CHAPTER 6 • First Trimester Screening for Chromosomal Aneuploidies
INTRODUCTION
The incidence of fetal numerical chromosomal aneuploidies such as trisomy 21 (T21;
Down syndrome), trisomy 18 (T18; Edwards syndrome), and trisomy 13 (T13; Patau
syndrome) increases with advancing maternal age. The presence of fetal chromosomal
aneuploidies has been associated with significant pregnancy complications such as
multiple malformations, growth restriction, and perinatal deaths. Prenatal screening for
chromosomal aneuploidies has received significant attention over the past 30 years and
is now considered an integral part of prenatal care. Several major developments
impacted prenatal screening for chromosomal abnormalities, such as the identification
of ultrasound markers for aneuploidy, the introduction of the second trimester
biochemical screen, the introduction of the first trimester screen with nuchal
translucency (NT), and recently fetal cell-free DNA in maternal plasma. Advancement
in aneuploidy screening has currently led to the prenatal identification of most fetuses
with chromosomal abnormalities. The largest study to date on the first trimester role of
thickened NT and major malformations in the detection of chromosomal aneuploidies
was recently published1 and included a total of 108,982 fetuses with 654 cases of
trisomies 21, 18, or 13. The presence of at least one of the following findings: thickened
NT (>3.5 mm), holoprosencephaly, omphalocele, or megacystis had the potential to
detect 57% of all aneuploidies. Interestingly, one or more of these four findings was
found in 53% of all T21, in 72% of all T18, and 86% of all T13 fetuses.1 In this
chapter, we present detailed first trimester sonographic features of aneuploidies in
addition to aspects of other genetic diseases and syndromes.
FIRST TRIMESTER ULTRASOUND AND MATERNAL
BIOCHEMICAL MARKERS IN ANEUPLOIDY
Trisomy 21
The association in the first trimester fetus of increased nuchal fluid and aneuploidy wasfirst described more than two decades ago,2–4 and this finding has led to the
establishment of first trimester aneuploidy screening with NT and biochemical markers.
A thickened NT has been correlated with the presence of trisomy 21 (T21) and T21
fetuses have a mean NT thickness of 3.4 mm.5 In a study involving 654 fetuses with T21,
more than half were shown to have an NT ≥3.5 mm.1 The NT in the normal fetus
increases with increasing crown-rump length (CRL) measurement and NT screening has
been successfully used to adjust the pregnancy’s aneuploidy a priori risk established by
maternal age. This has been one of the most important elements of aneuploidy screening
as it resulted in a significant reduction in unnecessary invasive testing on pregnant
women with advanced maternal age.
In pregnancies with T21 fetuses, the maternal serum concentration of free β-human
chorionic gonadotropin (β-hCG) is about twice as high and pregnancy-associated
plasma protein A (PAPP-A) is reduced to half compared to euploid pregnancies (Table
6.1). Although NT measurement alone identifies about 75% to 80% of T21 fetuses, the
combination of NT with maternal biomarkers in the first trimester increases the T21
detection rate to 85% to 95%, while keeping the false-positive rate at 5%.5,6 Indeed, in
a recent prospective validation study of screening for trisomies 21, 18 and 13 by a
combination of maternal age, fetal NT, fetal heart rate and serum free β-hCG and PAPPA at 11+0 to 13+6 weeks of gestation in 108,982 singleton pregnancies, T21, 18, and 13
were detected in 90%, 97%, and 92% respectively with a false-positive rate of 4%.6
Monosomy X was also detected in more than 90% of cases along with more than 85%
of triploidies and more than 30% of other chromosomal abnormalities.6 In addition to
NT, other sensitive first trimester ultrasound markers of T21 include absence or
hypoplasia of the nasal bone (Fig. 6.1), cardiac malformations (atrioventricular septal
defect) with or without generalized edema (Figs. 6.2 and 6.3), tricuspid regurgitation
(Fig. 6.4A), aberrant right subclavian artery (Fig. 6.4B), echogenic intracardiac focus
(Fig. 6.4C), and increased impedance to flow in the ductus venosus (Fig. 6.5). First
trimester features of fetuses with T21 are listed in Table 6.2. Additional first trimester
findings in T21 fetuses are shown in images in various chapters of this book.
Table 6.1 • Biochemical and Sonographic Features of Trisomies 21, 18,
and 13
NT Mixture Model Euploid Trisomy
21
Trisomy
18
Trisomy
13
CRL-independent distribution,
% 5 95 70 85
Median CRL-independent NT,mm 2.0 3.4 5.5 4.4
Median serum free β-hCG,
MoM 1.0 2.0 0.2 0.5
Median serum PAPP-A, MoM 1.0 0.5 0.2 0.3
Absent nasal bone, % 2.5 60 53 45
Tricuspid regurgitation, % 1.0 55 33 30
Ductus venosus reversed Awave, % 3.0 66 58 55
NT, nuchal translucency; CRL, crown-rump length; β-hCG, β-human
chorionic gonadotropin; MoM, multiple of the median; PAPP-A, pregnancyassociated plasma protein A.
From Nicolaides KH. Screening for fetal aneuploidies at 11 to 13 weeks.
Prenat Diagn. 2011;31:7–15; copyright John Wiley & Sons, with
permission.
