The nuchal translucency and the fetal heart: a literature review

Transcription

PRENATAL DIAGNOSIS
Prenat Diagn 2009; 29: 739–748.
Published online 27 April 2009 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/pd.2281
REVIEW
The nuchal translucency and the fetal heart: a literature
review
S. A. Clur1,2 *, J. Ottenkamp1,2 and C. M. Bilardo3
1
Department of Pediatric Cardiology of the Emma Children’s Hospital, Academic Medical Centre, Amsterdam, The Netherlands
The Centre for Congenital Heart Anomalies Amsterdam-Leiden (CAHAL), The Netherlands
3
Department of Obstetrics and Gynecology, Academic Medical Centre, Amsterdam, The Netherlands
2
In this overview the current knowledge of the relationship between an increased nuchal translucency (NT)
measurement and fetal heart structure and function in chromosomally normal fetuses is reviewed. Relevant
pathophysiological theories behind the increased NT are discussed. Fetuses with an increased NT have an
increased risk for congenital heart disease (CHD) with no particular bias for one form of CHD over another.
This risk increases with increasing NT measurement. Although the NT measurement is only a modestly
effective screening tool for all CHD when used alone, it may indeed be effective in identifying specific CHD
“likely to benefit” from prenatal diagnosis. The combination of an increased NT, tricuspid regurgitation and
an abnormal ductus venosus (DV) Doppler flow profile, is a strong marker for CHD. A fetal echocardiogram
should be performed at 20 weeks’ gestation in fetuses with an NT ≥95th percentile but <99th percentile. When
the NT measurement is ≥99th percentile, or when tricuspid regurgitation and/or an abnormal DV flow pattern
is found along with the increased NT, an earlier echocardiogram is indicated, followed by a repeat scan at
around 20 weeks’ gestation. The resultant increased demand for early fetal echocardiography and sonographers
with this special expertise needs to be planned and provided for. Copyright  2009 John Wiley & Sons, Ltd.
KEY WORDS:
cardiac function; congenital heart disease; nuchal translucency; chromosomal abnormality; fetus
INTRODUCTION
For almost 20 years the association between an increased
fetal neck thickness and chromosomal and cardiac
abnormalities has fascinated researchers. In 1987, Benacerraf et al. published the association of Down’s syndrome with an increased nuchal fold thickness measured
after 16 weeks gestation in 5500 fetuses. Nicolaides
et al. (1992) subsequently described an increased risk
of chromosomal anomalies in fetuses with an excessive
nuchal fluid accumulation at 10–14 weeks’ gestation.
The nuchal translucency (NT) was then defined as a
transient subcutaneous collection of fluid behind the fetal
neck seen ultrasonographically at 11–14 weeks’ gestation (Nicolaides et al., 1992). The definition of normal
ranges for the NT measurement followed. The 95th percentile for NT measurement increases with gestational
age between 11 and 14 weeks and is approximately
2.5 mm depending on crown rump length, whereas the
99th percentile is fixed at 3.5 mm. After 14 weeks the
normal NT regresses, coinciding with a reduction in placental resistance and the beginning of fetal renal function
(Pajkrt et al., 1995; Pandya et al., 1995, Snijders et al.,
1998).
Quite soon it became clear that an increased NT
is not only a marker for chromosomal anomalies but
*Correspondence to: S. A. Clur, Department of Pediatric Cardiology, Emma Children’s Hospital, Academic Medical Centre,
Meibergdreef 9, Amsterdam, The Netherlands.
E-mail: [email protected]
Copyright  2009 John Wiley & Sons, Ltd.
also a nonspecific sign of a disturbance in normal early
development. In the presence of a normal karyotype,
an enlarged NT can be observed in fetuses affected by
a variety of structural and genetic disorders, of which
congenital heart defects (CHD) are the most common
(Hyett et al., 1996a, 1997; Bilardo et al., 1998, 2001,
2007; Hafner et al., 1998; Souka et al., 1998, 2001,
2005; Ghi et al., 2001; Michailidis and Economides,
2001; Orvos et al., 2002; Makrydimas et al., 2003,
2005; Westin et al., 2006, 2007). Hyett et al. (1996a)
were the first to report an association between an
increased NT measurement and CHD in a small group
of chromosomally normal fetuses. The idea that the NT
could also be a marker for CHD evolved from here.
