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Prenatal diagnosis: Lessons learned and future challenges

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Ultrasound Rev Obstet Gynecol 2002;2:195–204

Prenatal diagnosis: lessons learned and

future challenges
A. Kurjak, F. Stipoljev and M. Stanojevic

Department of Obstetrics and Gynecology, Medical School University of Zagreb, Sveti Duh Hospital, Zagreb, Croatia
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Key words: Prenatal diagnosis / Ultrasound / Genetic techniques

INTRODUCTION
A few months ago the world’s population reached
6 billion. The news is daunting, given that the
figure has doubled since 1960. Yet 6 billion actually
represents significant progress made in the past
30 years in reducing birth rates, improving health
care and giving women greater access to education
and economic opportunities1. How do these new
data affect perinatal medicine? Having 300 000
births every day is not the only problem. Indeed,
we are witness to dramatic changes in population
demographics in the developed world, which have
far-reaching consequences for health services. This
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likely, therefore, that there are many more genetic
diseases affecting the fetus that have not yet been
recognized, and many that may be incorrectly
diagnosed2. It can be shown that technological
advances in the fields of both obstetric procedures
during pregnancy and laboratory technology
have influenced each other, and that laboratory
investigators have constantly pushed clinicians
and vice versa.
After three decades of amazing scientific and
clinical progress in prenatal medicine, it is clear

that most advances have been made, and will

is not only evident from an increasingly aging pop-
ulation, but also from an increase in the number of
women who become pregnant at a more advanced
maternal age, many of whom are opting to have a
single child.
Hardly any area in medicine has experienced such
dramatic advances during the past three decades as
the complex field of prenatal diagnosis. We have
learned many lessons and we can foresee new,
significant challenges. Some of them are reviewed
in this article.
In the past 30 years, two principal tools have
dramatically changed the methods of acquiring
knowledge of fetal disease: amniocentesis and
ultrasonography. The former allows for the cyto-
genetic, biochemical, molecular and immuno-
logical analysis of the fetus. The latter allows for
a detailed morphological, functional, behavioral
and developmental analysis of the fetus.
Prenatal diagnosis has its roots in the hope and
desire to improve perinatal outcomes, to reduce
perinatal mortality, to reduce the familial suffering
and pain caused by fetal and neonatal death, and
to reduce the burden of disease that is inherited
or begins in utero. We are aware that there are many
more abnormal embryos than fetuses, and
many more fetuses than children and adults
affected by diseases owing to mutations. It is
continue to be made, using ultrasound and genetic
laboratory techniques to complement each other.
Indeed, the progress and future development of
perinatal medicine depend upon the development
of prenatal diagnosis and its integration with fetal
therapy and fetal pathology. However, for prenatal
diagnosis to be appropriate, of good quality
and accurate, detailed knowledge of genetic and
acquired fetal disease is necessary2.
WHAT THREE-DIMENSIONAL AND
FOUR-DIMENSIONAL SONOGRAPHY
ADD TO PRENATAL DIAGNOSIS
The more recent technological breakthroughs in
diagnostic ultrasound have surpassed all expecta-
tions. With these advances, clinicians now have
the tools to contend with many significant diag-
nostic challenges. At the same time, these new
technologies are so numerous, and have been
introduced in such rapid succession, that consider-
able confusion surrounds how these technologies
work and how they should best be used in prenatal
diagnosis.
Indeed, with the advent and evolution of three-
dimensional (3D) ultrasound technology during
the past 10 years, we now stand at a threshold
in non-invasive diagnosis. It is clear that the

CORRESPONDENCE: Professor A. Kurjak, Department of Obstetrics and Gynecology, Medical School University of Zagreb, Sveti
Duh Hospital, Sveti Duh 64, 10000 Zagreb, Croatia