Figure 6.1: Midsagittal view of the face in six fetuses with trisomy 21 between
11 and 13 weeks of gestation. Note the various thicknesses of the nuchaltranslucency (asterisk) and the absence (A, C, F) or poor ossification (B, D, E)
of the nasal bone (arrows).
Figure 6.2: Sagittal view of the fetal head and chest (A) and transverse view of
the chest (B) in a fetus with trisomy 21 at 13 weeks of gestation. Note the
presence of early hydrops with body skin edema (white arrows in A and B) and
a thickened nuchal translucency (asterisk in A). Note also the presence of an
atrioventricular septal defect (yellow arrow) in B.
Figure 6.3: Transverse views of the fetal chest at the level of the four-chamber
view in gray scale (A) and color Doppler (B) in a fetus with trisomy 21 at 12
weeks of gestation. Note the presence of an atrioventricular septal defect
(asterisk) in A and B, which represents the typical cardiac anomaly of thissyndrome. Also note the associated body edema (arrows), which resolved at
16 weeks upon follow-up. See Figure 6.4 for additional sonographic markers of
trisomy 21 in the first trimester. LV, left ventricle; RV, right ventricle.
Trisomy 18 and Trisomy 13
Thickened NT is not specific to T21 as it can be also found in other aneuploidies. In
T18 and T13, NT median values were shown to be 5.5 and 4.0 mm, respectively.5,6 The
PAPP-A value is also reduced in both trisomies with a median value of 0.2 MoM for
T18 and 0.3 MoM for T13. Unlike in T21, free β-hCG values are decreased in T18 and
T13 with median values of 0.2 MoM and 0.5 MoM, respectively (Table 6.1). For
physicians and sonographers with expertise in the first trimester ultrasound examination,
T18 or T13 is often first suspected by the presence of typical ultrasound features, rather
than by biochemical screening. In a study involving 5,613 normal fetuses and 37 fetuses
with T18, the first trimester ultrasound examination was found to be a good screening
test for T18.7 The mean NT thickness was 5.4 mm in T18 fetuses as compared to 1.7
mm in euploid fetuses.7 Congenital heart defects were observed in 70.3% of T18 fetuses
and in 0.5% of euploid fetuses and extracardiac malformations were identified in
35.1% of T18 fetuses and in 0.8% of euploid fetuses.7 Only one case of T18
demonstrated no sonographic markers of aneuploidy.7
Figure 6.4: Additional sonographic findings in fetuses with trisomy 21 in the
first trimester. Tricuspid regurgitation shown in A on color and pulsed (arrow)
Doppler, an aberrant course of the right subclavian artery (ARSA) shown in Band an echogenic intracardiac focus shown in the left ventricle (LV) in C
(arrow). RA, right atrium; RV, right ventricle.
Figure 6.5: Ductus venosus (DV) Doppler flow assessment in two fetuses (A
and B) with trisomy 21 at 13 weeks of gestation. Note the presence of reverse
flow during the atrial contraction phase (A) of the cardiac cycle (arrow). Fetus
A had no associated cardiac defect, whereas fetus B had a cardiac defect,
which may explain the more severe reverse flow of the A-wave (arrow in B).
Normal Doppler waveforms of the ductus venosus show antegrade flow
throughout the cardiac cycle with low impedance. S, systolic flow; D, diastolic
flow.
Table 6.2 • First Trimester Features of Trisomy 21
Thickened nuchal translucency (NT)
High human chorionic gonadotropin (HCG, β-hCG)
Low pregnancy-associated plasma protein A (PAPP-A)
Absent or hypoplastic nasal boneReversal of flow in diastole or high impedance flow in ductus venosus
Tricuspid regurgitation
Increased fronto-maxillary-facial (FMF) angle, short maxilla reflecting
midface hypoplasia
Aberrant right subclavian artery
Echogenic focus
Echogenic bowel
Renal tract dilation
Increased peak velocity in the hepatic artery
Ductus venosus directly draining into the inferior vena cava
Structural anomalies such as atrioventricular septal defect, tetralogy of
Fallot, and others
Figures 6.6 to 6.17 show common sonographic features of T18 in the first trimester,
including thickened NT (Figs. 6.6, 6.8, and 6.9), absent/hypoplastic nasal bone (Figs.
6.6 and 6.8), dilated fourth ventricle/abnormal posterior fossa (Figs. 6.6 to 6.8),
megacystis (Fig. 6.7), spina bifida (Figs. 6.7 and 6.8), cardiac malformations (Figs.
6.10 to 6.12), small omphalocele (Figs. 6.6, 6.7, and 6.13), abnormal extremities (Figs.
6.14 and 6.15), cleft lip and palate (Figs. 6.6 and 6.15), short CRL (Figs. 6.6, 6.7, and
6.15), and single umbilical artery/cord abnormalities (Fig. 6.16 and 6.17).1,8
Figure 6.6: Midsagittal view of the body of a fetus with trisomy 18 at 12 weeks
of gestation showing several typical abnormalities. Note the short crown-lumplength (1), the thickened nuchal translucency (2), the absence of an ossified
nasal bone (3), the dilated fourth ventricle (4), the small omphalocele with
bowel content (5), and the maxillary gap as a sign of cleft lip and palate (6).
