Abnormal Ductus Venosus Flow With Increased Nuchal Translucency

1. Abnormal Ductus Venosus Flow in
First-Trimester Fetuses With Increased
Nuchal Translucency
Relationship With the Type of Cardiac Defect?
Yolanda M. de Mooij, MD, Monique C. Haak, MD, PhD,
Margot M. Bartelings, MD, PhD, Jos W. Twisk, MA, PhD,
Adriana Gittenberger-de Groot, PhD, John M. G. van Vugt, MD, PhD,
Mireille N. Bekker, MD, PhD
Received December 28, 2009, from the Departments
of Obstetrics and Gynecology (Y.M.d.M., M.C.H.,
J.M.G.v.V., M.N.B.) and Clinical Epidemiology and
Biostatistics (J.W.T.), VU University Medical Center,
Amsterdam, the Netherlands; and Department of
Anatomy and Embryology, Leiden University Medical
Center, Leiden, the Netherlands (M.M.B., A.G.-d.G.).
Revision requested January 25, 2010. Revised
manuscript accepted for publication March 8, 2010.
Address correspondence to Yolanda M. de Mooij,
MD, Department of Obstetrics and Gynecology, VU
University Medical Center, Suite PK6 -170, Postbus
7057, 1007-MB Amsterdam, the Netherlands.
E-mail: [email protected]
Article
Objective.The purpose of this study was to evaluate ductus venosus flow velocities and a possible
relationship with the type of cardiac defect in fetuses with increased nuchal translucency (NT).
Methods. Seventy-two fetuses with normal NT and 137 fetuses with increased NT (>95th percentile)
were evaluated. The ductus venosus pulsatility index for veins (PIV), late diastolic velocity (velocity dur-
ing atrial contraction [a-V]), and intracardiac velocities were evaluated. In cases of pregnancy termina-
tion, a postmortem examination was performed. Cardiac defects were grouped into septal defects, left
and right inflow obstruction, left and right outflow obstruction, and other defects. Data were evalu-
ated by multilevel analysis. Results.A cardiac defect was found in 45 fetuses with increased NT. Fetuses
with increased NT showed a higher ductus venosus PIV and a lower a-V compared to fetuses with nor-
mal NT (P< .05). Within the group of fetuses with increased NT, a higher PIV and a lower a-V were
found in cases with a cardiac defect compared to cases with a normal heart (P< .001). No differences
in PIV and a-V were found between the types of cardiac defects. Intracardiac velocities showed no dif-
ferences between fetuses with normal and increased NT, irrespective of the presence of a cardiac defect.
Conclusions. Ductus venosus flow velocities in fetuses with increased NT are not related to a certain
type of cardiac defect. This indicates that the altered ductus venosus flow velocities found in fetuses
with increased NT cannot be explained by cardiac failure due to a specific altered cardiac anatomy.
Key words:cardiac defect; Doppler sonography; ductus venosus; nuchal translucency; sonography.
Abbreviations
a-V, velocity during atrial contraction; JLS, jugular lym-
phatic sac; NT, nuchal translucency; PIV, pulsatility index
for veins
onographic measurement of nuchal translucen-
cy (NT) in human fetuses between 11 and 14
weeks’ gestation is a widely used screening
method to identify chromosomal abnormali-
ties.
1,2
Increased NT is also associated with structural
anomalies such as cardiac defects and several genetic
syndromes.
3
Several mechanisms, such as a disturbance in lymphat-
ic development, an altered extracellular matrix, and car-
diac failure, have been proposed to play a role in the
pathophysiologic mechanism of increased NT.
4–9
Cardiac
failure has been suggested because of the high propor-
S
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2. tion of cardiovascular malformations and abnor-
mal ductus venosus Doppler flow velocities in both
euploid and aneuploid fetuses with increased
NT.
4,5,10–13
It was hypothesized that a cardiac
defect could result in impaired cardiac function
resulting in a lower velocity of the ductus veno-
sus and subsequently enlargement of the NT.
4,12
To our knowledge, however, no study has been
performed to assess whether altered ductus
venosus flow velocities in fetuses with increased
NT are related to a specific type of cardiac defect
or anatomy.
The goal of this study was to evaluate whether
ductus venosus flow alterations in fetuses with
increased NT could be explained by hemody-
namic changes due to a certain type of cardiac
defect. In addition, ductus venosus flow veloci-
ties in relation to intracardiac velocities were
assessed. The hypothesis that increased NT is
caused by cardiac failure due to a certain type of
cardiac defect was tested.