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Challenges for prenatal diagnosis
progression from two to three dimensions has
brought with it a variety of new options for
storing and processing image data and displaying
anatomical structures. This technology gives
ultrasound the multiplanar capabilities that previ-
ously were reserved for computed tomography
and magnetic resonance imaging. In addition, it
can generate surface-rendered and transparent
views that provide entirely new diagnostic
capabilities.
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Recent literature in relation to the application of
new diagnostic modalities in prenatal diagnosis is
reviewed below, but first, a novel, promising
assessment of the nasal bones in screening for
trisomy 21 is described.
Nasal bone assessment in screening for
trisomy 21
It is known that skeletal abnormalities in fetuses
with Down’s syndrome include brachycephaly:
long bones with reduced growth velocity, hypo-
plasia of the middle phalanx of the fifth digit
and absence of ossification of the nasal bones.
Ossification of the nasal bones, which can be
detected in normal fetuses from 14 weeks of
gestation, was absent in one-quarter of trisomic
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fetuses, regardless of gestational age3. A post-
mortem radiographic study of the axial skeleton
showed malformation or agenesis of the nasal
bones in 19/31 (61%) of trisomy 21 and in 8/10
(80%) of trisomy 18 fetuses4,5.
The nasal bones are formed by intramembranous
ossification of connective tissue of the nasal cap-
sule. Using transvaginal sonography, its ossifica-
tion is first visualized at a crown–rump length
(CRL) of 42 mm and increases linearly with
gestation. Ossification centers appear as increased
echogenicity of the bones seen from the first
trimester6. The normal range of nasal bone length
is 4 mm at 14 weeks to 12 mm at 35 weeks of
gestation7.
Most importantly, the absence of nasal bone is a
factor independent of nuchal translucency (NT)
thickness. Therefore, its assessment is additional
to the classic NT screening program. A recent
study showed that the absent nasal bone like-
lihood ratio for trisomy 21 was 146, and with
present nasal bone this ratio was 0.278. To quote
the optimistic statement of Cuckle in a Lancet
editorial: ‘It is the time for total shift to first-
trimester screening for Down’s syndrome’9.
Advances in three-dimensional sonography
Baba and Satoh were the first to use the surface-
rendering techniques of 3D ultrasound for clinical
application in obstetrics10. Since then, 3D ultra-
sound has been shown to be especially useful in
the evaluation of fetal anomalies. A recent study
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Kurjak, Stipoljev and Stanojevic
showed that 3D ultrasound images provide, in
51% of cases, additional information, in 45% of
cases they are equivalent to two-dimensional (2D)
ultrasound and in 4% of cases are disadvantageous
in detecting fetal anomalies11. Although there
is still no large randomized study, it is clear that
3D ultrasound is more helpful in evaluating
fetuses with facial anomalies12–15, hand and foot
abnormalities16–18, and axial spine and neural tube
defects.
Facial abnormalities
Examination of the fetal face with 2D sonography
usually requires a long examination period and an
experienced ultrasonographer, because multiple
cross-sectional images must be reconstructed in
the examiner ’s mind. Moreover, according to the
Eurofetus Study, the sensitivity of routine 2D
sonography for detecting cleft lips and palates is
only 18%19. Therefore, in situations in which
facial anomalies are suspected on conventional
sonographic examination, the additional use of
3D ultrasonography is recommended20–22.
This modality has also been shown to be especially
useful in detecting and localizing facial clefting.
The images of the face obtained in three
dimensions can be displayed in two fashions:
multiplanar view and surface-rendered pictures.
However, a successfully surface-rendered image is
obtained in only about 72% of fetuses scanned
between 20 and 35 weeks6. Berge and colleagues
found a strong relationship between the types of
facial cleft, associated malformations, chromo-
somal abnormalities and fetal outcome23.
In screening for aneuploidies, analysis of the fetal
head and face can be useful. Nyberg and asso-
ciates24 proposed criteria to classify fetal cleft lip
and palate based on the degree of lesion. They also
correlated each class with outcome and found
that unilateral or bilateral cleft lip and palate are
associated with an approximate 31% aneuploidy
rate. Finally, midline facial clefts are often associ-
ated with extremely poor outcome, in contrast to a
more favorable result with lateral defects.
Ear abnormalities
Since Hall25 reported that dysplastic ears are
present in 60% of fetuses with Down’s syndrome,
prenatal evaluation of the ear seemed to be useful
in screening for aneuploidies. Using 2D ultra-
sound, only the auricular geometry may be
visualized. However, volume images with surface
rendering provide more helpful detail of the
morphology, and spatial information including
lying axis, orientation and cranial location of the
fetal ears. By using three-dimensional reconstruc-
tion, the examiners are able to diagnose a
dysplastic ear by morphology analysis, and also