See Figures 6.7 to 6.11 for associated fetal abnormalities with trisomy 18.
Figure 6.7: Midsagittal view of the body of a fetus with trisomy 18 at 13 weeks
of gestation showing typical associated abnormalities. Note the presence of a
short crown-rump length (1), an omphalocele (2), a megacystis (3), an
abnormal posterior fossa (4), and thickened brainstem and no fluid in the fourth
ventricle due to an open spina bifida (5). Note that the nuchal translucency (6)
is not markedly thickened.
Figure 6.8: Midsagittal view of the fetal face in three fetuses (A–C) with
trisomy 18 at 13, 12, and 14 weeks of gestation, respectively. Note the
presence of a normal nuchal translucency (NT) in A, a mildly increased NT in C,and a markedly increased NT in B. All three fetuses have an absent or poorly
ossified nasal bone (NB). The posterior fossa is an interesting marker in
trisomy 18 and can be normal as in fetus A, but is often dilated as seen in fetus
B (open arrow) and occasionally compressed as in fetus C (double headed
arrow) in the presence of an open spina bifida. Fetus A was diagnosed with
trisomy 18 due to the presence of radius aplasia (see Fig. 6.14) and cardiac
abnormalities. Fetus B has a cleft in the maxilla (arrow) suggesting the
presence of a facial cleft.
Figure 6.9: Axial views of the fetal head in two fetuses with trisomy 18 at 12
weeks of gestation. Note the presence of early hydrops and thickened nuchal
translucency/cystic hygroma (asterisk) in both fetuses (A and B). Fetus B also
has a dilated fourth ventricle (open arrow).Figure 6.10: Axial views of the chest in three fetuses (A–C) with trisomy 18
and cardiac anomalies at 11, 13, and 13 weeks of gestation, respectively. In
fetus A and B, an atrioventricular septal defect (AVSD) is shown in gray scale
in A (arrow) and in color Doppler in B (arrow). Fetus C initially appeared to
have a univentricular heart, but a follow-up ultrasound a week later confirmed
the presence of an AVSD as well. Hydrops and skin edema (asterisk) are often
found as shown in A and B. LV, left ventricle; RV, right ventricle.
Figure 6.11: Cardiac valves are often insufficient in fetuses with trisomy 18 inthe first trimester of pregnancy. A: Color and pulsed Doppler across the
tricuspid valve in a fetus with trisomy 18 at 13 weeks of gestation showing the
presence of mild tricuspid regurgitation (arrow). B: Color and pulsed Doppler
across the tricuspid valve in a fetus with trisomy 21 at 13 weeks of gestation
showing the presence of severe tricuspid regurgitation (arrow). RA, right
atrium; RV, right ventricle.
Figure 6.12: Three-vessel-trachea view in color and pulsed Doppler in a fetus
at 12 weeks of gestation with dysplastic or polyvalvular pulmonary valve with
stenosis and insufficiency, a finding that is typical for trisomy 18 and 13. A:
Antegrade flow across the pulmonary artery (PA) in systole (blue arrow). B:
Retrograde flow in PA in diastole (red arrow). C: The spectral Doppler across
the PA demonstrating the bidirectional flow. This finding can also affect the
aortic valve and is often accompanied by fetal hydrops and fetal demise. Ao,
aorta.Figure 6.13: Axial views of the fetal abdomen at the level of the umbilical cord
insertion in three fetuses (A–C) with trisomy 18 at 13, 12, and 12 weeks of
gestation, respectively. Note the presence of an omphalocele (arrows) in each
fetus, which is a typical finding in trisomy 18. In fetus A and B, the omphalocele
is small with bowel content, which is commonly seen in trisomy 18. In fetus C,
the liver is in the omphalocele sac. Note the presence of fetal hydrops in all
fetuses.
Figure 6.14: Abnormal hands in two fetuses (A and B) with trisomy 18 at 12
and 13 weeks of gestation, respectively. Note the presence of bilateral clubbed
hands in fetus A (yellow arrows) and radial aplasia in fetus B (white arrows).Figure 6.15: Midsagittal view (A) and 3D surface mode view (B) of a fetus at
12 weeks of gestation with trisomy 18. Note the presence of the following
features: short crown-rump length (1), normal nuchal translucency thickness
(2), facial cleft with protrusion and maxillary gap (yellow arrow) (3), and an
omphalocele (4). B: The facial cleft (yellow arrow) and bilateral radial aplasia
(white arrows), which are not demonstrated in A.Figure 6.16: Axial planes of the lower abdomen in two fetuses (A and B) with
trisomy 18 at 12 weeks of gestation. Note in fetus A the presence of a single
right umbilical artery (R.UA) next to the bladder (open arrow), with the absence
of the left UA (solid arrow with “?”). Fetus B has a single left umbilical artery
(L.UA) in addition to an omphalocele (asterisk). The solid arrow with “?” in B
denotes the absence of the R.UA.Figure 6.17: A: A parasagittal plane of the fetal abdomen and chest in color
Doppler in a fetus with trisomy 18 at 12 weeks of gestation. Note the direct
connection of the ductus venosus (DV) with the inferior vena cava (IVC) in A. B:
A cross section of the umbilical cord in the amniotic cavity of another fetus with
trisomy 18 at 12 weeks of gestation. Note the presence of a cord cyst in B
(arrows). These cord and umbilical vessel abnormalities represent subtle
findings in trisomy 18 and also in trisomy 13 (see Fig. 6.24). Additional
malformations were found in both fetuses. HV, hepatic vein; UV, umbilical vein.Figure 6.18: Axial plane of the fetal head (A) and midsagittal plane of the face
(B) in a fetus with trisomy 13 at 12 weeks of gestation. Note the presence of
typical craniofacial abnormalities with holoprosencephaly, demonstrated in A
(asterisk) and severe facial cleft in B (arrow).Figure 6.19: Axial planes of the fetal head in two fetuses (A and B) with
trisomy 13 at 12 and 13 weeks of gestation respectively with alobar
holoprosencephaly (asterisk). A is obtained by the transabdominal approach
and B is obtained by the transvaginal approach.
