hiippala et al., 2001; Souka et al.,
2001], and congenital lymphedema
[Souka et al., 2002b]. In congenital
neuromuscular disorders such as fetal
akinesia deformation sequence, [Ville
et al., 1992; Nadel et al., 1993; Pandya
et al., 1995; Hyett et al., 1997a], myo-
tonic dystrophy [Bilardo et al., 1998;
Souka et al., 2001], and spinal muscular
atrophy, [Rijhsinghani et al., 1997;
Bilardo et al., 1998; Van Vugt et al.,
1998; Stiller et al., 1999; Souka et al.,
2001; de Jong-Pleij et al., 2002] increased
NT may be the consequence of impaired
lymphatic drainage due to reduced fetal
movements. Nuchal thickening due to
severe amniotic band sequence is prob-
ably due to a combination of limited fetal
movement and a constriction of the fetal
body. For example, more than 80% of
fetuses with a body stalk defect have an
increased NT [Daskalakis et al., 1997;
Smrcek et al., 2003b].
Fetal Anemia
Genetic causes of fetal anemia (a-
thalassemia [Lam et al., 1999b], Black-
fan-Diamond anemia [Souka et al.,
2002], congenital erythropoietic por-
phyria [Pannier et al., 2003], dysery-
thropoietic anemia [Souka et al., 2002],
Fanconi anemia [Tercanli et al., 2001]),
and congenital infection-related anemia
[Petrikovsky et al., 1996; Smulian
et al., 1998; Markenson et al., 2000;
Sohan et al., 2000], can present with
increased fetal NT. Severe red blood cell
alloimmunization does not usually occur
prior to 16 weeks of gestation, presum-
ably because the fetal reticuloendothelial
system is too immature to cause suffi-
cient RBC destruction [Nicolaides
et al., 1988]. Consequently, red blood
cell alloimmunization is not associated
with increased fetal NT.
Fetal Hypoproteinemia
Hypoproteinemia is implicated in the
pathophysiology of both immune and
non-immune hydrops fetalis [Nicolaides
et al., 1985a,b]. In the first trimester, the
underlying mechanism for the increased
NT in fetuses with congenital nephrotic
syndrome of the Finnish type and diffuse
mesangial sclerosis may be hypoprotei-
nemia due to severe proteinuria [Souka
et al., 2002]. Relative hypoproteinemia
may be a contributing factor to the
genesis of nuchal thickening in a number
of fetal disorders, including aneuploidy
[Nicolaides et al., 1985b].
Fetal Infection
Maternal and fetal infection can be
found in approximately 10% of cases
with non-immune hydrops fetalis seen
in the second or third trimesters where
no other cause is evident. However, in
the first trimester, serologic studies
in mothers carrying chromosomally
normal fetuses with thickened NT do
not show an increased prevalence of a
recent infection when compared to
mothers whose fetuses have normal
NT [Sebire et al., 1997]. Therefore,
with the exception of Parvovirus B19,
maternal evaluation for infectious causes
of thick NT is not warranted. The
thickened NT associated with Parvo-
virus B19 infection is felt to be due to a
combination of fetal anemia and myo-
carditis-related cardiac dysfunction
[Petrikovsky et al., 1996; Smulian et al.,
ARTICLE
1998; Markenson et al., 2000; Sohan
et al., 2000].
IMPLICATIONS OF A THICK
NUCHAL TRANSLUCENCY
Overview
There is a direct correlation between the
NT thickness and the prevalence of
chromosomal defects [Snijders et al.,
1998], major fetal abnormalities, mis-
carriage, and fetal and neonatal death
[Souka et al., 1998, 2001; Michailidis
and Economides, 2001]. By performing
a systematic ultrasound evaluation of the
fetus at 11–13 þ 6 weeks of gestation
starting with the NT measurement, one
can accurately estimate the likelihood of
chromosomal abnormalities and a wide
range of non-chromosomal defects
including malformations, deformations,
and genetic syndromes.
By performing a systematic
ultrasound evaluation of the
fetus at 11–13 þ 6 weeks of
gestation starting with the NT
measurement, one can
accurately estimate the
likelihood of chromosomal
abnormalities and a wide range
of non-chromosomal defects
including malformations,
deformations, and genetic
syndromes.
Just as the prevalence of fetal problems
increases with nuchal thickening, finding
a thin NT is associated with a reduction
of risk in women with an increased a
priori risk. In fetuses with a thickened
NT, once the presence of aneuploidy has
been ruled out, the risk of other fetal
abnormalities does not statistically
increase until the NT measurement
reaches the 99th centile. The NT
measurement representing this centile
throughout the 11–13 þ 6 weeks time
period is essentially steady at 3.5 mm
[Michailidis and Economides, 2001].
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Nuchal Translucency
and Aneuploidy
The prevalence of chromosomal defects
increases exponentially with increasing
NT thickness. The relation between
fetal NT and chromosomal defects was
derived from a multicenter screening
study involving 96,127 singleton preg-
nancies [Snijders et al., 1998]. It is this
distribution of NT measurements which
is used most commonly for quality
assurance by comparing operator speci-
fic distributions to it. It is now recog-
nized that measuring the NT is an
excellent screening method for fetal
aneuploidy. The performance of the test
can be improved even further by com-
bining it with first trimester biochemical
markers (free-beta hCG and PAPP-A)
and other sonographic markers such as
the NB, TCV Doppler flow evaluation,
or DV Doppler flow (see below). Briefly,
for a 5% screen positive rate, the
detection rate for Down syndrome is
approximately 75% for maternal age and
NT, 90% for combined screening using
maternal age, NT, free-beta hCG, and
PAPP-A, and 94% using combined
screening consisting of maternal age,
NT, free-beta hCG, PAPP-A, and either
NB, TCV flow, or DV flow [Nicolaides
et al., 2005). NT screening is also highly
effective in screening for other types of
aneuoploidy such as trisomies 18 and
13, Turner syndrome, and triploidy
[Snijders et al., 1998]. (For further
details of combined screening, see Prof.