to determine whether the ears are low-set.
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Challenges for prenatal diagnosis
Recognition of this ear malformation can contri-
bute to diagnoses of aneuploidies.
Central nervous system anomalies
Three-dimensional ultrasound provided additional
information in 92% of extracerebral central
nervous system (CNS) anomalies including
encephalocele and spinal neural tube defects.
Simultaneous display of three orthogonal planes
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makes the determination of topographic relation-
ships much easier11.
According to the Eurofetus Study, the sensitivity
of routine 2D sonography for detecting enceph-
alocele is 85.4%. Despite its relatively high
sensitivity, 2D ultrasound is inferior, compared
with 3D, in evaluating the lesion, in terms of
determining the exact location of the extracranial
mass and the amount of extracranial tissue in the
encephalocele19. According to the Eurofetus Study,
the sensitivity of routine 2D sonography for
detecting spina bifida without hydrocephalus is
66.3%. However, the location and extent of a
lesion cannot be evaluated accurately with 2D
sonography. However, localization of spinal
defects can be accurately accomplished by using
simultaneous multiplanar imaging19. Axial skele-
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tal anomalies (scoliosis or segmentation defects)
are better visualized by 3D than by 2D ultrasound
in 56% of cases. These anomalies are displayed
better using rotation of volume-rendered images.
Fetal weight estimation by three-dimensional
ultrasound
For many years, fetal weight has been assessed by
determining the abdominal circumference. Among
all the possible sections and parameters of the fetal
trunk, the abdominal circumference was chosen
because it reflects the changes in liver size that
occur early in many fetuses with growth abnor-
malities. This method does not consider soft tissue
thickness, despite evidence that abnormal tissue
content may be a reliable indicator of fetal growth
aberrations26–28. Catalano and colleagues29
showed that, although neonatal fat mass repre-
sents only 14% of birth weight, it explains 46% of
its variance. Some authors reported that birth
weight estimation based on volumetry of the
upper arm30 or thigh31 using new formulae is far
more accurate than the classical approach.
Nuchal cord
Three-dimensional surface imaging did not
provide more useful diagnostic information,
compared with 2D and color Doppler ultrasound,
for detecting nuchal cord in utero32. However,
the ability to view the nuchal cord (subjective
assessment of the ease of visualization of the
nuchal cord) was better with three-dimensional
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Kurjak, Stipoljev and Stanojevic
sonography than with 2D or color Doppler
ultrasound.
Limb deformities
In 63% of fetuses with hand or foot anomalies, 3D
ultrasound scans are advantageous when com-
pared with 2D ultrasound images. These include
cases of clenched and contracted hands, as well as
club and rocker-bottom feet11,18. Therefore, 3D
ultrasonography is the method of choice for
optimal morphological reconstruction of fetal
extremities, including even detailed morphology
and fingers and toes. Surface-rendering-mode
imaging has been accepted as the best technique
for the evaluation of topographic relationships
between the segments of each limb and morpho-
logy of fingers and toes.
This new diagnostic tool has the potential to
facilitate the depiction of fetal distal extremities.
Budorick and co-workers17 reported that the
normal features of distal extremities may be
demonstrated more often with 3D than with 2D
ultrasound (85% vs. 52%). Three-dimensional
ultrasound has a better potential to facilitate
depiction of the fetal digits. Ploeckinger-Ulm and
colleagues33 reported that the antenatal depiction
rate of all fetal digits was higher with 3D than
with 2D ultrasound (74.3% vs. 52.9%, p < 0.05).
Moreover, distinguishing between the thumb and
fingers, counting fingers and clear depiction of
overlapping fingers on surface-rendered images
can be easier than with 2D ultrasound. Therefore,
if there is suspicion on 2D ultrasound of poly-
dactyly or overlapping fingers, 3D ultrasono-
graphy should be recommended.
Four dimensions: the new diagnostic frontier
The latest developments of 3D and four-
dimensional (4D) sonography enable the precise
study of embryonic and fetal activity and
behavior.
With 4D ultrasound, movements of the head, body
and all four limbs and extremities can be seen
simultaneously in three dimensions34. Therefore,
the earliest phases of human anatomical and
motor development can be visualized and studied
simultaneously. It is clear that neurological
development in terms of early fetal motor activity
and behavior, detailed with 2D real-time ultra-
sonography35,36, needs to be re-evaluated using
this new technique.
Recently, our group37 studied the development of
the complexity of spontaneous embryonic and
fetal movements. With advancing gestational age
the movements become more and more complex.
The increase in the number of axodendritic and
axosomatic synapses between 8 and 10 weeks, and
again between 12 and 15 weeks38, correlates with
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Challenges for prenatal diagnosis
periods of fetal movement differentiation and the