Figure 6.20: Trisomy 13 with severe facial anomalies in three fetuses (A–C) at
13, 13, and 14 weeks of gestation, respectively. Fetus A shows a median cleft
in association with holoprosencephaly, no maxilla is seen (arrow), and the
nuchal translucency (NT) (asterisk) is not thickened. Fetus B is examined
transvaginally and shows a thickened NT (asterisk), a bilateral cleft with
protrusion (solid arrow), and a dilated fourth ventricle (open arrow). Fetus C
had no thickened NT (asterisk), a normal fourth ventricle, and retrognathia
(arrow). All three fetuses had severe additional anomalies.
Features of T13 on first trimester ultrasound include craniofacial abnormalities
(Figs. 6.18 to 6.20), cleft lip/palate (Figs. 6.18 and 6.20), thickened NT (Fig. 6.20),
abnormal extremities with polydactyly (Fig. 6.21), cardiac abnormalities (Fig. 6.22),
renal abnormalities (Fig. 6.23), and umbilical cord/abdominal venous abnormalities
(Figs. 6.23 and 6.24).1,8
First trimester features of fetuses with T18 and T13 are listed in Table 6.3.
Additional first trimester findings in T18 and T13 fetuses are shown in images in
various chapters of this book.Figure 6.21: Polydactyly in two fetuses with trisomy 13 at 14 weeks and in
gray scale in fetus A and at 12 weeks and in 3D surface mode in fetus B.Figure 6.22: A: Fetal tachycardia demonstrated on spectral Doppler of the
tricuspid valve in a fetus with trisomy 13 at 12 weeks of gestation, with fetal
heart rate (FHR) at 193 beats per minute (bpm). B: Color Doppler at the fourchamber view in a fetus with trisomy 13 at 14 weeks of gestation. Note the
presence in B of discrepant ventricular filling with a narrow left ventricle (LV).
C: The three-vessel-trachea view of the fetus shown in B. Note in C the narrow
aortic arch (AO) in comparison with the pulmonary artery (PA). Cardiac findings
in fetuses with trisomy 13 are common and include tachycardia (>175 per
minute), intraventricular echogenic foci, an aberrant right subclavian artery, and
cardiac defects, predominantly left ventricular outflow tract obstruction. RV,
right ventricle.
Figure 6.23: A: A parasagittal view of the abdomen in a fetus at 12 weeks of
gestation with trisomy 13 and renal abnormalities. Note the presence in A of
hyperechogenic kidneys (arrow) and megacystis (asterisk). Fetus in B also has
trisomy 13 at 14 weeks of gestation. Note in B the presence of a single
umbilical artery, a finding similar to trisomy 18. Fetus in C has trisomy 13 at 12
weeks of gestation and shows a small omphalocele, another finding commonly
seen in trisomy 18 fetuses in early gestation.Figure 6.24: A: A parasagittal plane of the fetal abdomen and chest in color
Doppler in a fetus with trisomy 13 at 13 weeks of gestation. Note the direct
connection of the ductus venosus (DV) with the inferior vena cava (IVC) in A. B:
A cross section of the umbilical cord in the amniotic cavity of another fetus with
trisomy 13 at 14 weeks of gestation. Note the presence of a large cord cyst
(asterisk/arrows) in B. These cord and umbilical vessel abnormalities represent
subtle findings in trisomy 13 and in trisomy 18 as shown in Figure 6.17.
Additional malformations were found in both fetuses. UV, umbilical vein.
