Ultrasound Obstet Gynecol 2003; 21: 490493

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.119

Prenatal diagnosis of hypoplastic left heart syndrome

and trisomy 18 in a fetus with normal nuchal translucency
and abnormal ductus venosus blood flow at 13 weeks
of gestation

J. M. MARTINEZ CRESPO, M. DEL RIO,
O. GOMEZ, A. BORRELL, B. PUERTO, V. CARARACH
and A. FORTUNY
Department of Obstetrics and Gynaecology, ICGON, Hospital Clinic, Barcelona, Spain

K E Y W O R D S: congenital heart disease; ductus venosus; early echocardiography; nuchal translucency; trisomy 18

ABSTRACT first-trimester ultrasound for dating, early screening

We describe a case of early prenatal diagnosis of a major
congenital heart anomaly and trisomy 18 in a low-risk
pregnant woman. Nuchal translucency (NT) measure-
ment at 13 weeks gestation was 1.2 mm and Doppler
evaluation of the ductus venosus detected a persistent
reversed flow during atrial contraction. This finding
prompted us to perform fetal echocardiography which
showed hypoplastic left heart syndrome. Karyotyping fol-
lowing chorionic villus sampling diagnosed trisomy 18.
Review of the recent literature suggests that the finding of
an abnormal ductus venosus Doppler pattern in the late
first trimester of pregnancy may be an early sign of either
congenital cardiac or chromosomal abnormality, even in
the presence of normal NT screening. Copyright 2003
ISUOG. Published by John Wiley & Sons, Ltd.
INTRODUCTION
Nuchal translucency (NT) measurement at 1114 weeks
gestation is a well-established method of screening for
chromosomal abnormalities1 , and has also been found
to be highly associated with congenital heart diseases,
their prevalence increasing exponentially with increasing
NT2 4 . Recently, some authors have further reported
a strong association between abnormal ductus venosus
blood flow and not only chromosomal abnormalities5 8
but also cardiac malformations7 9 . Our hospital is
involved in a prospective study on the evaluation of
ductus venosus velocimetry in all pregnancies at low
risk for chromosomal abnormalities undergoing routine
for structural abnormalities and NT assessment at
1114 weeks gestation. The cut-off for advanced
maternal age as an indication for an invasive procedure
in our setting is 38 years. We present a case of the early
prenatal diagnosis of hypoplastic left heart syndrome at
13 weeks gestation in a fetus which was later diagnosed
as having trisomy 18. NT assessment had been completely
normal and the finding of an abnormal ductus venosus
blood flow raised the suspicion of a cardiac anomaly and
the recommendation for fetal karyotyping.
CASE REPORT
This was the first pregnancy of a 36-year-old woman, with
two second-degree relatives affected by Down syndrome
(her second cousin and a cousin of her husband), and with
no other congenital anomalies or history of consanguinity.
A first-trimester transvaginal scan (Acuson Aspen; Acuson
Inc., Mountain View, CA, USA) at 13.5 weeks of gestation
by last menstrual period revealed a normally grown
fetus with a crownrump length (CRL) of 69 mm,
with normal NT (1.2 mm) but an abnormal ductus
venosus blood flow, showing reversed flow during atrial
contraction and an increased pulsatility index (PI = 2.62).
The umbilical artery also showed reversed end-diastolic
velocities whereas the fetal heart rate was within the
normal range (158 bpm).
There were no other gross structural anomalies.
A complete fetal echocardiographic examination in
a segmental approach was performed as previously
described10 . The main features were a huge right heart

Correspondence to: Dr J. M. Martnez Crespo, Department of Obstetrics and Gynaecology, ICGON, Hospital Clinic, Villarroel 170, 08036
Barcelona, Spain (e-mail: 26625jmc@comb.es)
Accepted: 21 December 2002