onset of general movements and complex activity
patterns such as swallowing, stretching and
yawning, seen easily using the 4D technique. At
7–8 weeks of pregnancy, gross body movements
begin, consisting of changing the position of
the head towards the body. At 9–10 weeks of
pregnancy, limb movements begin, consisting
of changing the position of extremities towards
the body without extension or flexion in the elbow
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and knee. At 10–12 weeks of pregnancy, complex
limb movements are noted, consisting of changes
in the positions of limb segments towards each
other, such as extension and flexion in the elbow
and knee.
At 12–15 weeks of pregnancy, swallowing, stretch-
ing and yawning activities become evident. In
addition to these activities, it is now feasible to
study a full range of facial expressions including
smiling, crying and eyelid movement. It is hoped
that the 4D technique will help in the better
understanding of both somatic and motoric
development of the early embryo. It might also
help in the more precise study of both fetal and
parental behavior34.
ADVANCES IN MOLECULAR GENETICS
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As a result of the increased knowledge of DNA
chemistry, and detailed understanding of the
cellular mechanisms controlling genetic material,
molecular genetics has evolved as a powerful
diagnostic technique. The application of this
knowledge to the analysis of human disease is
probably the most powerful tool ever used in
diagnosis. The localization and characterization of
human genes has explained the etiology, patho-
genesis and prognosis of a large, growing number
of conditions, making their diagnosis and prog-
nosis more accurate and, in some cases, possible for
the first time. These advances have greatly
improved the possibility of detecting gene
mutations, which cause many diseases. Prenatal
diagnosis was initially restricted to standard cyto-
genetic techniques, which allowed only the
diagnosis of chromosomal diseases. The intro-
duction of fetal ultrasonography in routine
practice increased the number of chromosomal
and genetic diseases that can be diagnosed in the
embryonal and fetal period39. Specific fetal ultra-
sound markers for different trisomies are now
known40. However, some of the most frequently
diagnosed genetic diseases have a higher incidence
rate, compared to that of common chromosomal
diseases such as trisomy 18 and trisomy 13
(Table 1).
The diagnostic frequency of specific anomalies
varies primarily depending on the availability of
imaging technology and on the skills of the
sonographer. Correct prenatal diagnosis is of
importance, as accurate genetic counselling is fully
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Kurjak, Stipoljev and Stanojevic
Table 1
Diagnostic frequency of some chromosomal and genetic
disorders
Trisomy 21 1 : 800
Structural aberrations 1 : 1000
Microdeletion syndromes 1 : 1000–2000
Cystic fibrosis 1 : 1600–2500
Werdnig–Hoffman disease 1 : 6000
Trisomy 13 1 : 10 000
Myotonic dystrophy 1 : 8000
Trisomy 18 1 : 8000
Phenylketonuria 1 : 14 000–20 000
Triploidy 1 : 60 000
dependent on it. Table 2 lists the specific ultra-
sonographic findings in some genetic disorders
indicating the necessity for further prenatal molec-
ular testing41–50.
It is well known that the use of invasive pro-
cedures, such as amniocentesis, chorionic villus
sampling, fetal biopsies or cordocentesis, carries
variable risk of fetal loss. Present trends in prenatal
diagnosis include the routine use of biochemical
parameters in maternal serum, in combination
with ultrasonographic markers, to perform risk
screening for fetal aneuploidy. Many of the
maternal serum markers have been used as
diagnostic markers for non-invasive screening of
fetal aneuploidies in low-risk populations. Prenatal
biochemical screening for trisomy 21 includes the
combination of maternal age with maternal serum
α-fetoprotein and free β-human chorionic gonado-
tropin (β-hCG)51; in addition with unconjugated
estriol these markers can detect about 65% of
aneuploid pregnancies with a 5% false-positive
rate52. The use of increased fetal nuchal thickness
in combination with maternal serum pregnancy-
associated plasma protein-A (PAPP-A) and free
β-hCG has significantly increased the sensitivity of
the screening program for trisomy 21 in the first
trimester of pregnancy. The detection rate
increases to 90%, with a false-positive rate of
5%53. Interphase-fluorescence in situ hybridization
(FISH), using amniotic fluid with specific probes
for chromosomes 13, 18, 21 and sex chromosomes,
should be offered in pregnancies of 20 weeks or
greater with abnormal ultrasound findings indi-
cating the presence of trisomy 13, 21 or 18. The
use of FISH of interphase and metaphase chromo-
somes is routinely carried out in prenatal
diagnosis of microdeletion syndromes (Prader–
Willi, Angelman syndrome, Miller–Dieker,
Williams syndrome, Smith–Magenis syndrome).
However, women of advanced age have an
increased risk of carrying a fetus with a chromo-
somal aberration, and many are reluctant to be
exposed to the risks associated with an invasive
prenatal diagnostic procedure. A further concern is
the high false-positive rate for the detection of
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Challenges for prenatal diagnosis Kurjak, Stipoljev and Stanojevic