Table 6.3 • First Trimester Features of Trisomy 18 and 13
Trisomy 18 Trisomy 13
Nuchal
translucency
(median)
5.5 mm 4.0 mm
Free β-hCG
(median) 0.2 MoM 0.5 MoM
PAPP-A
(median) 0.2 MoM 0.3 MoM
Growth restriction Growth restrictionFetal growth
Brain
Rarely holoprosencephaly
Occasionally choroid plexus
cysts
Typically holoprosencephaly
Occasionally choroid plexus
cysts
Posterior
fossa
Cystic dilation of posterior
fossa. Signs of brainstem
thickening and IT
compression as marker for
open spina bifida
Cystic dilation of posterior
fossa
Face
Absent nasal bone, flat
profile, retrognathia,
occasionally median clefts
Severe midline facial
anomalies: hypotelorism,
pseudocyclopia, proboscis,
arrhinia, median clefts,
retrognathia, absent nasal
bone
Neck and skin Thickened NT and severe
hydrops
Thickened NT and severe
hydrops
Heart
Tricuspid regurgitation,
aberrant right subclavian
artery, echogenic focus,
structural cardiac anomalies
especially septal defects
(AVSD; VSD), conotruncal
anomalies such as tetralogy
of Fallot and double outlet
right ventricle, polyvalvular
dysplastic semilunar valves
Tachycardia, tricuspid
regurgitation, echogenic
focus, aberrant right
subclavian artery, structural
cardiac anomalies, especially
left ventricular outflow tract
obstruction (HLHS, CoA,
etc.), and polyvalvular
dysplastic semilunar valves
Abdomen
Omphalocele (often with
bowel only), Diaphragmatic
hernia
Abnormal ductus venosus
course with connection with
inferior vena cava
Rarely omphalocele or other
bowel anomalies, abnormal
ductus venosus course with
connection with inferior vena
cava
Urogenital
anomalies Horseshoe kidneys M kidengeaycsystis, hyperechogenic
Skeletal Radius aplasia, club hands,
Polydactylyanomalies clenched fingers, spina bifida
Umbilical cord Single umbilical artery, cord
cyst
Single umbilical artery, cord
cyst
Free β-hCG, free β human chorionic gonadotropin; PAPP-A, pregnancyassociated plasma protein A; NT, nuchal translucency; AVSD,
atrioventricular septal defect; VSD, ventricular septal defect; HLHS,
hypoplastic left heart syndrome; CoA, coarctation of aorta.
Monosomy X
The NT is often enlarged in fetuses with monosomy X (Turner syndrome). This enlarged
NT has a median value of 7.8 mm5 and has often been described as a cystic hygroma
(Figs. 6.25 and 6.26). The occurrence of monosomy X is not related to maternal age.
Typically, lymphatic disturbances in monosomy X are not limited to the neck region but
involve the whole body including the presence of hydrothorax, ascites, and skin edema
(Fig. 6.27). Nasal bone is generally present in fetuses with monosomy X.8 Maternal
serum-free β-hCG is normal (1.1 MoM) and PAPP-A is low (0.49 MoM). 9 Typical first
trimester features in monosomy X are listed in Table 6.4 and include fetal tachycardia
and left ventricular outflow tract obstruction (Fig. 6.28), renal anomalies such as the
presence of horseshoe kidneys as well as feet edema. Some of these anomalies are often
difficult to diagnose in the first trimester. In a first trimester study involving 31 cases of
monosomy X and 5,613 euploid controls, NT measurement (8.8 mm) and fetal heart rate
(171 beats per minute) in monosomy X were significantly greater than in euploid
controls (NT = 1.7 mm and fetal heart rate 160 beats per minute).10 In monosomy X
fetuses, congenital heart defects and hydrops were noted in 54.8% and 43.8%,
respectively.10 None of the monosomy X cases demonstrated absent sonographic
markers of aneuploidy.10 Additional first trimester findings in monosomy X fetuses are
shown in images in various chapters of this book.
Triploidy
In triploidy, there is a complete additional haploid set of chromosomes resulting in 69
chromosomes in each cell instead of 46 chromosomes. The additional haploid set can
be of maternal or paternal origin. The “paternal” type is called diandric triploidy and
the “maternal” type is called digynic triploidy. These two types of triploidy have
different features, which can be often differentiated on ultrasound.Figure 6.25: Midsagittal planes of the fetal body in two fetuses (A and B) with
monosomy X (Turner syndrome) at 11 and 13 weeks of gestation, respectively.
Note the presence of a marked thickened nuchal translucency (asterisks) in A
and fetal hydrops and cystic hygroma in B. Maternal age is often not increased
and the nasal bone is typically ossified (arrows).
Figure 6.26: Three fetuses (A–C) with Turner syndrome and neck
abnormalities, all at 13 weeks of gestation. Fetus A and B has cystic hygromas
(asterisks), whereas fetus C has lateral neck cysts (long arrows). Fetal scalp
edema is seen in all fetuses (short arrows). Intracerebral structures are normal
in all fetuses. 4V, fourth ventricle.Figure 6.27: A: A midsagittal plane of the body in a fetus with monosomy X at
13 weeks of gestation. Note the presence in A of marked thickened nuchal
translucency (NT)/cystic hygroma with body edema (asterisks). B: An axial
plane of the chest in another fetus with monosomy X at 11 weeks of gestation.
Note the presence in B of bilateral pleural effusion (arrows). H, heart.