K. Spencer’s review in this issue.)
Nuchal Translucency in
Euploid Fetuses—Fetal Death
In chromosomally normal fetuses, the
prevalence of fetal death increases expo-
nentially with NT thickness. Based on
combined data from two studies that
included 4,540 chromosomally normal
fetuses with increased NT and no
obvious structural defects, the incidence
of miscarriage or fetal death increased
from 1.3% in those with NT between
the 95th and 99th centiles to about 20%
for NT of 6.5 mm or greater [Souka
et al., 1998, 2001]. Another study of
6,650 pregnancies undergoing NT
screening, reported that in chromoso-
mally normal fetuses the incidence of
miscarriage or fetal death was 1.3% in
those with NT below the 95th centile,
1.2% for NT between the 95th and 99th
centiles and 12.3% for NT above the
99th centile (3.5 mm) [Michailidis and
Economides, 2001]. The authors’ con-
clusion was that once aneuploidy is ruled
out, the risk of fetal mortality did not
statistically increase until the NTreached
3.5 mm or above. The majority of fetuses
that die do so by 20 weeks; they usually
show progression from increased NT to
severe hydrops fetalis. Chromosomally
and structurally normal fetuses with
history of thickened NT that are found
to be alive and well during an ultrasound
study at 20 weeks, with no evidence of
nuchal fold thickening or non-immune
hydrops, are no longer considered at an
increased risk for perinatal or long-term
morbidity and mortality.
Nuchal Translucency in Euploid
Fetuses—Fetal Structural Defects
Several studies have reported that
increased fetal NT thickness is associated
with a high prevalence of major fetal
abnormalities [Ville et al., 1992; van
Zalen-Sprock et al., 1992; Hewitt, 1993;
Johnson et al., 1993; Nadel et al., 1993;
Shulman et al., 1994; Trauffer et al.,
1994; Salvesen and Goble, 1995; Hewitt
et al., 1996; Moselhi and Thilganathan,
1996; Reynders et al., 1997; Bilardo
et al., 1998; Fukada et al., 1998, 2002;
Pajkrt et al., 1998; Souka et al., 1998,
2001; Van Vugt et al., 1998; Adekunle
et al., 1999; Schwarzler et al., 1999;
Maymon et al., 2000; Bilardo et al., 2001;
Hiippala et al., 2001; Mangione et al.,
2001; Michailidis and Economides,
2001; Senat et al., 2002; Cheng et al.,
2004; Bahado-Singh et al., 2005]. The
prevalence of major fetal abnormalities in
chromosomally normal fetuses increases
proportionately with NT thickness, from
1.6%, in those with NT below the 95th
centile [Michailidis and Economides,
2001] to 2.5% for NT between the
95th and 99th centiles and exponentially
thereafter to about 45% for NT of 6.5
mm or more [Souka et al., 1998, 2001].
Statistically, the risk of major fetal
abnormalities does not increase until
the NT reaches 3.5 mm or above.
49
INCREASED NUCHAL
TRANSLUCENCY—TYPES
OF ABNORMALITIES
Overview
A wide range of fetal abnormalities has
been reported in fetuses with increased
NT. The prevalence of major cardiac
defects, [Gembruch et al., 1993; Achiron
et al., 1994; Hyett et al., 1996, 1997,
1999; Bilardo et al., 1998; Josefsson
et al., 1998; Souka et al., 1998, 2001;
Schwarzler et al., 1999; Zosmer et al.,
1999; Ghi et al., 2001; Mavrides et al.,
2001; Michailidis and Economides,
2001; Orvos et al., 2002; Galindo
et al., 2003; Hafner et al., 2003; Lopes
et al., 2003; Makrydimas et al., 2003;
McAuliffe et al., 2003; Smrcek et al.,
2003], diaphragmatic hernia, [Bulas et al.,
1992; Nadel et al., 1993; Pandya et al.,
1995; Van Vugt et al., 1998; Mangione
et al., 2001; Souka et al., 2001; Varlet
et al., 2003], exomphalos [Ville et al.,
1992; Nadel et al., 1993; Pandya et al.,
1995; Snijders et al., 1995; Cha’Ban
et al., 1996; van Zalen-Sprock et al.,
1997; Adekunle et al., 1999; Mangione
et al., 2001; Souka et al., 2001; Senat
et al., 2002; Schemm et al., 2003], body
stalk anomaly [Van Vugt et al., 1998;
Smrcek et al., 2003], skeletal defects [Fisk
et al., 1991; Hewitt, 1993; Soothill et al.,
1993; Trauffer et al., 1994; Meizner and
Barnhard, 1995; Ben Ami et al., 1997;
Eliyahu et al., 1997; Hernadi and
Torocsik, 1997; Petrikovsky et al.,
1997; den Hollander et al., 1997; Brady
et al., 1998; Fukada et al., 1998; Hafner
et al., 1998; Hill and Leary, 1998; Souka
et al., 1998, 2001; Adekunle et al., 1999;
Lam et al., 1999; Hiippala et al., 2001;
Hull et al., 2001; Makrydimas et al.,
2001; Mangione et al., 2001; Percin
et al., 2001; Fukada et al., 2002;
Monteagudo et al., 2002; Souka et al.,
2002; Souter et al., 2002; Clem-
entschitsch et al., 2003; Viora et al.,
2003b], and certain genetic syndromes,
such as congenital adrenal hyperplasia
[Masturzo et al., 2001; Fincham et al.,
2002; Flores Anton et al., 2003], fetal
akinesia deformation sequence, [Ville et al.,
1992; Nadel et al., 1993; Pandya et al.,
1995; Hyett et al., 1997; Souka et al.,
2001], Noonan syndrome [van Zalen-
50 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
Sprock et al., 1992; Johnson et al., 1993;
Trauffer et al., 1994; Reynders et al.,
1997; Bilardo et al., 1998; Adekunle
et al., 1999; Achiron et al., 2000;
Hiippala et al., 2001; Souka et al.,
2001], Smith–Lemli–Opitz syndrome
[Hobbins et al., 1994; Hyett et al.,
1995; Pandya et al., 1995; Sharp et al.,
1997; Souka et al., 2001], and spinal
muscular atrophy [Rijhsinghani et al.,
1997; Bilardo et al., 1998; Van Vugt
et al., 1998; Stiller et al., 1999; Souka
et al., 2001; de Jong-Pleij et al., 2002],
appears to be substantially higher in
fetuses with a thickened NT compared
to the general population. However, in
other cases the association is less definite,
primarily due to the extremely rare
nature of many of these disorders.