Increased NT and the risk of CHD
It was Hyett et al. again who, in 1999, reported that
in a cohort of 29 154 pregnancies, 56% of the fetuses
with major CHD had an increased NT measurement. The
prevalence of CHD was seen to increase with increasing
NT thickness. Based on this data, the NT measurement
could be used as a first screening step in the detection
of CHD, identifying high-risk fetuses for referral to specialized centers for echocardiography. By performing an
echocardiogram on the 1% of fetuses with a NT measurement ≥99th percentile, 40% of major CHD could be
identified. This report was welcomed with much enthusiasm as the NT measurement could lead to the improvement of the still rather disappointing prenatal CHD
Received: 1 December 2008
Revised: 6 February 2009
Accepted: 9 March 2009
Published online: 27 April 2009
740
S. A. CLUR ET AL.
detection rate (15–55% depending on the expertise of
the centre and screening protocol used), (Cooper et al.,
1995; Rustico et al., 1995; Tegnander et al., 1995; Montana et al., 1996; Bull, 1999). Seven subsequent studies,
however, tended to show less promising results (Bilardo
et al., 1998; Hafner et al., 1998, 2003; Josefsson et al.,
1998; Schwarzler et al., 1999; Mavrides et al., 2001;
Michailidis and Economides, 2001; Orvos et al., 2002)
(See Table 1). In a meta-analysis of these eight studies, including 58 492 fetuses, Makrydimas et al. (2003)
found that a NT measurement >99th percentile had a
sensitivity and specificity of 31% and 98.7% respectively, with a positive likelihood ratio of 24 for the
diagnosis of major CHD. A sensitivity and specificity of
37% and 96.6% respectively was found using the 95th
percentile cut-off.
Subsequent studies of large low-risk populations of
chromosomally normal fetuses reported even lower
detection rates for CHD (Bahado-Singh et al., 2005;
Westin et al., 2006; Müller et al., 2007; Simpson et al.,
2007). (See Table 1.) Simpson et al. (FASTER Consortium 2007), for instance, in a prospective study of 34 622
fetuses, found a sensitivity of only 15.4% using 2.0 multiples of the median (MoM), (approximating the 98th
percentile), cut-off. Similarly, our group found a sensitivity of 15.4% in 4144 low-risk pregnancies using
the 95th percentile cut-off (Müller et al., 2007). The
exclusion of septated cystic hygroma in the First and
Second Trimester Evaluation of Risk (FASTER) study
may partially explain their low detection rate. Had septated cystic hygroma been included, their CHD detection
rate would have been 35.3% (Malone et al., 2005; Hyett
et al., 2007; Simpson et al., 2007). Cystic hygroma was,
however, included in the definition of an increased NT in
the study of Müller et al. (Müller et al., 2007). Another
recently published meta-analysis of seven studies chose
a different approach and defined the relationship between
an enlarged NT (cut-off 1.7 MoM at a false positive rate
of 5%) and specific CHD “likely to benefit” from prenatal diagnosis. The definition of CHD likely to benefit
from prenatal diagnosis included a defect that is not satisfactorily reparable and can lead to serious disability,
and for which the offer of a pregnancy termination would
be discussed, or a defect that is not satisfactorily reparable after birth, but in utero treatment can reduce morbidity or a defect where prenatal diagnosis can lead to
an altered postnatal management with proven improved
prognosis, such as ductal dependant lesions (Wald et al.,
2008). Wald et al. (2008) found an enlarged NT in 52%
of these CHD.
The comparison of all the above-mentioned screening
studies is not straightforward due to differences in cutoff points used to define an increased NT (95th or 99th
percentile, 1.7, 2, 2.5 or 3 MoM), gestational ages at the
time of NT measurement (10 + 4 to 13 + 6 vs. 11 to
14 weeks’ gestation), study populations (high vs. lowrisk), study design (prospective vs. retrospective) and the
definition of major CHD. When using the 95th percentile
cut-off, the reported prevalence of CHD varied between
2 and 20%. Despite all the above-mentioned variables,
these studies do agree that the prevalence of CHD is
in the order of 6 times higher in fetuses with a NT
≥99th percentile than in an unselected population. As
such, an increased NT is an indication to exclude CHD.
NT screening, when used alone, is only a modestly
efficient strategy for detecting all CHD, but may indeed
be effective in detecting specific CHD likely to benefit
from prenatal diagnosis.
The median NT thickness is significantly higher
in fetuses with major CHD compared to those with
normal hearts (Ghi et al., 2001). In a pooled analysis
of data from four large fetal echocardiography centers,
Makrydimas et al. (2005) found a NT measurement
of ≥2.5 mm and ≥3.5 mm in 35.5% and 23% in
397 chromosomally normal fetuses with major CHD
respectively. The proportion of cases with an increased
NT was similar for each subtype of CHD. The median
gestational age at CHD diagnosis was 16.1 weeks’ when
the NT was ≥3.5 mm compared to 22.1 weeks’ when
<3.5 mm. (Makrydimas et al., 2005).