Table 6.4 • First Trimester Features of Monosomy X
Marked thickened nuchal translucency (NT), cystic hygroma, early hydrops
High human chorionic gonadotropin (HCG, β-hCG)
Low pregnancy-associated plasma protein A (PAPP-A)
Normal nasal bone
Cardiac abnormalities: tachycardia, left ventricular outflow obstruction,
hypoplastic left heart syndrome, coarctation of the aorta, aberrant right
subclavian artery, tricuspid regurgitation
Renal anomalies: horseshoe kidney, renal pelvis dilation
Ductus venosus abnormalities: directly draining into inferior vena cava,
reversal flow of A-wave or high impedance
Female gender
NT can be thickened in both diandric and digynic triploidy, but is often within thenormal range. The typical pattern of diandric triploidy includes the presence of a molar
placenta (Fig. 6.29), with a normally grown fetus, whereas in digynic triploidy, severe
growth restriction is noted with a small but not molar placenta. These placental
differences are reflected in the profile of biochemistry with diandric triploidy
associated with increased maternal serum-free β-hCG and mildly decreased PAPP-A
and digynic triploidy associated with markedly decreased maternal serum free β-hCG
and PAPP-A.11,12 Another important first trimester feature of digynic triploidy is the
presence of significantly short CRL and a marked difference in size between the
abdominal and head circumference, typically of more than “2 weeks” of gestational
age13 (Figs. 6.30 to 6.32). This discrepancy in dimensions between the head and
abdomen is an almost pathognomonic sign of digynic triploidy.
Figure 6.28: Axial plane at the level of the four-chamber view in gray scale (A)
and the three-vessel-trachea view in color Doppler (B) in a fetus with
monosomy X at 13 weeks of gestation. Note the presence in A of ventricular
disproportions with a narrow left ventricle (LV). In B, a narrow aortic arch (AO)
is noted in comparison with the pulmonary artery (PA), suggesting the presence
of aortic coarctation. Also note the presence of skin edema (asterisks) in A and
B. The presence of left ventricular outflow tract anomaly including aortic
coarctation or hypoplastic left heart syndrome is a typical finding in fetuses with
monosomy X. RV, right ventricle.Figure 6.29: Ultrasound of the placenta in a pregnancy at 11 weeks of
gestation with diandric triploidy. Note the presence of molar placental changes
(arrows). See text for details.Figure 6.30: Axial planes of the fetal abdomen (A) and head (B) in a fetus with
digynic triploidy at 12 weeks of gestation. Note the marked difference in size
between the abdominal (A) and head (B) circumference, of more than “2
weeks” of gestational age. See text for details.Figure 6.31: Midsagittal planes of the body in two fetuses (A and B) with
digynic triploidy, both at 13 weeks of gestation. Note in both fetuses the
marked difference in size between the abdominal (yellow arrows) and head
(white arrows) dimensions. This discrepancy in dimensions between the head
and abdomen is an almost pathognomonic sign of digynic triploidy. In addition,
the crown-rump length is significantly short, reflecting the presence of early
growth restriction. See 6.32 for the 3D surface mode views.Figure 6.32: Three-dimensional ultrasound in surface mode in two fetuses (A
and B) with digynic triploidy; same fetuses as in Figure 6.31. Note the marked
difference in dimensions between the abdomen (yellow arrows) and the head
(white arrows) in both fetuses. See text for details.
A high detection rate for triploidy is also achieved with first trimester screening for
T21. In a study involving 198,427 women with singleton pregnancies who underwent
first trimester screening between 11+2 and 14+0 weeks of gestation, the overall
detection rate of triploidy was 25/30 (83.3%), primarily resulting from an abnormal
first trimester screening in 23/30 and structural abnormalities in 2/30.12 A smaller CRL
than expected was found in 95% of the fetuses with data available for evaluation and
eight of 30 fetuses had a larger biparietal diameter than expected for gestational age.12
Typical features of triploidy are presented in Table 6.5 and additional first trimester
findings in triploidy fetuses are shown in images in various chapters of this book.
NONINVASIVE PRENATAL TESTING
Noninvasive prenatal testing (NIPT) is a relatively new genetic testing that is offered as
a screening test in the first (and second trimester of pregnancy) for trisomies 21, 13, 18,
monosomy X, and sex chromosome abnormalities. The test is based upon the presence
of fetal cell-free DNA (cfDNA) in the maternal circulation primarily from placental
cells apoptosis. Placental cell apoptosis releases into the maternal circulation small
DNA fragments that can be detected from about 4 to 7 weeks of gestation.14 It is
estimated that about 2-20% of circulating cfDNA in the maternal circulation is fetal in
origin.14 The half-life of cfDNA is short and is typically undetectable within hours afterdelivery.15 Details of the technical aspect of NIPT are beyond the scope of this book but
the various tests that are clinically available are based upon the isolation and counting
of cfDNA using sequencing methods.
Table 6.5 • First Trimester Features of Triploidy
Digynic (Maternal)
Triploidy
Diandric (Paternal)
Triploidy
Nuchal
translucency Normal Increased
Free β-hCG
(median) 0.18 MoM 8 MoM
PAPP-A (median) 0.06 MoM 0.75 MoM
Growth
Short crown-rump length,
severe growth restriction
with discrepant
head/abdominal
circumference >2 wk
Normal growth or short
crown-rump length
Head
Proportional large head, dilated fourth ventricle,
compressed posterior fossa as a clue for spina bifida,
holoprosencephaly
Heart Cardiac anomalies, aberrant right subclavian artery,
echogenic focus, tricuspid regurgitation
Abdomen Echogenic bowel, single umbilical artery, absent gall
bladder, echogenic kidneys
Limbs, skeletal Clenched hands, syndactyly, club feet, spina bifida
Free β-hCG, free β human chorionic gonadotropin; PAPP-A, pregnancyassociated plasma protein A.