Cardiac Defects
The pathophysiologic reasons why car-
diac lesions may be associated with
nuchal thickening are discussed earlier
(see above). Clinical studies have proven
this association. In three studies with a
combined total of 30 fetuses with major
cardiac defects diagnosed by echocar-
diography at 11–14 weeks, 83% had
increased NT [Achiron et al., 1994;
Smrcek et al., 2003]. In screening studies
the prevalence of major cardiac defects in
fetuses with NT below the 95th centile
was in 1.6 per 1,000 based on examina-
tion of 63,894 fetuses [Hyett et al., 1997,
1999; Ghi et al., 2001; Mavrides et al.,
2001; Michailidis and Economides,
2001; Lopes et al., 2003; McAuliffe
et al., 2003]. The NT measurements in
fetuses with a thickened NT were
stratified and the prevalence of major
cardiac defects for various NTranges was
determined: NT of 2.5–3.4 mm, 1%;
NT of 3.5–4.5 mm, 3%; NT of 4.5–
5.4 mm, 7%; NT of 5.4–6.4 mm, 20%;
NT of 6.5 mm or more, 30%. Combin-
ing the results of eight studies dealing
with a total of 67,256 low-risk pregnan-
cies shows a detection rate of 37.5% for a
false positive rate of 4.9% [Bilardo et al.,
1998; Josefsson et al., 1998; Hyett et al.,
1999; Schwarzler et al., 1999; Mavrides
et al., 2001; Michailidis and Econo-
mides, 2001; Orvos et al., 2002; Hafner
et al., 2003]. Based on a meta-analysis of
screening studies, the detection rates of
congenital cardiac defects of about 37%
and 31% for NT cut-offs of the 95th and
99th centiles, respectively, could be
achieved. It was estimated that fetal
echocardiography in all chromosomally
normal fetuses with NT above the 99th
centile would identify one major cardiac
defect in every 16 patients examined
[Makrydimas et al., 2003]. Additionally,
this analysis showed that the perfor-
mance of screening by increased NT
does not vary with the type of cardiac
defect. Similar results were obtained in a
multicenter study where nuchal thick-
ening was found to be increased in all
types of heart defects: left as well as right
heart lesions, septal defects, outflow tract
disorders, laterality disorders, and com-
plex heart lesions [Makrydimas et al.,
2005].
Improvements in the resolution of
ultrasound machines have now made it
possible to perform a detailed fetal
cardiac evaluation even in the first
trimester of pregnancy [Gembruch
et al., 1993; Carvalho et al., 1998;
Zosmer et al., 1999; Simpson et al.,
2000]. In fetuses with major defect, the
early scan can either lead to the correct
diagnosis or at least raise suspicions so
that follow-up scans are carried out.
Conversely, a majority of cardiac defects
can be ruled out if the heart is normal in
its ultrasound appearance even at this
early stage of pregnancy. It must be
stressed that an echocardiogram,
whether it is performed in the first
trimester or later, needs to be done by
individuals trained to do so (for further
details on ultrasound screening and
diagnosis of congenital heart defects,
see Prof. Allan’s review in this issue).
Is Increased Nuchal Translucency
in Euploid Fetuses Associated With
Developmental Delay?
A number of studies have reported on
the long-term follow up of chromoso-
mally and anatomically normal fetuses
with increased NTwith an overall rate of
developmental delay of 2.6% [Nadel
et al., 1993; Brady et al., 1998; Van Vugt
et al., 1998; Adekunle et al., 1999;
Maymon et al., 2000; Hiippala et al.,
ARTICLE
2001; Senat et al., 2002; Cheng et al.,
2004]. Only one of the studies had a
control arm [Nadel et al., 1993]. No
difference was noted in the rate of
developmental delay between the study
group and controls.
Does the Appearance of Nuchal
Translucency Change Prognosis?
In the second and third trimesters of
pregnancy, abnormal accumulation of
fluid behind the fetal neck can be
classified as either a cystic hygroma or
nuchal edema [Chervenak et al., 1983;
Benacerraf et al., 1987]. About 75% of
fetuses with a cystic hygromas in the
second trimester have a chromosomal
abnormality, out of which 95% is Turner
syndrome [Azar et al., 1991]. Nuchal
edema in the second trimester has a
number of potential causes. Chromoso-
mal abnormalities are found in about
one-third of these fetuses with about
75% being trisomies 21 or 18 [Nico-
laides et al., 1992]. Nuchal edema can
also be associated with non-chromoso-
mal disorders such as fetal cardiovascular
and pulmonary defects, lymphatic
abnormalities, skeletal dysplasias, con-
genital infection and metabolic, and
hematological disorders [Nicolaides
et al., 1992].
In the first trimester, the term
increased NT is used irrespectively of
whether the collection of fluid contains
septations and regardless of how far
down the fetal back the fluid layer
extends [Nicolaides et al., 1992]. A
report on 29 fetuses with abnormally
large nuchal fluid accumulations at 10–
13 weeks’ gestation showed that the
appearance of the nuchal fluid could
neither predict the prevalence of chro-
mosomal abnormalities nor the overall
prognosis [Cullen et al., 1990a]. In a
recent study involving 386 fetuses with
NT measurement at or above the 95th
centile, septations were demonstrated in
a transverse suboccipitobregmantic view
in each case [Molina et al., 2006]. The
FASTER trial excluded those cases
where septations were seen and in a sep-
arate study, with the authors controver-
sially concluding that outcome of fetuses
with thickened NT differ according to
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
appearance [Malone et al., 2005]. A
critical evaluation of the statistical anal-
ysis used in this article was subsequently
published [Sonek et al., 2006b]. Further-
more, subsequent analysis of the data did
show that NT size rather than appear-
ance is most important [Comstock et al.,
2006]. The risk of fetal abnormalities
and perinatal morbidity and mortality
are related to the NT thickness and not
to its appearance.