The risk of CHD increases exponentially with increasing NT measurement. In Table 2, the rates of CHD per
degree of NT enlargement reported in several studies
are summarized. The frequency of CHD varies from
0.6–5% when the NT is between 2.5 and 3.5 mm, to
64% when the NT measurement is above 8.5 mm (Hyett
et al., 1997, 1999, 2004; Ghi et al., 2001; Galindo et al.,
2003; Lopes et al., 2003; McAuliffe et al., 2004; Atzei
et al., 2005; Bahado-Singh et al., 2005; Simpson et al.,
2007; Clur et al., 2008). The combined findings of ten
studies are summarized in Figure 1. (Hyett et al., 1997,
1999; Ghi et al., 2001; Galindo et al., 2003; Lopes et al.,
2003; McAuliffe et al., 2004; Atzei et al., 2005; BahadoSingh et al., 2005; Simpson et al., 2007; Clur et al.,
2008).
In conclusion, a NT measurement ≥95th percentile
identifies fetuses with an increased risk of CHD. They
should be referred for fetal echocardiography, preferably
in early pregnancy when the NT is ≥3.5 mm or when
additional markers of CHD are also present as will be
discussed below.
Why is there an increased risk of CHD
when the NT is increased?
To help understand the relationship between the increased NT and CHD better, a few of the relevant
hypotheses linking the increased NT and the heart
structure and function will be discussed.
Cardiac failure or dysfunction
The idea that (transient) cardiac failure, either due to
intrinsic myocardial dysfunction or secondary to the
CHD themselves, leads to the fluid accumulation causing
the nuchal edema is commonly encountered, especially
in the obstetric literature (Berger, 1999; Mol, 1999).
The finding of an increased mRNA of cardiac atrial
and brain natriuretic peptide in trisomic fetuses with an
increased NT was seen as supportive evidence for this
hypothesis (Hyett et al., 1996b). However, it may not be
valid to extrapolate a postnatal fluid regulation process
to the 11–14-week-old trisomic fetus. In monochorionic
twins, discordancy for increased NT has been indicated
Prenat Diagn 2009; 29: 739–748.
DOI: 10.1002/pd
3.3/1000 (n = 4214)
1.7/1000 (n = 29 154)
2/1000 (n = 4474)
3.5/1000 (n = 7339)
1.7/1000 (n = 6606)
9.6/1000 (n = 3655)
2.1/1000 (n = 12 978)
2.8/1000 (n = 58 492)
2.6/1000 (n = 8167)
7.8/1000 (all) 3.3/1000
(major) (n = 16 383)
5.8/1000(all) 3.1/1000
(major) (n = 4144)
6.5/1000 (all) 1.5/1000
(major) (n = 34 266)
Hafner et al., 1998
Hyett et al., 1999
Schwarzler et al., 1999
Mavrides et al., 2001
Michailidis and
Economides, 2001
Orvos et al., 2002
Hafner et al., 2003
Makrydimas et al., 2003
Bahado-Singh et al.,
2005 (BUN)
Westin et al., 2006
Müller et al., 2007
1/43 = 2.3% (NT ≥
3.5 mm)
4/49 = 8.2% (all)
3/49 = 6.1% (major)
(NT ≥ 3.5 mm)
2/21 = 9.5% (major)
7/209 = 3.4% (major)
(NT = 2.5 or > MoM)
13/424 = 3.1% (all)
8/426 = 1.9% (major)
(NT ≥ p95)
2/100 = 2% (major)
19/569 = 3.3% (all)
8/569 = 1.4% (major)
(NT = 2 or > MoM)
—
—
26/454 = 5.7%
—
—
3/60 = 5% (NT ≥
3.5 mm)
3/73 = 4.1% (major)
—
20/315 = 6.3%
0/6 = 0%
Prevalence
CHD/NT ≥ p99 + normal