Materials and Methods
Women referred to our hospital for tertiary care
because of increased NT were asked to partici-
pate in the study. A total of 135 singleton and 2
bichorial twin pregnancies were examined. Two
of these 137 fetuses were part of bichorial twins
of which only the fetuses with increased NT were
included. Increased NT was defined as NT above
the 95th percentile. A control group of 73 fetuses
with normal NT was created from women
attending our hospital for first-trimester screen-
ing. All patients received written information and
gave informed consent. The Medical Ethical
Committee of VU University Medical Center
approved the study.
Gestational age was calculated on the basis of
the reported last menstrual period and adjusted
according to the crown-rump length if appropri-
ate. After inclusion, sonographic examinations
were performed weekly by 3 experienced sonog-
raphers (Y.M.d.M., M.C.H., and M.N.B.) between
11 and 17 weeks’ gestation (Table 1). The number
of examinations differed because of different ges-
tational ages at the initial scan and patients’
cooperation. Nuchal translucency was measured
using a transabdominal probe (4–8 MHz,
Voluson 730 Expert series, Voluson E8; GE
Healthcare, Kretztechnik, Zipf, Austria; or 2–4
MHz, HDI 5000; Philips Healthcare, Bothell, WA)
according to the guidelines of the Fetal Medicine
Foundation.
14
Flow velocity waveforms of the ductus venosus
were obtained from a right ventral midsagittal
plane of the fetal trunk during fetal quiescence.
Color flow was used to visualize the venous cir-
culation. The pulsed Doppler gate (0.7–1.5 mm)
was placed in the inlet of the ductus venosus
where it originates from the umbilical vein. Care
was taken to avoid contamination of the flow
waveforms of the umbilical vein and inferior
vena cava.
15
The interrogation angle was kept as
low as possible and always less than 60°. An aver-
age of 3 consecutive high-quality waveforms was
used to analyze the peak systolic velocity, late
diastolic velocity (velocity during atrial contrac-
tion [a-V]), and time-averaged velocity. These
variables were used to calculate the pulsatility
index for veins (PIV = systolic velocity – a-V/time-
averaged velocity).
To obtain flow velocity waveforms across the
mitral and tricuspid valves, the pulsed Doppler
sample gate was placed just distal from the valves
in an apical 4-chamber view in the absence of
fetal movements. Adjustment was made for the
insonation angle, which never exceeded 40°.
Peak flow velocities in early diastole (E wave) and
late diastole with atrial contraction (A wave) were
measured, and the E/A ratio was calculated.
Digital images of each examination were stored.
The cardiac defects were grouped into 6 cate-
gories according to the hemodynamic classifica-
tion adapted from Atzei et al
16
: septal defects, left
inflow obstruction, right inflow obstruction, left
outflow obstruction, right outflow obstruction,
and other defects. Where more than 1 of the cat-
egories potentially applied, obstruction was
given precedence over a septal defect.
16
1052 J Ultrasound Med 2010; 29:1051–1058
Abnormal Ductus Venosus Flow With Increased Nuchal Translucency
Table 1.Examinations per Fetus (n = 209)
Fetuses With Fetuses With
No. of Normal Increased
Examinations NT (n = 72) NT (n = 137)
1059
21046
34927
4135
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3. de Mooij et al
Karyotyping was performed by chorionic villus
sampling or amniocentesis. In case of termina-
tion of the pregnancy, suction aspiration was
performed, or labor was induced. A postmortem
morphologic examination was performed if the
patient approved. The fetus or aspiration tissue
was fixed in formalin 4%. Subsequently, a post-
mortem evaluation of the whole fetus or the fetal
heart (in case of suction aspiration) was per-
formed using a dissection microscope. An exten-
sive sequential segmental analysis of the heart
was performed by an experienced cardiac mor-
phologist (M.M.B.). In ongoing pregnancies, a
second-trimester sonographic examination was
performed in all cases. After delivery, the parents
completed questionnaires concerning their
neonate’s health. If necessary, medical records
were studied to gain additional information.
The ductus venosus indices PIV and a-V and
intracardiac velocities of fetuses with normal
and increased NT, with respect to the presence of
a heart defect, were compared. Within the group
of fetuses with increased NT, the ductus venosus
PIV and a-V and intracardiac velocities of
euploid and aneuploid fetuses were compared.