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. CASE REPORT
Hypoplastic left heart syndrome and trisomy 18
Figure 1 Color Doppler fails to demonstrate significant flow
through the mitral valve in comparison with the tricuspid valve.
The four-chamber view shows right heart dominance with small
left atrium and ventricle.
dominance in the four-chamber view, with very small
left atrium and ventricle. No significant flow through
the mitral valve could be demonstrated by color Doppler
(Figure 1). The right outflow tract was markedly larger
than the left one, which was tiny, and a turbulent high-
velocity flow (150 cm/s) was detected through the aortic
valve, suggesting severe aortic stenosis. Without the need
for a confirmatory scan, these findings were consistent
with hypoplastic left heart syndrome, and the parents
opted for fetal karyotyping.
Cytogenetic analysis following chorionic villus sam-
pling diagnosed trisomy 18. The echocardiographic fea-
tures and persistent reversed flow pattern in the ductus
venosus and normal NT remained on a subsequent exam-
ination a week later. After genetic counseling the patient
elected to terminate the pregnancy. Unfortunately, ter-
mination of pregnancy (TOP) was not performed at our
center and a detailed pathological examination was not
performed due to the lack of integrity of the fetal specimen
after termination.
DISCUSSION
We report a case of trisomy 18 diagnosed in a low-
risk pregnancy after the identification of a major heart
defect in which the NT was normal, but the ductus
venosus Doppler was abnormal at 13 weeks of gestation.
Several atypical points make our case remarkable from
an ultrasonographic point of view. Among the more
common autosomal aneuploidies, trisomy 18 has been
reported as the one in which fetal growth is more severely
affected during the first trimester11,12 . In the present case,
surprisingly, fetal growth by CRL was strictly normal.
However, the most striking findings were the abnormal
Doppler studies in both the umbilical artery and ductus
Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd.
491
venosus while NT was normal. Indeed, cardiac function
impairment and major heart defects, both likely to be
a cause of abnormal ductus venosus flow, have been
advocated as the underlying mechanisms for the nuchal
fluid accumulation. However, it is not clear whether the
cardiac defect is the cause of the increased NT or whether
both events are the result of another mechanism related
to the pathogenesis of increased NT13 15 .
Two studies5,6 performed in pregnancies at high
risk for chromosomal abnormalities undergoing fetal
karyotyping, more commonly because of advanced
maternal age or increased NT, were the first to
report a significant series of chromosomal abnormalities
detected by ductus venosus flow abnormalities. Matias
et al. noted that most of the trisomic fetuses with
increased NT also had abnormal ductus venosus flow,
so the probability of having a chromosomal abnormality
in fetuses with enlarged NT was greater when an
abnormal ductus venosus flow was found5 . However,
Borrell et al. found poor correlation between both
parameters, although concordant results were observed
in most (65%) of the affected fetuses6 . Recently, larger
series with a higher proportion of women at low-
risk for chromosomal abnormalities7,16 confirmed these
previous results, suggesting that evaluation of the ductus
venosus blood flow during early gestation could be
a useful second-line screening test for chromosomal
defects if used in combination with NT measurement,
increasing the specificity and thus reducing unnecessary
invasive testing, while maintaining an optimal detection
rate for chromosomal anomalies5 9,16 . This could be
particularly useful in women at high-risk for chromosomal
abnormalities who are reluctant to undergo an invasive
procedure.
Matias et al.9 reported that among chromosomally
normal fetuses showing increased NT (above the 95th