chromosomes
5/134 = 3.7% (NT ≥
2.5 mm)
2/47 = 4.3% (NT ≥
3 mm)
4/63 = 6.3% (NT ≥
2.5 mm)
28/1822 = 1.5% (NT ≥
p95)
1/122 = 0.8% (NT ≥
2.5 mm)
4/258 = 1.6% (NT ≥
2.5 mm)
4/235 = 1.7% (NT ≥
p95) (major)
18/101 = 17.8% (NT ≥
3 mm) 9/101 = 8.9%
(major)
7/649 = 1.1% (NT ≥
p95)
66/2782 = 2.4% (NT ≥
p95)
3/378 = 0.8% (NT ≥
2.5 mm)
Prevalence CHD/NT
≥ p95 + normal
chromosomes
2/24 = 8% (all)
2/13 = 15.4% (major)
19/224 = 8.5% (all)
8/52 = 15.4% (major)
24/68 = 35.3% (if
cystic hygromas are
included)b
3/17 =
17.7% (≥2.5 mm)
29.4% (>p95) (major)
13/127 = 10.2% (all)
8/55 = 14.5% (major)
37%
18/35 = 51.4% (NT ≥
3 mm) (all)
9/20 = 45% (major)a
7/27 = 25.9%
4/11 = 36.4% (major)
4/26 = 15.4%
1/9 = 11.1%
28/50 = 56%
2/4 = 50% (NT ≥
3 mm)
4/14 = 28.6%
5/13 = 38.5%
CHD with NT ≥ p95/
CHD total (%) = detection
rate
2/24 = 8% (all)
2/13 = 15.4% (major)
15/224 = 6.7% (all)
7/52 = 13.5% (major)
4/127 = 3.1% (all)
3/55 = 5.5% (major)
1/17 =
5.9% (≥3.5 mm)
31%
—
8/35 = 22.8% (all)
3/11 = 27.3%
3/26 = 11.6%
—
20/50 = 40%
—
—
0/13 = 0%
CHD with NT
≥ p99/CHD total
(%) = detection rate
BUN, First Trimester Maternal Serum Biochemistry and Fetal Nuchal Translucency Screening Study Group; FASTER, First and Second Trimester Evaluation of Risk; CHD, congenital heart defects;
MoM, multiples of the median (2.0 MoM = 98.3rd percentile, 2.5 MoM = 99.4th percentile); NT, nuchal translucency; p95 = 95th percentile; p99 = 99th percentile.
a As reported in Hyett,
b Hyett et al., 2007.
2004.
3.1/1000 (n = 1590)
Bilardo et al., 1998
Simpson et al., 2007
(FASTER)
8.9/1000 (n = 1460)
Josefsson et al., 1998
Study
Prevalence
CHD/1000
in euploid cohort (n)
Table 1—The risk of major cardiac defects and the cardiac defect detection rate related to NT measurement ≥p95 and p99 in fetuses with normal chromosomes as found in
different studies
NUCHAL TRANSLUCENCY AND THE FETAL HEART
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DOI: 10.1002/pd
5.3
0.8
—
Hyett et al., 1999
Ghi et al., 2001a
53.4
Galindo et al.,
2003
78/5039
15.5
18.8
(2 or > MoM)
(<2 MoM)
—
14.1
30.2
(78.7)
43/1284
33.5
(2.5 or > MoM)
(23.3)
35.2
(59.4)
33.5
—
(78.4)
30
(145.5)
—
(NT 4–4.9 mm)
(112.6)
(NT ≥ 4 mm)
—
(215.7)
52.2
—
31.3
(70.4)
—
(31.4)
28.9
CHD/1000 NT
3.5–4.4 mm
(NT ≥ 3.5 mm)
(49.5)
(3 or > MoM)
71.4
(132.5)
30/401
74.8
64.4
(183.0)
—
70
(NT 5–5.9 mm)
(177.6)
(NT ≥ 5 mm)
102
82.8
(NT 4.4–6.4)
(140.9)
90.9
CHD/1000 NT
4.5–5.4 mm
(NT ≥ 4.5 mm)
85.7
(195.1)
9/60
150
140
(126.7)
200
(NT 6–6.9)
(241.4)
(NT ≥ 6 mm)
240
—
(233)
—
(195.1)
—
CHD/1000 NT
5.5–6.4 mm
(NT ≥ 5.5 mm)
—
(277)
8/42
190.5
—
(260)
(300)
—
(242.4)
(NT ≥ 7 mm)
—
190.5
(303.6)
CHD/1000 NT
6.5–8.4 mm
(NT ≥ 6.5 mm)
9/14
643
(643)
CHD/1000
(NT ≥
8.5 mm
CHD, congenital heart defects; MoM, multiples of the median (2.0 MoM = 98.3rd percentile, 2.5 MoM = 99.4th percentile, 3 MoM = 99.7th percentile); NT, nuchal translucency; p95 = 95th percentile.
a Not included in Total (review article or cohort is included in another study).
b Cystic hygromas not included.