Why Is 11–13 þ 6 Weeks an
Optimal Time for Nuchal
Translucency Measurement?
Even at this early stage in pregnancy, an
ultrasound evaluation is more than just
estimation of gestational age and NT
measurement. Therefore, it is prudent to
choose a time in early gestation when the
most information can be gathered about
a fetus in a single examination and still
fulfill requirements for NT screening. It
is clear that fetal anatomic evaluation is
very gestational-age dependent and its
benefit prior to 11 weeks of gestation is
limited. Specifically, the following struc-
tures have been shown not to lend
themselves for an adequate evaluation
prior to 11 weeks: presence or absence of
normally ossified fetal skull (important
in detection of acrania/anencephaly)
[Green and Hobbins, 1988], evaluation
of cardiac anatomy (cardiac anatomy
cannot be evaluated prior to 11 weeks
gestation) [Johnson et al., 1992; Gem-
bruch et al., 1993; Braithwaite et al.,
1996], evaluation of the abdominal
umbilical cord insertion (presence of
the physiologic gut herniation prior to
11 weeks gestation makes the diagnosis
of an omphalocele difficult) [Snijders
et al., 1995; van Zalen-Sprock et al.,
1997], identification and size of the
urinary bladder (see below) [Braithwaite
et al., 1996; Rosati and Guariglia, 1996;
Sebire et al., 1996] NB (lack of ossifica-
tion of the NB prior to 11 weeks render
its evaluation useless in screening for
Down syndrome [Sandikcioglu et al.,
1994]).
There are three main reasons why
the upper limit of 13 þ 6 weeks was
selected. One is due to the fact that the
screening by measuring the NT
51
becomes less efficient beyond this point: ined in 15,046 (97.4%) cases and the NB
the prevalence of increased fluid accu- was absent in 185 of 15,048 (1.2%)
mulation within the nuchal area chromosomally normal fetuses and in
in chromosomally abnormal fetuses 282 of 412 (68.4%) fetuses with trisomy
decreases beyond this point in gestation 21 [Sonek et al., 2006].
[Benacerraf et al., 1987; Nicolaides et al.,
1992a,b; Souka et al., 2001]. Further-
more, the acquisition of an appropriate Combined data from the
NT measurement becomes much more
ultrasound studies mentioned
difficult at 14 weeks and beyond (only
90% of the cases) as compared to earlier above shows that that the fetal
gestational ages (98–100%) [Whitlow profile was successfully
and Economides, 1998; Mulvey et al.,
examined in 15,046 (97.4%)
2002]. Thirdly, by placing a relatively
early gestational age limit on the timing cases and the NB was absent
of the screen, one allows for the option
of an earlier and therefore safer form of
in 185 of 15,048 (1.2%)
termination of the affected fetuses. chromosomally normal fetuses
In women who did not have a and in 282 of 412 (68.4%)
previous scan to date the pregnancy, it
is best to schedule the NT scan at 12– fetuses with trisomy 21.
13 weeks’ gestation, which allows for small
errors in dating [Mulvey et al., 2002].
OTHER MARKERS FOR The prevalence of NB absence changes
FETAL ANEUPLOIDY with ethnicity (it is highest in individuals
of African origin), NT thickness (it
Nasal Bone Evaluation increases as the NT measurement
increases), and the crown rump mea-
In 1866 Langdon Down noted that a
surement (it decreases with gestational
common characteristic of patients with
age). Therefore, likelihood ratios in
trisomy 21 is a small nose [Down, 1866].
screening for trisomy 21 must be
Anthropometric [Farkas et al., 2001],
adjusted to account for these factors
radiological [Keeling et al., 1997;
[Cicero et al., 2003, 2004]. If the NB is
Stempfle et al., 1999; Larose et al.,
found to be absent between 11 and 12
2003; Tuxen et al., 2003], and histolo-
weeks, it is appropriate to examine the
gical studies [Minderer et al., 2003;
fetus 1 week later. The results of that scan
Tuxen et al., 2003], have demonstrated
can be used to calculate the risk of
an objective difference in NB findings
trisomy 21, thus reducing the false
between euploid individuals and those
positive rate. (For further details of
with trisomy 21. Since the initial
combined screening using additional
description of this phenomenon by
ultrasound markers, see Prof. Spencer’s
ultrasound [Sonek and Nicolaides,
review in this issue.)
2002], a number of studies have been
In order for the NB evaluation to
published indicating that absence of the
perform reliably as a screening tool, a
NB in the first trimester [Cicero et al.,
strict scanning protocol has to be
2001, 2003c, 2004b; Otano et al., 2002;
followed (Table II). This requires train-
Orlandi et al., 2003; Viora et al., 2003;
ing and ongoing audit. As expected,
Wong et al., 2003; Zoppi et al., 2003] is
the ability to evaluate the NB improves
highly associated with trisomy 21.
with time [Cicero et al., 2003]. None-
theless, ultrasound NB evaluation
Association of NB Absence With
should be achievable without extending
Chromosomal Abnormalities
the length of ultrasound examination as
Combined data from the ultrasound both NT and NB are obtained in the
studies mentioned above shows that that midsagittal plane [Kanellopoulos et al.,
the fetal profile was successfully exam- 2003].