Furthermore, within the group of fetuses with
cardiac defects, the ductus venosus PIV and a-V
and intracardiac velocities were assessed for the
different types of cardiac defects.
Data were studied using general estimating
equation analysis (SPSS version 15.0; SPSS Inc,
Chicago, IL). This method takes into account the
fact that the same patients are repeatedly mea-
sured and allows missing observations and irreg-
ularly spaced time intervals.
Variables indicating fetuses with normal NT,
fetuses with increased NT without a cardiac
defect, and fetuses with increased NT with a car-
diac defect were used to create groups. Within
the group of fetuses with increased NT and a car-
diac defect, variables indicating septal defects,
left inflow obstruction, right inflow obstruction,
left outflow obstruction, right outflow obstruc-
tion, and other defects were used to create
groups. We analyzed whether Doppler flow mea-
surements of the compared groups differed sig-
nificantly in relation to advancing gestational
age. If necessary, a log transformation was
used to account for non-normality of the data.
General estimating equation analysis was also
used to assess a possible relationship between
Doppler flow measurements and NT size (corre-
lation coefficient). The statistical significance
level was set at P= .05.
Results
In total, 73 fetuses with normal NT and 137 fetus-
es with increased NT were included in the study.
In the group of fetuses with normal NT, 1 patient
was excluded from further analysis because of an
intrauterine fetal death due to a fetal growth
restriction at 28 weeks’ gestation. A postmortem
examination revealed no abnormalities in this
case. Follow-up was complete, and in all 72
cases, healthy neonates were born. The charac-
teristics of the 209 fetuses included are listed in
Table 2.
In cases of increased NT, invasive tests were
offered but refused in 3 cases. In these cases,
healthy neonates without dysmorphic features
were born and were considered euploid. A nor-
mal karyotype was found in 83 of the 137 fetuses
with increased NT (61%); 54 fetuses (39%) were
aneuploid. Figure 1 shows the disposition of the
fetuses with increased NT included in the study.
The presence or absence of a cardiac defect in
fetuses with increased NT was known by follow-
up after birth or postmortem examinations in
118 of the 137 fetuses (86%). In 14 of the 137
cases (5%), heart morphologic features were only
assessed by prenatal sonography, and post-
Table 2. Characteristics of the Fetuses With Normal and Increased NT at the First Sonographic Examination
Normal NT (n = 72) Increased NT (n = 137)
Characteristic Mean (SD) Range Mean (SD) Range
Maternal age, years 34.4 (3.6) 26–41 33.5 (4.5) 21–44
Gestational age, wk + d 11 + 4 (0 + 3) 11 + 0–13 + 2 12 + 4 (0 + 5) 11 + 0–13 + 6
NT, mm 1.2 (0.4) 0.7–2.2 4.9 (2.4) 2.4–14.0
Crown-rump length, mm 54.0 (5.9) 41.9–72.5 61.7 (10.1) 41–84.4
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4. mortem examinations were refused. In 7 of these
cases, a cardiac defect was suspected. The car-
diovascular anomalies (n = 45) included septal
defects (n = 20, ventricular and atrioventricular),
left inflow obstruction (n = 5, hypoplastic left
heart syndrome), left outflow obstruction (n = 8,
coarctation of the aorta, aortic valve atresia, and
stenosis), right outflow obstruction (n = 5, tetralo-
gy of Fallot, pulmonary valve atresia, and stenosis),
and other (n = 7, cardiomyopathy, polyvalvular dis-
ease, and an aberrant right subclavian artery).
Ductus Venosus Flow Velocities
The ductus venosus was successfully assessed in
181 of the 221 examinations of fetuses with nor-
mal NT (82%) and in 203 of the 251 examinations
of fetuses with increased NT (81%). The ductus
venosus PIV was significantly higher in fetuses
with increased NT compared to fetuses with
normal NT between 11 and 16 weeks’ gestation
(P< .05). Within the group of fetuses with
increased NT, a significantly higher ductus veno-
sus PIV was found in aneuploid fetuses com-
pared to euploid fetuses and in fetuses with a
cardiac defect compared to fetuses with a nor-
mal heart (P< .001). No significant differences in
the ductus venosus PIV were found between the
different types of cardiac defects (Figure 2).
Greater NT was associated with a higher ductus
venosus PIV (r= 0.64; P< .001).