Total
Clur et al., 2008
Simpson et al.,
2007b
18.2
6
10
4.8 (NT 2–2.4 mm)
4.9 (NT < median)
8.7 (median ≤ NT < p95)
1.3
1.9, (NT <2 mm)
Bahado-Singh
et al., 2005
Atzei et al., 2005
1.6
17
Hyett et al.,
2004a
Souka et al.,
2005a
41
McAuliffe et al.,
2004
(NT 2.5–3.9 mm)
12.6
Lopes et al.,
2003
24.9
5.4
CHD/1000
p95 ≥
NT <3.5 mm
Hyett et al., 1997
Study
CHD/1000
NT < p95
Table 2—The prevalence of major cardiac defects according to nuchal translucency measurement as reported in different studies
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S. A. CLUR ET AL.
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DOI: 10.1002/pd
Figure 1—Prevalence of congenital heart defects/1000 related to NT
measurement.
NB: The data used for the construction of this graph are derived from
Table 2. An exponential trend line has been added using Microsoft
Excel 2007. CHD, congenital heart disease; NT, nuchal translucency
as an early marker of twin-to-twin transfusion syndrome
where cardiac failure is known to play a role (Nicolaides
et al., 2002). Here the early imbalance in the circulatory
volume, (volume overload vs anemia), shared by the
twins could cause the nuchal edema.
If cardiac failure causes the nuchal edema, then
cardiomegaly, ascites, peripheral edema, and pericardial
and pleural effusions would also be expected. Ascites,
peripheral edema and effusions, however, are usually not
seen in fetuses with an increased NT.
Abnormal ductus venosus Doppler flow profile:
Much of the early data regarding cardiac hemodynamics
in early pregnancy has been based on Doppler waveform
analysis. An abnormal ductus venosus (DV) Doppler
flow profile, where during late diastole, coincident with
atrial contraction, reduced or reversed flow is seen,
has been interpreted as indicative of cardiac failure
as it was assumed to reflect increased central venous
pressure (Montenegro et al., 1997; Matias et al., 1997,
1999). Martinez et al. (2003) however, failed to find a
correlation between the pulsatility index in the jugular
vein and that of the DV in 179 first trimester fetuses with
an increased NT. Flow reversal during atrial contraction
indicates that the pressure in the right atrium is higher
than in the portal system but does not necessarily imply
heart failure. It may be seen in situations of diastolic
cardiac dysfunction, restricted flow through the foramen
ovale, increased adrenergic drive and during hypoxia
when the sphincter-like DV dilates and vessel wall
compliance increases (Simpson and Sharland, 2000;
Kiserud, 2001; Allan, 2006). The fluid balance in the
11–14-week fetus is taxed due to the tendency to
increased preload as intrinsic renal function has not
yet developed and the circulating blood volume is
increasing. Also, the afterload is increased as placental
resistance is still high. The immature ventricles are less
compliant and thus small alterations in intravascular
fluid volume may be enough to produce the abnormal
DV flow patterns (Reed et al., 1986; Tulzer et al.,
743
1994; van Splunder et al., 1996; Leiva et al., 1999;
Matias et al., 1999). A temporary abnormality of the
DV itself, possibly abnormal diameter regulation or
increased vessel compliance, could also potentially cause
the abnormal flow pattern. Bekker et al. (2005a) found
the DV endothelium to be abnormally thick in trisomy
16 mice, the mouse model for human trisomy 21.
An abnormal DV flow profile in fetuses with an
increased NT measurement is associated with CHD,
chromosomal malformations and an adverse pregnancy
outcome (Montenegro et al., 1997; Borrell et al., 1998;
Matias et al., 1998, 1999; Carvalho, 1999; Bilardo et al.,
2001; Antolin et al., 2001; Favre et al., 2003; Haak
et al., 2003, 2005; Sedmera et al., 2005; Oh et al.,
2007). The abnormal DV flow is temporary, resolving
as the increased NT disappears (Huisman and Bilardo,
1997; Matias et al., 1998). The combined data from
seven studies, including 600 chromosomally normal
fetuses with a NT ≥95th percentile, showed CHD in
4.8% (29) of the fetuses, 96.6% (28) of which also had
an abnormal DV flow pattern at 11 to 13 + 6 weeks’
gestation (Maiz et al., 2008). Maiz et al. (2008), in a
cohort of 191 11 to 13 + 6-week-old fetuses with an NT
≥3.5 mm, observed an abnormal DV flow pattern in
11/16 (68.8%) fetuses with CHD and 40/175 (22.9%)
without CHD. The prevalence of an abnormal DV flow
increased with NT thickness in fetuses without CHD
but not in those with CHD. The authors conclude that in
fetuses with a NT ≥3.5 mm the finding of an abnormal
DV flow is associated with a three-fold increase in the
likelihood of CHD, whereas a normal flow pattern halves
the risk.