Table 2
Specific ultrasonographic findings for some genetic disorders that should indicate further molecular testing

Genetic disorder Ultrasound markers Prenatal diagnosis

Cystic fibrosis hyperechogenic bowel CA

(Muller et al., 199341; Stipoljev et al. 199942) DNA analysis of CFRT gene
Phenylketonuria IUGR CA
(Levy et al., 200143) microcephaly DNA analysis of PAH gene
heart defect
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Werdnig–Hoffman disease arthrogryposis CA

(Burglen et al. 199644; Stiller et al., 199945) heart defect (VSD, ASD) DNA analysis of SMN and NAIP
genes
Myotonic dystrophy polyhydramnios (AFI > 25) plus abnormal CA
(Esplin et al., 199846) position of extremities DNA analysis of DMPK gene
Pallister–Killian syndrome diaphragmatic hernia CA (fibroblasts and fetal blood)
(Paladini et al., 200047) polyhydramnios
short femur
Roberts syndrome cleft lip and palate CA (C banding: premature
(Paladini et al., 199648) early IUGR chromosome separation)
heart defect
phocomelia (most severe cases)
polyhydramnios
Miller–Dieker syndrome omphalocele CA
(Chitayat et al., 199749) ventriculomegaly FISH (17p13)
Beckwith–Wiedermann syndrome omphalocele plus polyhydramnios CA
(Ranzini et al., 199750) > 25 weeks’ gestation: polyhydramnios plus FISH (11p15.5)
accelerated fetal growth
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CA, chromosomal analysis; CFRT, cystic fibrosis; IUGR, intrauterine growth restriction; PAH, phenylalanine hydroxylase; VSD, ventricular
septal defect; ASD, atrial septal defect; SMN, survival motor neuron; NAIP, neuronal apoptosis inhibiting protein; AFI, amniotic fluid index;
DMPK, dystrophia myotonica protein kinase; FISH, fluorescence in situ hybridization