1054 J Ultrasound Med 2010; 29:1051–1058
Abnormal Ductus Venosus Flow With Increased Nuchal Translucency
Figure 1.Disposition of the 137 fetuses with increased NT included in the study. Cardiovascular anomalies (n = 45) included septal defects (n = 20), left
outflow obstruction (n = 8), right outflow obstruction (n = 5), left inflow obstruction (n = 5), and other (n = 7).
‡
Postmortem examinations were not possi-
ble: selective reduction in twin pregnancy (n = 2).
†
Postmortem examinations were unsuccessful because of the absence of the fetal heart in the aspiration
specimen (n = 2) and a severely damaged heart (n = 2).
§
Karyotype, 46,XY, der(18)t(3;18)(q27;p11.1).
*
Noonan syndrome was diagnosed postnatally on the
basis of clinical symptoms; the infant died at 1 year.
**
Noonan syndrome confirmed with DNA analysis (n = 2). IUFD indicates intrauterine fetal death.
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5. The ductus venosus a-V was significantly lower
in fetuses with increased NT compared to fetus-
es with normal NT (P< .001; Figure 3). Within the
group of fetuses with increased NT, a significant-
ly lower ductus venosus a-V was found in aneu-
ploid fetuses compared to euploid fetuses and in
fetuses with an abnormal heart compared to
fetuses with a normal heart (P< .001). No signifi-
cant differences in the ductus venosus a-V were
found between the different types of cardiac
defects (Figure 4). Greater NT was associated with
a lower ductus venosus a-V (r= –0.61; P< .001).
Intracardiac Flow Velocities
In 187 of the 219 measurements of fetuses with
normal NT (85%), intracardiac flow velocity
waveforms (tricuspid and mitral valves) could be
recorded. In 168 (77%) of the 219 measurements
of fetuses with increased NT, intracardiac flow
velocity waveforms could be obtained. No signifi-
cant differences in the intracardiac velocities (E
wave, A wave, and E/A ratio) between fetuses
with normal and increased NT were found (data
not shown). Within the group of fetuses with
increased NT, no significant differences in intrac-
ardiac velocities were found between fetuses
with and without a cardiac defect. Within the
group of fetuses with increased NT, aneuploid
fetuses showed significantly lower E and A waves
of the mitral and tricuspid valves compared to
the euploid fetuses (P< .05). The E/A ratio of the
mitral and tricuspid valves did not show signifi-
cant differences (data not shown). No relation-
ship between intracardiac flow velocities and NT
size was found.
Discussion
This study evaluated whether ductus venosus
flow alterations in fetuses with increased NT can
be explained by hemodynamic changes due to a
certain type of cardiac defect. In the group of
fetuses with increased NT, those with a cardiac
defect showed a significantly higher PIV and a
lower a-V of the ductus venosus. No significant
differences were found between the different
types of cardiac defects. Previous reports also
showed a relationship between altered ductus
venosus flow velocities in fetuses with increased
NT and cardiac defects.
12,13,17
However, to our
knowledge, a study assessing increased NT and
ductus venosus flow in relation to type of cardiac
abnormalities has not been reported previously.
Impaired cardiac function due to cardiac
defects has been suggested to play a role in the
development of increased NT.
4,12
Abnormal duc-
tus venosus flow velocities could be the result of
an increase in ventricular end-diastolic pressure
due to impaired atrial contraction.
4
Left and
right heart obstructions, for example, pulmonary
valve stenosis, could result in an increase in right
ventricular pressure and reversed flow in the
ductus venosus during atrial contraction. Hyett
et al
5
proposed that increased NT could be
J Ultrasound Med 2010; 29:1051–1058 1055
de Mooij et al
Figure 2.Mean ductus venosus PIV of fetuses with normal and increased NT with respect to the type of cardiac defect. GA indicates
gestational age.
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6. 1056 J Ultrasound Med 2010; 29:1051–1058
Abnormal Ductus Venosus Flow With Increased Nuchal Translucency
Figure 3.Ductus venosus flow velocity waveforms showing normal flow and reversed flow during atrial contraction (a-V) in a fetus
with normal NT (A) and a fetus with increased NT (B). A, Gestational age, 12 weeks; NT, 1.2 mm; normal heart; karyotype, 46,XX.