52 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c ARTICLE

which is defined as the angle between

TABLE II. Requirements for a Standardized View to Evaluate the NB in the the upper surface of the upper palate and
First Trimester the frontal bone. The apex of the angle is
the anterior most aspect of the maxilla
1. Gestational age: 11 þ 0 to 13 þ 6 weeks (CRL 45–84 mm)
(Fig. 2). In this study, three-dimensional
2. View: mid-sagittal (the fetus must be facing toward the transducer)
(3D) volumes of the fetal head which
3. Image size: the upper thorax and the fetal head should occupy 75% of the image
were obtained before fetal karyotyp-
4. The angle of insonation should be at 90 degrees with the longitudinal axis of the NB
ing at 11–13þ6 were retrospectively
(i.e., the face of the transducer should be parallel to the longitudinal axis of the NB)
reviewed. A precise midline sagittal view
5. Two echogenic lines (skin of the nasal bridge and the NB underneath it) forming the
of the face was generated using a multi-
so-called ‘‘equal sign’’ must be seen in order to document the presence of the nasal
planar mode and the FMF angle was
bone
measured in 100 fetuses with trisomy 21
6. The line representing the nasal bone should be at least as echogenic as the overlying
and 300 chromosomally normal fetuses.
skin
The mean FMF angle was significantly
7. A third echogenic line representing the skin of the tip of the nose is seen located
larger in the trisomy 21 fetuses than in
anteriorly to the ‘‘equal sign’’ in the mid-sagittal view
the chromosomally normal fetuses
NB, nasal bone; CRL, crown-rump length measurement. (mean 88.78, range 75.4–1048 vs. mean
78.18, range 66.6–89.5, P < 0.001).
Sixty-nine percent of the trisomy
In contrast to the above studies, the 21 fetuses [De Biasio and Venturini, 21 fetuses had an FMF angle, which
NB was felt to be present in all nine 2002]. was greater than 95th centile (858) of the
trisomy 21 fetuses identified in the Nevertheless, in many experienced euploid population. Forty percent of
FASTER trial [Malone et al., 2004] centers, at 11þ0 –13þ6 weeks the fetal the trisomy 21 fetuses had an FMF
and questions were raised whether this profile can be successfully examined in angle which was above the upper limit
marker could be implemented in broad more than 95% of cases. The NB is of the range of angles (908) of the
screening programs. However, they absent in about 70% of trisomy 21 euploid population. Only 2% of the
were able to examine only 76% of the fetuses, 55% trisomy 18 fetuses, and affected fetuses had an FMF angle
6,316 fetuses scanned at 10–13 weeks. 34% trisomy 13 fetuses, making NB below the 50%. There was no significant
Potential differences in techniques used evaluation an important addition to our association between the FMF angle and
are illustrated in another publication armamentarium of markers for fetal crown-rump length, NT thickness, or
[Welch and Malone, 2003]. Despite aneuploidy [Cicero et al., 2004]. presence/absence of the NB in either
these differences, there is strong con- the trisomy 21 or the chromosomally
Fetal Measurements as Markers in
sensus among leading authors that failure normal fetuses. The authors postulated
the First Trimester
to adopt a strict protocol can result in a three possible mechanisms for the
very low detection rate. Certainly, a A novel method for evaluating the increased FMF angle in trisomy 21
significant lack of standardization relative position of the fetal maxilla with fetuses. First, it may be due to a dorsal
accounts for the finding of a retro- respect to the forehead was recently displacement of the upper palate with
spective study of stored images where introduced [Sonek et al., 2006]. This is respect to the forehead. Second, the
NB was present in all five trisomy done by measuring the FMF angle, increased angle can be produced by

Figure 2. A: FMF angle in a chromosomally normal fetus. B: FMF angle in a trisomy 21 fetus.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
frontal bossing, though this is not
recognized a feature of trisomy 21.
Finally, the difference in the FMF angles
could result from differences in the
direction of the longitudinal axis of the
upper palate—a deviation of this axis
toward the base of the skull would lead to
an increase in the FMF angle. However,
the third hypothesis does not lend itself
easily to an objective evaluation. A
prospective evaluation of this technique
with two-dimensional ultrasound is
ongoing.
There are several other measure-
ments in the first trimester, which
are more common in chromosomally
abnormal fetuses compared with chro-
mosomally normal population. Growth
can be reduced even in the first trimester
in trisomy 18, triploidy and, to a lesser
degree in trisomy 13 and Turner syn-
drome. However, in the case of trisomy
21, the crown-rump lengths are not
different from the euploid fetuses [Dru-
gan et al., 1992; Kuhn et al., 1995;
Nicolaides et al., 1996; Bahado-Singh
et al., 1997; Jauniaux et al., 1997;
Schemmer et al., 1997; Sherrod et al.,
1997]. Several other fetal measurements
have been investigated as possible mar-
kers for trisomy 21: maxillary length,
[Cicero et al., 2004] ear length, [Sacchini
et al., 2003], femur length [Longo et al.,
2004], and humeral length [Longo et al.,
2004]. Even though statistical differ-
ences between trisomy 21 and euploid
fetuses have been shown to exist, the
actual differences in these measurements
are so small that they are not clinically
useful. Likewise, differences in fetal heart
rate have been shown between euploid
and aneuploid fetuses: relative tachycar-
dia in trisomy 13 and Turner syndrome
and bradycardia in trisomy 18 and
triploidy. However, the slight increase
in FHR in trisomy 21 is not significant
enough to be clinically useful [Liao et al.,
2000].
Fetal Structural Defects
as Markers in the First Trimester
The finding of a two-vessel cord in the first
trimester is not associated with an
increased prevalence of trisomy 21 but
increases the risk of trisomy 18 approxi-
mately sevenfold [Rembouskos et al.,
2003]. Since the presence of a single
umbilical artery in the first trimester can
be demonstrated only with the aid of
color Doppler mapping, adherence
to the ALARA principle (radiation
exposures As Low As Reasonably
Achievable) suggests that routine eva-
luation of the number of umbilical
vessels at this point in gestation may
not be warranted.