percentile) only those with an abnormal ductus venosus
blood flow were at risk for congenital heart disease.
Since this series refers only to a chromosomally normal
population, this finding might contradict most previous
reports that suggested a cardiac involvement in the
pathogenesis of NT and would be in agreement with
our previous report suggesting that ductus venosus and
NT are independent variables amenable to be combined
to enhance detection of fetal aneuploidies6 . Recently,
Campbell et al. reported a case of mosaic trisomy 8
in a fetus with normal NT diagnosed at 12 weeks
gestation, and the only indication for karyotyping was
an abnormal ductus venosus blood flow17 . The authors
concluded that it would be worth investigating the
association between abnormal ductus venosus flow, fetal
chromosomal abnormalities and cardiac defects in low-
risk pregnant women. Indeed, there is still a paucity of
good data on the frequency of abnormal ductus venosus
flow in fetuses with normal NT and normal outcome.
In order to obtain reliable measurements, adherence
to strict methodological criteria is of paramount
importance when assessing Doppler studies of the ductus
venosus during the late first trimester of pregnancy. An
Ultrasound Obstet Gynecol 2003; 21: 490493.
492
acceptable reproducibility has been reported using both
the transvaginal and the transabdominal approach18 20 .
This has been supported by the fact that both the
intraobserver and interobserver repeatability of the PI
for veins measurement were acceptable allowing the
detection of moderate to large changes in Doppler,
but with considerable variability in measuring absolute
velocities19,20 . Furthermore, a qualitative classification
of the flow velocity waveforms based on the presence,
absence or reversal of flow during the atrial contraction
appeared to be a reproducible method20 . Thus, both the
PI and the presence of flow during the atrial contraction
seem to be reproducible parameters to implement in a
screening setting.
An extremely abnormal umbilical artery pattern with
reversed end-diastolic blood flow was detected in the
present case. This finding can be considered as an
ominous sign when found in the first trimester, since
16/17 cases reported to date in the literature had abnormal
outcome, in particular 11 chromosomal anomalies, two
cardiac defects and two hydrops21 . Furthermore, in a
previous study we observed that trisomic 18 fetuses
have an abnormal rising trend in umbilical PI in early
pregnancy, which may be related to the early onset of
fetal growth restriction related to inadequate placentation
and dislocation of the trophoblastic shell22 .
Transabdominal second-trimester echocardiography at
2022 weeks gestation is still the established method for
diagnosing cardiac anomalies23 . However, there is strong
evidence in the literature to support the view that fetal
echocardiography performed in high-risk pregnancies for
congenital heart defects by expert operators is reliable for
diagnosing most major structural heart defects in the first
and early second trimesters of pregnancy, thus allowing
optimization of management, offering karyotyping and
reducing emotional trauma to the parents through early
counseling or TOP10,24 28 . As noted in the present case,
color and pulsed Doppler are critically useful at this time
of gestation to confirm normal inflow to the ventricles and
to identify the outflow tracts, since gray-scale imaging is
not always sufficient for an accurate examination of the
heart.
A drawback of the present report is that precise
pathological follow-up could not be obtained. We want
to stress the difficulties in the early diagnosis of this
condition, a common false-negative diagnosis being one
of early fetal echocardiography10,25 . It is well known
that hypoplastic left heart is a developing condition that
can be missed on an early scan25 , although ventricular
asymmetry, reverse perfusion of the aorta and/or a jet
of an aortic stenosis can be expected also in early