Direct cardiac function measurement in fetuses with
an increased NT: Direct measurements of cardiac function are required to determine if impaired cardiac function is responsible for the increased NT measurement or
not. Simpson and Sharland (2000) measured the left ventricular ejection fraction in fetuses with a ventricular septal defect around 20 weeks’ and showed no significant
difference between fetuses who had had an increased NT
and those who had not. Their measurements of cardiac
function were made after the increased NT would have
resolved in most cases. The finding of a normal cardiac function at 20 weeks’ gestation does not exclude
possible cardiac dysfunction at the time when the NT
was increased, however. Rizzo et al. (2003) looked at
cardiac function at 20–23 weeks’ gestation in chromosomally normal fetuses with an increased NT (>95th
percentile) compared to normal controls. They found
a significantly decreased E-wave velocity and E/A (Ewave divided by A-wave) and E/TVI (E-wave divided
by time velocity integral) ratios across the atrioventricular valves in fetuses who had had an increased NT at
11–14 weeks’ gestation compared to controls, suggesting reduced myocardial relaxation. It seems illogical that
diastolic dysfunction should be found at 20–23 weeks’
gestation when the increased NT will have already
resolved in most cases. A possible explanation is that
the diastolic dysfunction was also present at the time of
the increased NT and may even have been more evident at that time. If this abnormal diastolic function is
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DOI: 10.1002/pd
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S. A. CLUR ET AL.
to be linked with the abnormal DV flow profiles seen
in fetuses with an increased NT, abnormal A waves
during atrial contraction would also be expected, which
was not found. They also found no evidence for systolic
dysfunction in these fetuses using pulmonary and aortic
peak velocities and time to peak velocity as indicators
of systolic function (measures of outflow resistance).
To be absolutely sure that there was no cardiac failure at the time of the increased NT measurement direct
measurements of fetal cardiac function at 11–14 weeks’
gestation were needed. Huggon et al. (2004), provided
this when they measured the myocardial performance
index and E/A ratio across the atrioventricular valves
in a series of 638 fetuses at 11–14 weeks’ gestation.
They found no significant differences in cardiac function between normal fetuses, fetuses with chromosomal
defects, fetuses with CHD and fetuses with an increased
NT (>4 mm) and normal chromosomes. Haak et al.
(2005) also found no difference in atrioventricular valve
flow velocities between normal fetuses and those with
an increased NT at 11–14 weeks’ gestation. Within the
group with an increased NT they also found no difference between those with and those without CHD. These
findings do not support a causal relationship between
the increased NT and diastolic, systolic or global cardiac
dysfunction.
Tricuspid regurgitation at 11–14 weeks’ gestation:
The phenomenon of tricuspid regurgitation (TR) in
young fetuses is interesting. Atrioventricular valve
regurgitation is present in 6.3% of 7–8-week-old normal
fetuses. The prevalence increases to 44% at 10 weeks’
gestation and falls to 3.5–6% at 11 to 13 + 6 weeks’
gestation. The TR disappears with the disappearance
of the NT (Huggon et al., 2003; Faiola et al., 2005;
Mäkikallio et al., 2005). TR is highly associated with
aneuploidy, particularly trisomy 21 and its prevalence
increases with the NT thickness and is substantially
higher in fetuses with, than those without CHD (Huggon
et al., 2003; Faiola et al., 2005). In chromosomally normal fetuses the finding of TR at 11 to 13 + 6 weeks’
gestation is associated with an eight-fold increase in
the risk for CHD (Faiola et al., 2005). The etiology of
the TR is uncertain and may be related to small alterations in the already taxed hemodynamic balance of the
11–14-week fetus. However, both increased afterload
and preload cause right ventricular dilatation which is
almost never seen in these fetuses with TR in the absence
of CHD. The decreased compliance of the fetal heart
may explain this discrepancy, and delayed diastolic function maturation may be the clue to its causation. Delayed
tricuspid valve delamination has also been proposed to
explain the transient TR in aneuploid fetuses (Lammers
et al., 1995; Allan, 2006).
Do CHD cause the increased NT?