The fetal urinary bladder can be
visualized in approximately 50% of
fetuses at 10 weeks’ gestation and in
essentially all normal fetuses by 13
weeks’ gestation [Braithwaite et al.,
1996; Rosati and Guariglia, 1996; Sebire
et al., 1996]. Finding megacystis (long-
itudinal diameter of 7 mm or more) in
the first trimester is associated with an
increased risk of a wide range of
chromosomal abnormalities. Bladder
measurements of 7–15 mm are asso-
ciated with an approximately 24%
chance of aneuploidy, primarily triso-
mies 18 and 13 [Liao et al., 2003].
Finding megacystis
(longitudinal diameter of 7 mm
or more) in the first trimester is
associated with an increased
risk of a wide range of
chromosomal abnormalities.
Bladder measurements of
7–15 mm are associated with an
approximately 24% chance of
aneuploidy, primarily
trisomies 18 and 13.
In chromosomally normal fetuses,
90% of megacystis in this range resolves
spontaneously [Liao et al., 2003]. Greater
degrees of megacystis (>15 mm) are less
likely to be associated with aneuploidy
(11.4%) (Favre et al., 1999). Unfortu-
nately, they lead to progressive obstruc-
tive uropathy even in the chromosomally
normal group. It is interesting to note
that megacystis is associated with an
53
increased NTregardless of the karyotype
[Liao et al., 2003].
An omphalocele is an abnormality
that has a high association with chro-
mosomal defects, most commonly tris-
omy 18 [van Zalen-Sprock et al., 1997].
Since trisomy 18 has such a high rate of
mortality, its association with an ompha-
locele decreases significantly with gesta-
tional age: 61% at 11–13 þ 6 weeks
gestation, 30% in the second trimester,
and 15% at term [Maymon et al., 2000].
It appears that omphaloceles that contain
bowel only confer the highest risk of
aneuploidy. The presence of a physiolo-
gic mid-gut herniation can be a con-
founding variable and is one of the
reasons why NT screening should
be delayed until 11 weeks’ gestation
[Braithwaite et al., 1996; van Zalen-
Sprock et al., 1997]. Omphaloceles
are associated with an increased preva-
lence of nuchal thickening regardless of
karyotype [van Zalen-Sprock et al.,
1997].
Holoprosencephaly results from the
failure of the forebrain (prosencephalon)
to cleave normally. Based on the degree
to which the failure of cleavage occurs,
three types of holoprosencephaly exist.
In its most extreme form (alobar holo-
prosencephaly), only a single cerebral
ventricle is present and the thalami are
fused, making the diagnosis even in the
first trimester relatively reliable. This
condition is associated with a signifi-
cantly increased risk of aneuploidy
(30%), most commonly trisomy13
[Snijders et al., 1999]. The semilobar
and lobar types of holoprosencephaly
show segmentation of the lateral ven-
tricles to varying degrees, making
the diagnosis by prenatal ultrasound
difficult.
USE OF DOPPLER IN
SCREENING
Blood Flow Across the
Tricuspid Valve
Regurgitant flow across the TCV is
significantly more common in the pre-
sence of chromosomal defects, especially
at 11–13 þ 6 weeks [Huggon et al.,
2003; Faiola et al., 2005]. It has been
54 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
shown that at this gestational age the
prevalence of TCV regurgitation in
fetuses with trisomy 21 is about 74%
whereas only 7% of chromosomally
normal fetuses have this finding [Faiola
et al., 2005].
The evaluation begins by obtaining
an apical view of the four-chamber
heart. The ideal angle of insonation with
respect to the longitudinal axis of the
ventricular septum is 08 (i.e., the ven-
tricular septum is positioned vertically
on the image) but angles of up to 308 are
acceptable. A relatively large (approxi-
mately 3 mm) Doppler gate is placed
over the TCV in order to be able to
evaluate the blood flow in both direc-
tions. The biphasic forward flow across
the valve is identified during the cardiac
diastole and the atrial contraction. Dur-
ing the ventricular systole, however,
there should be very little if any flow
back across the closed TCV. Significant
TCV regurgitation is diagnosed if
reversed flow is noted and lasts for more
than 50% of ventricular systole. Since the
outflow tracts are in such a close
proximity to the atrioventricular valves,
it is not unusual to have their Doppler
footprint superimposed on the region of
the TCV. However, they are relatively
easy to differentiate from TCV regur-
gitation because of the differences in
their peak velocities and shapes of their
waveforms (for further details see
www.fetalmedicine.com).
An additional benefit of evaluating
the flow across the TCV is that there is an
association between an increased pre-
valence of cardiac defects and TCV
regurgitation, irrespective of the pre-
sence or absence of aneuploidy [Huggon
et al., 2003; Faiola et al., 2005]. There-
fore, if TCV regurgitation is noted and
the fetal chromosomes prove to be
normal, a more careful evaluation of
the cardiac anatomy is indicated.
Ductus Venosus
The DV directs well-oxygenated blood,
which arrives through the umbilical vein,
to the coronary and cerebral circulation.
It does so by preferentially streaming it
through the foramen ovale into the left
atrium. Blood flow in the ductus has a
characteristic waveform with high velo-
city during ventricular systole (S-wave)
and diastole (D-wave). There is a rapid
decrease in velocity during the atrial
contraction (a-wave) but forward flow is
normally maintained. The a-wave is
considered abnormal if there is a com-
plete cessation of forward flow or a
reversal of flow [Kiserud et al., 1994;
Hecher et al., 1995].
Abnormal ductal flow is associated
with chromosomal abnormalities, car-
diac defects and adverse pregnancy out-
come. In the combined data from six
studies, abnormal ductal flow was
observed in 273/5,462 (5.0%) chromo-
somally normal fetuses, 108/131
(83.3%) with trisomy 21 and in 205/
277 (74.0%) of all chromosomal
abnormalities [Antolin et al., 2001;
Mavrides et al., 2002; Murta et al.,
2002; Zoppi et al., 2002; Borrell et al.,
2003]. There may be an association
between increased fetal NT and the
presence of abnormal ductal flow but it
appears to be a weak one. These findings
suggest that Doppler evaluation of the
DV flow can be combined with NT
screening [Murta et al., 2002; Zoppi
et al., 2002; Borrell et al., 2003].