B, Gestational age, 12 weeks 5 days; NT, 5.4 mm; myocardial hypertrophy (atria and ventricles); karyotype, 47,XX+21.
AB
Figure 4.Mean ductus venosus a-V of fetuses with normal and increased NT with respect to the type of cardiac defect. GA indicates gestational age.
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7. explained by overperfusion of the head due to
preferential blood flow through the head and
neck as a result of an obstruction of the aortic
arch. However, in our data, no significant differ-
ences in the ductus venosus PIV between left and
right outflow obstructions and septal defects, for
example, were found. Also, not all fetuses with
increased NT and abnormal ductus venosus flow
waveforms had a diagnosis of a cardiac abnormal-
ity. Within the group of fetuses with increased NT,
the aneuploid fetuses showed significantly lower E
and A waves compared to the euploid fetuses,
which is in accordance with previous data from
our group.
18
However, within this group of fetuses,
no significant differences in intracardiac velocities
between fetuses with and without cardiac defects
were shown. The left and right ventricle function
was not diminished in fetuses with increased NT
because no differences in intracardiac velocities
were shown between fetuses with normal and
increased NT. In addition, no other signs of car-
diac failure such as pleural effusion and ascites
were found in the fetuses with increased NT. Thus,
the results of this study do not support the theory
that higher right ventricular pressure is responsi-
ble for the alterations in ductus venosus flow
velocities. A limitation of the study was the small
sample size of the groups with cardiac defects.
The fact that no relationship was found between
cardiac defects that could influence the hemody-
namics and ductus venosus flow velocities indi-
cates that cardiac failure alone cannot explain the
altered ductus venosus velocities and pathophys-
iologic mechanism of increased NT.
Another suggested explanation for increased
NT is a disturbance in lymphatic development.
First-trimester fetuses with increased NT mor-
phologically show nuchal edema accompanied
by a distended jugular lymphatic sac (JLS).
19
Lymphangiogenesis starts with the development
of the JLS, which normally reorganizes into lym-
phatic nodes after 10 weeks’ gestation.
20–22
Delayed reorganization of the JLS into lymph
nodes could explain both the transient and
regional character of increased NT.
Because this study shows that altered ductus
venosus flow velocities are not related to a spe-
cific type of cardiac defect such as outflow
obstruction, we hypothesize that a mechanism
other than cardiac failure is responsible for the
alterations found. Interestingly, a recent longitu-
dinal sonographic study by our group, investi-
gating fetuses with increased NT and a distended
JLS, showed a higher jugular vein and ductus
venosus PIV in those fetuses compared to fetuses
with normal NT.
23
A disturbance in venous
endothelial differentiation was suggested as an
explanation for these findings. Previous morpho-
logic studies of both fetuses with increased NT
and mouse embryos with trisomy 16, an animal
model for trisomy 21, showed abnormal
endothelial differentiation of the jugular venous-
lymphatic system.
24
Abnormal endothelial dif-
ferentiation also has been reported to play a
role in the development of cardiac defects.
25,26
Altered endothelial differentiation could explain
the finding that altered ductus venosus flow
velocities in fetuses with increased NT are inde-
pendent of a specific type of cardiac defect.
A broad range of abnormalities are associated
with increased NT.
1,3
One single explanation for
the origin of increased NT is therefore not likely.
A delay or disturbance in endothelial develop-
ment and differentiation could be a common
process related to the lymphatic abnormalities,
cardiac defects, and altered ductus venosus and
jugular vein flow found in fetuses with increased
NT. We hypothesize that a disturbance in endothe-
lial differentiation can vary from delayed but
physiologic development to more disturbed
development. Aneuploid fetuses with increased
NT probably endure a more severe disturbance
in endothelial differentiation.
Ductus venosus flow has been suggested as an
additional marker in first-trimester screening for
aneuploidy.
11,13
Our study, however, showed that
greater NT was related to a higher PIV and a
lower a-V of the ductus venosus. A recent study
by Maiz et al
27
showed a similar association
between NT size and the a-V of the ductus veno-
sus. In our opinion, this indicates that ductus
venosus flow is not an independent marker in
screening for aneuploidy.
In conclusion, we have shown that ductus
venosus flow velocities in fetuses with increased
NT are not related to a certain type of cardiac
defect. This indicates that the altered ductus
venosus flow velocities found in fetuses with an
increased NT cannot be explained by cardiac
failure due to specific altered cardiac anatomy.
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de Mooij et al
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