The initial findings of Hyett et al. (1995, 1996a) where
narrowing of the aortic isthmus and ascending aorta
abnormalities were documented in a significant proportion of chromosomally normal and abnormal fetuses
with an increased NT, stimulated the idea that altered
fetal hemodynamics secondary to the CHD themselves,
(e.g. overperfusion or venous congestion of the head
and neck), could cause the increased NT. However, several forms of CHD leading to different hemodynamic
patterns, irrespective of the size of the aorta or aortic isthmus, have been encountered in fetuses with an
increased NT. Many CHD associated with cardiac failure in postnatal life do not cause cardiac failure in
the fetus. The effect of intracardiac shunts on the fetal
heart, (volume overload and cardiac failure), is limited
by the increased fetal pulmonary vascular resistance and
systemic pressure in the fetal right ventricle (Rudolph,
2001). Moreover, CHD not associated with cardiac failure in prenatal or postnatal life are also associated with
an increased NT. With cardiac failure cardiomegaly
would be expected, as has been described in fetuses
with nonimmune hydrops (Skoll et al., 1991; Johnson
et al., 1992). Simpson and Sharland (2000), however,
found no increased cardiothoracic ratio, irrespective of
nuchal measurement, in fetuses with hypoplastic left
heart syndrome or an isolated ventricular septal defect
at 20 weeks’ gestation. This does not, however, exclude
the possibility that cardiomegaly may have been present
at the time of the increased NT.
Disorders of vasculogenesis and neurogenesis
Lymphangiogenesis: A primary disorder of lymphangiogenesis was suggested after the abnormal enlargement and persistence of jugular lymphatic sacs were
found in the neck region of fetuses with an increased
NT (Haak et al., 2002; Bekker et al., 2005b). A delay
in the reconnection of the lymphatic sacs with the
venous system may affect venous hemodynamics retrogradely causing the abnormal DV waveforms seen.
Later, with continued development, the lymphatic sacs
may be remodeled into lymph nodes and the excess of
fluid may drain away explaining the transient nature of
the increased NT.
Neural crest migration abnormality: The neck, head
and the adrenergic nerves of the DV have a common
embryonic origin, the neural crest (Coceani et al., 1984)
and blood vessels and nerves share many developmental
genes (Carmeliet, 2003), making the proposal of a neural
crest developmental anomaly, to link the increased NT,
CHD and the DV flow abnormalities, very attractive.
An over expression of Neural Crest Adhesion Molecule
(NCAM), affecting neural crest cell migration and
neuronal differentiation (Walsh and Doherty, 1997), has
been found in the neck, heart and DV of trisomy 16
mice (Bekker et al., 2005a). Neural crest ablation and
subsequent migration abnormalities have been shown
to lead to the development of CHD (Besson, 1986;
Kirby, 1991). However, if the problem is failure of
neural crest cell migration, then the CHD seen in
association with an increased NT would only include
defects of conotruncal septation, outflow tracts, great
vessels and aortic arch. Despite an initial suggestion
that abnormalities of the aortic arch are more commonly
Prenat Diagn 2009; 29: 739–748.
DOI: 10.1002/pd
745
found with an increased NT (Hyett et al., 1996a), it
appears that there is no definite bias towards one
particular type of CHD over another in these fetuses
(Simpson and Sharland, 2000; Ghi et al., 2001; Galindo
et al., 2003; Makrydimas et al., 2005; Allan, 2006; Clur
et al., 2008).
Early fetal flow disturbances: Normal flow patterns
affect the expression of the normal sequence of growth
factors required for the normal development of cardiac chambers (Sedmera et al., 2005). Studies in chick
embryos have shown that intracardiac flow disturbances
or hemodynamic disturbances induce structural malformations suggesting that they may be responsible for both
the CHD and the distension of tissues (Harh et al., 1973;
Stekelenburg-de Vos et al., 2003). Neural crest ablation
results in flow disturbances and the flow disturbances,
and not the failure of migration of the neural crest cells,
may cause the CHD (Allan, 2006).
Thus an insult at 6–8 weeks’ gestation (environmental e.g. hypoxia or nutritional, or genetic) may result in
fluid retention (Allan, 2006). The ensuing disturbances
in vascular endothelial development including lymphangiogenesis and hemodynamics at 7–10 weeks’ gestation
could then lead to the increased NT and altered growth
factor expression with the resultant CHD. The question
why fluid collection occurs in response to these insults
still needs to be answered.
Fetal echocardiography, when, on which
fetuses and by whom?
A finding of an increased NT identifies a new group
of fetuses at increased risk for CHD bringing with it
an increased demand for detailed fetal echocardiography. Adequate resources are required to accommodate
this in the future. Using a NT measurement ≥95th percentile as a cut-off for referral for echocardiogram, 1
major congenital heart defect can be expected to be
diagnosed per 33 referrals for fetal echocardiogram.