pregnancy in the most severe cases, as in the present
case. Whenever a TOP is performed, we recommend
the use of prostaglandins since other methods do not
usually allow the retrieval of suitable specimens for
appropriate examination for the correlation of ultrasound
and pathological findings. Ideally, the pathological
examination should be performed by a pathologist who
is familiar with the small size of the specimen and special
Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd.
Martnez Crespo et al.
examination techniques such as stereomicroscopy10,13 .
Only a complete diagnosis will make individual genetic
counseling possible and will validate the accuracy of early
fetal echocardiography as a diagnostic technique.
In common with many case reports, the significance of
the apparent relationship that the present case illustrates
cannot necessarily be extrapolated to the general situation.
We know that the majority of fetuses with major
chromosomal abnormalities have abnormally increased
NT and that some fetuses with normal NT have abnormal
ductus venosus flow. As previously mentioned, we do not
know how often a chromosomal abnormality coincides
with normal NT and abnormal ductus, and this does not
in itself have to imply a real relationship.
Doppler studies in early pregnancy are still confined
to the research arena29 , but the increase in their
use may confirm their value in the investigation of
certain first-trimester abnormalities. We conclude that
Doppler evaluation of the ductus venosus, and perhaps
also the umbilical artery, could be envisaged during
early pregnancy as an additional parameter together
with other well-established features, such as NT and
biochemical markers, to improve the prenatal detection
of fetal aneuploidies. Although only a few cases have
been reported to date, chromosomal and/or cardiac
abnormalities might be suspected in such instances, and
these observations deserve further validation by larger
series in unselected low-risk pregnancies.
REFERENCES
1. Snijders RJM, Noble P, Sebire N, Souka A, Nicolaides KH.
UK multicentre project on assessment of risk of trisomy 21
by maternal age and fetal nuchal translucency thickness at
1014 weeks of gestation. Lancet 1998; 351: 343346.
2. Hyett J, Perdu M, Sharland G, Snijders R, Nicolaides KH.
Using nuchal translucency to screen for major cardiac defects at
1014 weeks of gestation: population based cohort study. BMJ
1999; 318: 8185.
3. Devine PC, Simpson LL. Nuchal translucency and its relation-
ship to congenital heart disease. Semin Perinatol 2000; 24:
343351.
4. Souka AP, Krampl E, Bakalis S, Heath V, Nicolaides KH.
Outcome of pregnancy in chromosomally normal fetuses with
increased nuchal translucency thickness in the first trimester.
Ultrasound Obstet Gynecol 2001; 18: 917.
5. Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH.
Screening for chromosomal abnormalities at 1014 weeks: the
role of ductus venosus blood flow. Ultrasound Obstet Gynecol
1998; 12: 380384.
6. Borrell A, Antolin E, Costa D, Farre MT, Martinez JM, For-
tuny A. Abnormal ductus venosus blood flow in trisomy 21
fetuses during early pregnancy. Am J Obstet Gynecol 1998;
179: 16121617.
7. Antoln E, Comas C, Torrents M, Munoz A, Figueras F,
Echevarra M, Cararach M, Carrera JM. The role of ductus
venosus blood flow assessment in screening for chromosomal
abnormalities at 1016 weeks of gestation. Ultrasound Obstet
Gynecol 2001; 17: 295300.
8. Bilardo CM, Muller MA, Zikulnig L, Schipper M, Hecher K.
Ductus venosus studies in fetuses at high risk for chromosomal
or heart abnormalities: relationship with nuchal translucency
measurement and fetal outcome. Ultrasound Obstet Gynecol
2001; 17: 285287.
Ultrasound Obstet Gynecol 2003; 21: 490493.
Hypoplastic left heart syndrome and trisomy 18
9. Matias A, Huggon I, Areias JC, Montenegro N, Nicolaides KH.
Cardiac defects in chromosomally normal fetuses with abnormal
ductus venosus blood flow at 1014 weeks. Ultrasound Obstet
Gynecol 1999; 14: 307310.