However, examination of ductal flow
requires highly skilled operators since
the interference from adjacent vessels is a
commonly encountered.
Other Doppler Evaluations
Doppler evaluation of the uterine
arteries [Bindra et al., 2001], umbilical
artery [Jauniaux et al., 1996; Martinez
et al., 1997; Brown et al., 1998; Borrell
et al., 2001], umbilical vein [Brown et al.,
1999], jugular vein [Martinez et al., 2003],
and carotid artery [Martinez et al., 2003]
have been evaluated as possible markers
for fetal aneuploidy. Thus far, these
modalities have not been shown to be
clinically useful.
Integrated Sonographic
and Biochemical Screening
in the First Trimester
In order for new ultrasound markers to
be included in the combined screen (NT
and free beta hCG and PAPP-A), a
sufficient degree of independence has to
be present. This has been shown to be
ARTICLE
the case with NB [Cicero et al., 2003],
TCV Doppler [Falcon et al., 2006], and
DV [Borrell et al., 2003]. The Fetal
Medicine Foundation has developed
algorithms which allow for both NB
and TCV Doppler to be integrated in
the first trimester combined screen. It is
estimated that for a false positive rate
of 5%, the detection rate of trisomy
21 would be approximately 95% and
for a false positive rate of 2.5% the
detection rate would be approximately
90% if the combination of maternal age,
NT, maternal serum biochemistries, and
either NB or TCV Doppler are used.
The Fetal Medicine Founda-
tion has developed algorithms
which allow for both NB and
TCV Doppler to be integrated
in the first trimester combined
screen. It is estimated that for a
false positive rate of 5%, the
detection rate of trisomy 21
would be approximately 95%
and for a false positive rate of
2.5% the detection rate would
be approximately 90% if the
combination of maternal age, NT,
maternal serum biochemistries,
and either NB or TCV Doppler
are used.
This level of detection may be achieved
either if the new markers are evaluated in
all fetuses or if a two tiered approach is
taken [Nicolaides et al., 2005]. The latter
approach is based on segregating patients
into three risk groups based on a
combined (NT and biochemistries) risk
assessment: high-risk (>1:100), inter-
mediate (101–1,000), and low risk
(<1,000). The high-risk group is offered
an invasive diagnostic test and the low-
risk group is reassured. Additional mar-
kers (NB or TCV) are evaluated in the
intermediate group. If the evaluation is
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
positive for the additional marker, an
invasive diagnostic test is offered and if it
is absent, the patient is reassured. Data
based on 20,305 fetuses examined pro-
spectively supports the validity of both
approaches: a detection rate of approxi-
mately 94% for a false positive rate of 5%
and a detection rate of approximately
90% a false positive rate of 2.5% were
achieved regardless whether the NB was
examined in all fetuses or only in the
intermediate risk group [Cicero et al.,
2006]. (For further details of combined
screening using additional ultrasound
markers, see Prof. K. Spencer’s review
in this issue).
First Trimester Ultrasound as a
Diagnostic Tool
The detection of some fetal anomalies
during the 11–13 þ 6 week scan has
already been discussed above in connec-
tion with screening (cardiac defects,
diaphragmatic hernia, skeletal dysplasias,
omphalocele, amniotic band syndrome,
megacystis, and holoprosencephaly). The
following is a brief discussion regarding
several other anomalies of interest which
are not considered to have a very high
association with either an increased risk of
aneuploidy or NT thickening [Snijders
et al., 1996]. One of the many benefits of
combined first trimester screening is the
potential to detect approximately 50% of
severe major structural defects [Souka
et al., 2006].
The observation that anencephaly is
the result of acrania early in pregnancy
was originally made in an animal model
[Warkany, 1971]. This observation has
now been confirmed in human fetuses by
ultrasound [Schmidt and Kubli, 1982;
Johnson et al., 1985; Goldstein et al.,
1989; Rottem et al., 1989; Kennedy
et al., 1990]. The pathognomonic feature
of acrania is absence of the cranial vault.
The appearance of the brain usually
disordered, though this is not always the
case. However, unlike in the second
trimester and beyond, it is not absent. In
order for this diagnosis to be made at 11–
13 þ 6 weeks of gestation, the intracranial
anatomy needs to be carefully evaluated
and ossification of the cranial vault
searched for [Johnson et al., 1997].
The diagnosis of a meningocele/
encephalocele is based on the presence of
a defect in the skull, usually in the
occipital region. It may either be an
isolated finding or be a part of a
syndrome such as Meckel–Gruber syn-
drome [Pachi et al., 1989; Sepulveda
et al., 1997]. Either just meninges
(meningocele) or meninges and brain
tissue (encephalocele) protrude through
this opening [Bronshtein and Zimmer,
1991; van Zalen-Sprock et al., 1992].
The diagnosis of this defect can be made
in early pregnancy, though it may be
difficult prior to the time of ossification
of the cranial vault. A confounding
variable may be that the size of the
protrusion and its contents may vary
with gestational age. A case of a
temporary resolution of the lesion has
also been reported [Bronshtein and
Zimmer, 1991].
Hydranencephaly is a lethal condition
which is caused by a complete occlusion
of the internal carotid artery and its
branches resulting in an absence of
cerebral hemispheres. This condition
can be diagnosed early in pregnancy. In
one report, its appearance at 12 weeks’
gestation included a large head with
small hemispheres and a fluid filled
intracranial cavity with no midline echo
[Lin et al., 1992].
The diagnosis of an open spine defect
can be made by ultrasound in the mid-
second trimester with a high degree of
certainty. This is due to the fact that
this condition is essentially invariably
accompanied by typical cranial findings
at this point in gestation: scalloping of
the frontal bones which give the skull a
lemon-like shape in the transverse view
and caudal displacement of the cerebel-
lum giving it a banana-like shape in the
transverse view and causing the transcer-
ebellar diameter to be diminished
[Nicolaides et al., 1986]. Unfortunately,
these signs do not appear to be reliably
present in the first trimester. However,
the presence of a lemon sign has been
reported in some fetuses with an open
spine defect even in the first trimester
[Sebire et al., 1997].