This can be increased to 1 in 16 by using the 99th
percentile cut-off (Makrydimas et al., 2003). In their
consensus statement of 2008, The International Society of Ultrasound in Obstetrics and Gynaecology proposes fetal echocardiography at the time of detection
of the increased NT measurement (11–14 weeks) if the
NT is >3.5 mm, with a second scan at 20–22 weeks’
gestation. When the NT measurement is between 2.5
and 3.5 mm the echocardiogram can be performed at
18–20 weeks’ gestation along with the anomaly scan
(Lee et al., 2008). Even when the early echocardiogram shows no sign of a cardiac defect it is important to perform a follow-up scan later as trivial abnormalities at 11–14 weeks’ may progress to major CHD
during the pregnancy (Yagel et al., 1997, 2007; Carvalho, 2004). Progressive hypoplasia of the respective
ventricular chamber has been observed, for example,
in the setting of semilunar valves stenosis (Carvalho,
2004).
Early fetal echocardiography
An early fetal echocardiogram (performed in the late first
or early second trimester of pregnancy), has been shown
to be feasible, accurate, and safe (Comas Gabriel et al.,
2002; Haak et al., 2002; Huggon et al., 2002; Lopes
et al., 2003; Carvalho, 2004; McAuliffe et al., 2005;
Becker and Wegner, 2006; Smreck et al., 2006, Lombardi et al., 2007; Yagel et al., 2007; Bronshtein et al.,
2008). Two studies have focused on low-risk populations
using the transvaginal approach (Yagel et al., 1997; Rustico et al., 2000). However, transvaginal examination is
not favored by many women and caregivers, the pickup
rates for CHD were low and early echo-screening will
not replace the need for a follow-up scan later in the
pregnancy if still developing CHD are not to be missed.
The performance of a complete fetal echocardiogram
at the end of the first trimester requires expertise. With
modern equipment, it is usually possible, using the
abdominal approach, to define the situs and cardiac connections, identify the cardiac chambers and their symmetry, the crossing of the great vessels and to evaluate the
flow in the chambers and the great vessels using Doppler
and colour flow mapping (Carvalho, 2004; Allan, 2006;
Johnson and Simpson, 2007). A thorough knowledge
of the pathophysiology of CHD, their progression during gestation, the surgical possibilities and prognosis are
required to make a correct diagnosis and to adequately
counsel families. Early fetal echocardiography should
probably only be performed in centers experienced in
the technique and be reserved for fetuses at high risk
for CHD. It should be viewed as an adjunct to, and
not a replacement of, the 20-week scan (Johnson and
Simpson, 2007).
Earlier fetal echocardiography, performed soon after
the NT measurement, allows for an earlier diagnosis
of CHD and gives the parents more time to make an
informed decision regarding continuation of the pregnancy. Should they decide to interrupt the pregnancy,
then this can be performed earlier, more safely (Allan,
2006; Yagel et al., 2007; Bronshtein et al., 2008) and
with less long-term psychological sequelae (Korenromp
et al., 2005). If the pregnancy is continued, the timing,
location (hospital with neonatal intensive care, pediatric
cardiology and pediatric cardiac surgery facilities), mode
of delivery and direct postnatal care (prostaglandin E1
infusion or balloon atrioseptostomy) can be planned.
In this way the postnatal outcome of these babies can
be improved (Bonnet et al., 1999; Fuchs et al., 2007).
Where the early fetal echocardiogram shows no evidence for a cardiac defect it allows earlier reassurance
of couples considered at high risk for CHD.
CONCLUSIONS
Although the NT measurement alone appears only
to be a moderately effective screening tool for the
detection of all CHD, its role in the detection of specific
CHD likely to benefit from prenatal diagnosis seems
more promising. An increased NT is an important
Prenat Diagn 2009; 29: 739–748.
DOI: 10.1002/pd
746
S. A. CLUR ET AL.
criterion for identifying fetuses eligible for specialized
echocardiography. When TR and/or an abnormal DV
Doppler flow profile is found in association with an
increased NT, the risk of CHD increases and early
exclusion of CHD is warranted. Hopefully this strategy
will improve the prenatal CHD detection rate with a
resultant reduction in perinatal mortality.
We recommend echocardiography at 18–22 weeks’
gestation in fetuses with a NT ≥95th percentile but
<99th percentile. In fetuses with a NT measurement
≥99th percentile, or in which TR and/or an abnormal
DV flow pattern is found in addition to the increased
NT, an earlier echocardiogram is indicated. The stressful
period between the finding of an increased NT and the
making of a definite cardiac diagnosis is then reduced
allowing for a well-informed and unrushed decision
regarding pregnancy termination.
The need for an experienced echocardiographer and
up-to-date equipment cannot be stressed enough if early
echocardiography is to be accurate and beneficial.
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DOI: 10.1002/pd

The nuchal translucency and the fetal heart: a literature review

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