NIPT has very good performance with regard to screening for T21. In published
studies, the detection rate for T21 is at 99% for a false-positive rate of 0.16%.16,17
Detection rate for T18 is at 97% for a false-positive rate of 0.15%.16 The use of NIPT
is rapidly expanding and is now being offered as the primary screening test in
pregnancy. Even if the NIPT test has an excellent detection rate for T21, T18, and T13,
other aneuploidies remain missed.18–20
It should be emphasized that NIPT is a screening and not a diagnostic test and thuscaution should be used when NIPT is incorporated in the genetic evaluation of fetal
malformations. Given a relatively high association of anomalies with chromosomal
imbalance, the significance of a normal NIPT result in the setting of fetal anomalies
should be explained with the patient and further invasive diagnostic testing should be
recommended. Undoubtedly NIPT technology will expand over the next few years to
allow for screening of chromosomal deletions and duplications and is already available
for very few monogenic conditions.
FIRST TRIMESTER DIAGNOSIS OF GENETIC
DISEASES AND SYNDROMIC CONDITIONS
Screening for chromosomal aneuploidy in the first trimester with NT and other markers
has expanded the use of ultrasound in early gestation. This expansion in first trimester
ultrasound led to the detection of single or multiple fetal malformations, which in some
cases suggested the possible presence of a genetic syndrome. We presented in Chapter 5
four possible pathways that result in the detection of fetal anomaly in the first trimester.
These four pathways include: (1) the presence of an obvious structural anomaly on
ultrasound, (2) the detection of a thickened NT with resultant workup leading to the fetal
anomaly, (3) the presence of a positive family history leading to the detection of a
recurrent case and (4) the detection of the anomaly by a detailed ultrasound
examination. In the absence of a prior family history of a genetic syndrome with fetal
anomalies, the de novo diagnosis of a genetic syndrome in the first trimester is quite
challenging. When presented with a constellation of sonographic abnormalities in the
second or third trimester of pregnancy, an expert sonologist is commonly able to suggest
the presence of a specific syndrome. This is a more challenging task in the first trimester
however as the full display of all of the sonographic features of a genetic syndrome is
rare in early gestation. Nevertheless, there are four ways that syndromic conditions are
diagnosed in the first trimester:1.
2.
3.
4.
Figure 6.33: This figure shows the fetal profile (A) and the four-chamber view
in color Doppler, obtained transvaginally (B) in a pregnant patient referred at 30
years of age for nuchal translucency (NT) screening at 12 weeks of gestation.
A: An NT of 2 mm, within the normal range and an absent nasal bone (arrow).
B: A hypoplastic left ventricle (LV), suspicious for a hypoplastic left heart
syndrome with blood flow only demonstrated across the right atrium (RA) and
ventricle (RV) on color Doppler. Chorionic villous sampling revealed a partial
monosomy 9q and partial trisomy 2p as unbalanced translocation. Karyotyping
of parents’ chromosomes revealed a previously unknown balanced
translocation in the father.
The presence of an abnormal karyotype following an invasive diagnostic procedure
such as trisomies, triploidy, monosomy X and large unbalanced translocations,
deletions, and duplications.
The presence of microdeletions and microduplications, detected either with
fluorescent in situ hybridization (FISH) or with comparative genomic hybridization
(CGH or microarray).
Monogenic diseases detected by selective molecular genetic examination of a
special condition or with the use of next generation sequencing.
Genetic syndromes with “association” or “sequence” with no or not yet defined
molecular genetic background.Abnormal Karyotype, Deletions, Duplications
If an anomaly is detected on ultrasound, the authors believe that it is not advisable to
offer the NIPT test, as it is a screening test and will miss some significant chromosomal
abnormalities.18 Invasive diagnostic testing, such as chorionic villous sampling (CVS),
should be offered in that context. The traditional karyotypic analysis will detect the
presence of large balanced or unbalanced translocations (Fig. 6.33), rare mosaic
trisomies, marker chromosomes, and isochromosomes (Figs. 6.34 and 10.19) in
addition to numerical chromosomal abnormalities. Large chromosomal deletions can
also be identified on traditional karyotype analysis as in the majority of deletions 4p-
(Wolf–Hirschhorn syndrome) (Fig. 6.35) or deletion 18p- (De Grouchy syndrome) (Fig.