Pathognomonic feature of hydroce-
phaly is enlargement of the ventricles. It
appears that ventriculomegaly generally
55
does not develop until after the 14th
week of gestation. As such, hydroce-
phaly is not a condition, which can be
reliably diagnosed in the first trimester
[Mangione et al., 2001].
Dandy-Walker malformation (DWM)
is diagnosed if the cerebellar vermis is
partially or completely absent, leading to
a posterior fossa cyst. The normal
formation of the cerebellar vermis
extends well into the second trimester
making the diagnosis of DWM in the
first trimester very difficult [Babcook
et al., 1996; Ulm et al., 1997].
Gastroschisis is a result of a defect
involving the entire thickness of the
abdominal wall. It is usually located to
the right of the umbilical cord insertion.
Usually, only small bowel protrudes
through this opening, though other
abdominal organs have been noted to
do so. Unlike in the case of an
omphalocele, the cord insertion itself
is normal and this condition is not
associated with an increased risk of
aneuploidy. The diagnosis of a gastro-
schisis is relatively simple to make at
the 11–13 þ 6 week scan, as long as
care is taken to insonate the cord in-
sertion [Guzman, 1990; Kushnir et al.,
1990].
Bilateral renal agenesis invariably
results in oligohydramnios after 16
weeks of gestation. However, at the
11–13 þ 6 week scan, the amount of
amniotic fluid will be normal. The
inability to see the kidneys after a careful
search will raise a suspicion of bilateral
renal agenesis. However, the adrenals
can to some extent mimic the presence
of kidneys and the fetal bladder can be
visualized at this early gestational age
even in the presence of bilateral renal
agenesis making the definite diagnosis
very difficult (Bronshtein et al., 1994).
Other renal abnormalities have been
diagnosed at 11–13 þ 6 weeks of gesta-
tion: infantile polycystic kidney disease
[Bronshtein et al., 1992], multicystic
dysplastic kidney disease, [Bronshtein
et al., 1990; Economides and Braithwait,
1998], and hydronephrosis [Cullen et al.,
1990; Hernadi and Torocsik, 1997].
However, since all of the latter
conditions are variable in onset during
gestation and do not have a consistent
56 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS): DOI 10.1002/ajmg.c
ultrasound appearance in the first trime-
ster, they cannot be reliably diagnosed at
this early gestational age.
Multiple Gestations
There are several advantages of detection
and ultrasound evaluation of multiple
gestations at 11–13 þ 6 weeks of gesta-
tion. Firstly, the accuracy of determina-
tion of chorionicity at this gestational age
is essentially 100% [Monteagudo et al.,
1994; Sepulveda et al., 1996]. Early in
gestation, the chorion leave is covered by
chorionic villi, which atrophy as the
pregnancy progresses. Therefore, in the
first trimester, the dividing membrane in
dichorionic gestations is not only much
thicker overall compared to monochor-
ionic gestations, but it also demonstrates a
characteristic thickening at the point of its
junction with the placenta (so-called
lambda sign). In a pregnancy where the
dividing membrane is difficult to see,
differentiation between a monochorio-
nic/diamniotic and monoamniotic gesta-
tions can be made based on the number of
yolk sacs [Bromley and Benacerraf,
1995]. Second, use of biochemical
screening for fetal abnormalities in twins
is limited by its inability to differentiate
between the two fetuses, increasing the
importance of the sonographic compo-
nent of screening. This is especially true
in dichorionic/diamniotic gestations.
However, the addition of biochemical
markers to NT screening in twins does
reduce the false positive rate [Noble et al.,
1997; Spencer, 2000; Spencer and Nico-
laides, 2003]. In higher order multiple
gestations, the use of biochemical mar-
kers for clinical use is not yet available
[Maymon et al., 1999]. Third, multiple
gestations are at an increased risk for fetal
anomalies, especially midline defects.
Therefore, an early fetal anatomic evalua-
tion is especially useful. When using NT
measurements for screening, in mono-
chorionic gestations, one of the twins can
have a thickened NT due to an imbalance
in blood volumes between the two fetuses
(an early form of twin-to-twin transfu-
sion) [Spencer and Nicolaides, 2003].
This has to be taken into consideration
when estimating the risk of aneuploidy.
(For further details of combined screen-
ing in multiple gestations, see Prof.
Spencer’s review in this issue.)
CONCLUSION
Ultrasound provides a window through
which invaluable information about the
fetus, amniotic fluid, and the placenta
can be gained even in the first trimester.
Clearly, the days when a first trimester
obstetric ultrasound simply meant a
crown-rump measurement are over.
An early systematic evaluation of
the fetus is best done between 11 and
13 þ 6 weeks of gestation. At this point
in time, a measurement of the NT is
obtained, thus providing us with the
most robust fetal marker for aneuploidy
currently available. Incorporation of this
marker in a combined screen with
biochemical markers and/or other ultra-
sound marker such as NB evaluation or
TCV blood flow leads to detection rates
of over 90% for 5% screen positive rates
for trisomy 21. In multiple gestations,
NT screening is of even greater value
since biochemical markers do not per-
form as well as in singletons.
The often-understated benefit of
measuring the NT is its correlation with
other fetal defects and the overall risk of
fetal morbidity and mortality. Therefore,
its importance lies not only in its robust-
ness as a marker but also in a high degree of
versatility, which cannot be duplicated by
using biochemical markers. High-resolu-
tion ultrasound, especially when transab-
dominal and transvaginal approaches are
combined, allows for an early and accurate
evaluation of fetal anatomy.
In order for the various components
of ultrasound-based screening programs
and fetal evaluation to be effective, it is
imperative that sonographers receive
the appropriate training and accredita-
tion. The overall result is that prospective
parents are provided with significant
amount of useful information about
the fetus at an early gestational age with
clear medical and psychological benefits.
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