10. Comas C, Galindo A, Martnez JM, Carrera JM, Gutierrez-
Larraya F, De la Fuente P, Puerto B, Borrell A. Early prenatal
diagnosis of major cardiac anomalies in a high-risk population.
Prenat Diagn 2002; 22: 586593.
11. Drugan A, Johnson MP, Isada NB, Holzgreve W, Zador I,
Dombrowski MP, Sokol RJ, Hallak M, Evans MI. The smaller
than expected first-trimester fetus is at increased risk for
chromosome anomalies. Am J Obstet Gynecol 1992; 167:
15251528.
12. Khun P, Brizot ML, Pandya PP, Snijders RJ, Nicolaides KH.
Crownrump length in chromosomally abnormal fetuses at
10 to 13 weeks gestation. Am J Obstet Gynecol 1995; 172:
3235.
13. Hyett J, Moscoso G, Nicolaides K. Abnormalities of the heart
and the great arteries in first trimester chromosomally abnormal
fetuses. Am J Med Genet 1997; 69: 207216.
14. Montenegro N, Matias A, Areias JC, Castedo S, Barros H.
Increased fetal nuchal translucency: possible involvement of
early cardiac failure. Ultrasound Obstet Gynecol 1997; 10:
265268.
15. Simpson JM, Sharland GK. Nuchal translucency and congenital
heart defects: heart failure or not? Ultrasound Obstet Gynecol
2000; 16: 3036.
16. Zoppi MA, Putzolu M, Ibba RM, Floris M, Monni G. First-
trimester ductus venosus velocimetry in relation to nuchal
translucency thickness and fetal karyotype. Fetal Diagn Ther
2002; 17: 5257.
17. Campbell S, Mavrides E, Prefumo F, Presti F, Carvalho JS.
Prenatal diagnosis of mosaic trisomy 8 in a fetus with normal
nuchal translucency thickness and reversed end-diastolic ductus
venosus flow. Ultrasound Obstet Gynecol 2001; 17: 341343.
18. Montenegro N, Matias A, Areias JC, Barros H. Ductus venosus
revisited: a Doppler blood flow evaluation in the first trimester
of pregnancy. Ultrasound Med Biol 1997; 23: 171176.
19. Prefumo F, De Biasio P, Venturini PL. Reproducibility of ductus
venosus Doppler flow measurements at 1114 weeks of
Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd.
493
gestation. Ultrasound Obstet Gynecol 2001; 17: 301305.
20. Mavrides E, Holden D, Bland JM, Tekay A, Thilaganathan B.
Intraobserver and interobserver variability of transabdominal
Doppler velocimetry measurements of the fetal ductus venosus
between 10 and 14 weeks of gestation. Ultrasound Obstet
Gynecol 2001; 17: 306310.
21. Borrell A, Martinez JM, Farre MT, Azulay M, Cararach V,
Fortuny A. Reversed end-diastolic flow in first trimester
umbilical artery: an ominous sign for fetal outcome. Am J
Obstet Gynecol 2001; 185: 204207.
22. Martinez JM, Borrell A, Antolin E, Puerto B, Casals E, Ojuel J,
Fortuny A. Umbilical Doppler velocimetry in fetuses with
trisomy 18 at 10 to 18 weeks gestation. Prenat Diagn 1997;
17: 319322.
23. Allan L, Benacerraf B, Copel JA, Carvalho JS, Chaoui R,
Eik-Nes SH, Tegnander E, Gembruch U, Huhta JC, Pilu G,
Wladimiroff J, Yagel S. Isolated major congenital heart dis-
ease (Opinion). Ultrasound Obstet Gynecol 2001; 17:
370379.
24. Gembruch U, Knopfle G, Bald R, Hansmann M. Early diagnosis
of fetal congenital heart disease by transvaginal echocardiogra-
phy. Ultrasound Obstet Gynecol 1993; 3: 310317.
25. Yagel S, Weissman A, Rotstein Z, Manor M, Hegesh J,
Anteby E, Lipitz S, Achiron R. Congenital heart defects: natural
course and in utero development. Circulation 1997; 96:
550555.
26. Carvalho JS, Moscoso G, Ville Y. First trimester trans-
abdominal fetal echocardiography. Lancet 1998; 351:
10231027.
27. Simpson JM, Jones A, Callaghan N, Sharland GK. Accuracy
and limitations of transabdominal fetal echocardiography at
1215 weeks of gestation in a population at high risk for
congenital heart disease. Br J Obstet Gynaecol 2000; 107:
14921497.
28. Bronshtein M, Zimmer Z. The sonographic approach to the
detection of fetal cardiac anomalies in early pregnancy.
Ultrasound Obstet Gynecol 2002; 19: 360365.
29. Hecher K. Assessment of ductus venosus flow during the first
and early second trimesters: what can we expect? Ultrasound
Obstet Gynecol 2001; 17: 285287.
Ultrasound Obstet Gynecol 2003; 21: 490493.