6.36). Small deletions, termed microdeletions, such as 22q11 (DiGeorge syndrome),
are typically too small to be identified by this method (Fig. 11.6). Microdeletions can
be detected by the use of FISH, when such a condition is suspected (e.g., FISH for
deletion 22q11 in conotruncal anomalies) or by examining the complete chromosome
using CGH or microarray. This CGH technique has become popular recently despite its
cost and limitations. Some centers offer CGH as a first-line genetic testing after CVS or
amniocentesis, whereas others restrict its use to suspected DNA imbalance or as a
second-line test following normal karyotype analysis. Recent studies suggest that CGH
detects an additional 6% of chromosomal abnormalities over the aneuploidies in
pregnancies with fetal malformations.21,22
Monogenic Diseases and Other Syndromic Conditions
Many fetal anomalies identified in the first trimester can also be caused by a monogenic
inherent disease (e.g., skeletal anomalies, central nervous system anomalies associated
with ciliopathies, polycystic renal diseases, and others) and may escape detection with
CGH. In these cases, knowledge of typical sonographic features is needed in order to
test for the specific gene(s) involved. Recently, there has been an increased use of
selective panels for genetic diseases and in the future the use of next generation exon or
genome sequencing will be more widely used. Until then, expert sonographers and
sonologists should become familiar with fetal anomalies in the first trimester that are
commonly associated with monogenic inheritance patterns.Figure 6.34: A: A thickened nuchal translucency (4.7 mm) in a fetus at 11
weeks of gestation. B: The corresponding axial plane of the head and C is the
3D ultrasound in surface mode. Note the thickened nuchal translucency (NT) in
B and in C shown as transparent thickening in the dorsal aspect of the fetus
(arrows). At this stage no other anomalies were seen. Chorionic villous
sampling with prolonged cell culture revealed tetrasomy 9p.Figure 6.35: This 40-year-old pregnant woman was referred for first trimester
screening. A nuchal translucency (NT) of 3 mm was measured (asterisk) along
with absent nasal bone (arrow) as shown in A. An aberrant right subclavian
artery (ARSA) was also found in B with a course behind the trachea (T). We
had high suspicion for trisomy 21. Prolonged culture of cells from chorionic
villous sampling revealed deletion 4p- (red arrow). The distal part of the short
arm of chromosome 4 is absent. Keep in mind that noninvasive prenatal testing
in such a condition would have missed the diagnosis.
The ability to suggest the presence of a possible association of a fetal anomaly with
a monogenic type of inheritance vary based upon the expertise of the examiner and the
types of fetal anomalies. It is relatively easy, for instance, to suggest the diagnosis of
Meckel–Gruber syndrome (Figs. 8.21, 13.30, and 13.31), in the presence of an occipital
encephalocele and polydactyly in the first trimester. Noonan syndrome is suggested
when a markedly thickened NT is associated with normal karyotype and persists into the
second trimester (Fig. 9.45). The diagnosis of monogenic syndromes is difficult when
anomalies are subtle and expressivity of sonographic markers is incomplete in the first
trimester. In this setting, follow-up ultrasound examinations in the early second trimesterare required. In two cases, the authors have observed the presence of short femur and
polydactyly at 12 to 13 weeks of gestation and CVS revealed normal karyotype.
Follow-up ultrasound at 15 weeks revealed short ribs, which led us to suggest the
presence of short-rib-polydactyly or Ellis–Van Creveld syndrome, and molecular
genetic testing confirmed the diagnoses in both cases (Figs. 14.18 and 14.22) . Often,
genetic diseases are diagnosed in early gestation due to routine screening or in
diagnostic testing in the presence of maternal or paternal carrier status, and before any
sonographic markers are present. Examples of such conditions include cystic fibrosis,
tuberous sclerosis, fragile X, thalassemia, sickle cell, storage diseases, and others.
There are also associations as VATER association, or autosomal recessive inherited
conditions such as Fryns syndrome (Fig. 10.20) with no specific genetic identification
to date. Table 6.6 lists several genetic syndromes and conditions that the authors
diagnosed in the first trimester of pregnancy along with their corresponding ultrasound
figures, presented in various chapters of this book.
Detailed discussion of ultrasound features and genetic testing of all genetic
syndromes is beyond the scope of this book. Interested readers are referred to reference
books23 and Internet sites such as Online Mendelian Inheritance in Man
(www.OMIM.org) and Orphanet (www.orphanet.net).Figure 6.36: First trimester ultrasound at 13 weeks of gestation showing the
presence of alobar holoprosencephaly (asterisk) in A, abnormal face in B and
C, dysplastic kidneys (K) in D, vertebral anomalies (Vert.) in E, and clenched
fingers (arrow) in F. Chorionic villous sampling revealed a deletion of the small
arm of chromosome 18 (red arrow). 18p- deletions are typically associated
with holoprosencephaly as the TGIF gene is present on the short arm of
chromosome 18 as well as spinal and others anomalies. Keep in mind that
noninvasive prenatal testing in such a condition would have missed the
diagnosis.
Table 6.6 • Genetic and Syndromic Conditions Presented in This Book
along with the Corresponding Figures
Beckwith–Wiedemann syndrome Figure 12.18
Campomelic dysplasia Figure 14.23
CHARGE syndrome Figure 9.321.
2.
3.
4.
5.
6.
7.
8.
Diastrophic dysplasia Figure 14.20
Ellis–Van Creveld syndrome Figure 14.22
Femur-fibula-ulna (FFU) complex Figures 14.25 and 14.32
Fryns syndrome Figure 10.20
Grebe dysplasia Figure 14.33
Holoprosencephaly, autosomaldominant nonsyndromic Figure 8.30
Joubert syndrome Type 14 Figure 8.22
Meckel–Gruber syndrome Figures 8.21, 13.30, and 13.31
Noonan syndrome Figure 9.45
Osteogenesis imperfecta Type II Figures 14.18 and 14.19
Short-rib-polydactyly syndrome Figure 14.18
Thanatophoric dysplasia Figure 14.21
VACTERL–VATER association Figure 12.36
Walker–Warburg syndrome Figure 8.35
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