fetal aneuploidies associated with current non-
invasive methods. Because amniocentesis or
chorionic villus sampling, even when performed
by experienced operators using ultrasound
guidance, still contain an appreciable risk of com-
plications including fetal loss, there is strong
motivation to improve the screening tests for
aneuploidies, so that the ultrasound-guided pro-
cedures can be offered based on a much more
sophisticated risk analysis than just looking at
maternal age or ultrasound and biochemical screen
markers. This is where the fetal cell isolation
efforts and the ultrasound screening programs
meet as complementary, not necessarily alterna-
tive, methods54–64.
Recent advances in prenatal diagnosis have been
based on the development of reliable non-invasive
methods. Prenatal detection of both chromosomal
and genetic disorders has been successfully
performed using fetal cells from the maternal
circulation. Basel laboratory is a leading pioneer in
the enrichment of fetal cells from maternal blood,
with the aim of developing a non-invasive, risk-
free form of prenatal diagnosis. By using the (then)
novel method of magnetic activated cell sorting
(MACS), they were among the first to detect fetal
aneuploidies55,58,59,61,63,64.
Fetal cells found in maternal blood include
erythrocytes, trophoblasts, lymphocytes and
granulocytes, with their estimated number rang-
ing from 1/100 000 000 to 1/2765. False-positive
results in relation to a Y-specific signal are caused
by previous pregnancy with a male fetus; the life
span of fetal lymphocytes is more than 2 years in
the maternal circulation. This problem could be
overcome by using fetal cells with a short life span.
Separation procedures include double-density
gradient centrifugation, and flow or magnetic
sorting of fetal cells. Methods of nucleated red
blood cell (NRBC) recognition based on immuno-
cytochemical staining for fetal hemoglobin
combined with the FISH technique using chromo-
some-specific probes have also been described66.
Several factors influence an increased number of
fetal aneuploid cells in the maternal circulation,
including altered hematopoiesis in the early tri-
somic embryo, disturbed placental function owing
to disrupted chorionic villi and prolonged survival
of aneuploid NRBCs.
The introduction of new techniques in molecular
cytogenetics, especially FISH that identifies
specific DNA sequences labelled by fluorescent-
labelled probes, and the polymerase chain reaction
(PCR) that amplifies a particular gene region,

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Challenges for prenatal diagnosis Kurjak, Stipoljev and Stanojevic

enables us to penetrate the pathogenesis of an 1006 fetuses69. Chromosomal anomalies were

investigated genetic disorder67. Many in the field
are confident that we are indeed approaching that
elusive goal of being able to perform an accurate
prenatal diagnosis using non-invasive techniques,
such as the enrichment of fetal cells from the blood
of a pregnant woman, or the analysis of circula-
tory fetal DNA in maternal plasma.
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more frequent in fetuses with CHD than in live
births. The survival rate after diagnosis was poor
because of frequent parental choice to interrupt
pregnancy, and the complexity of the disease.
Much experience with fetal CHD allows good
diagnostic accuracy, based on postnatal and
pathological evaluation of the prenatal findings.
Knowledge of the natural history of heart mal-
formations and their treatment allows accurate

FETAL ECHOCARDIOGRAPHY: THE counselling of parents. Parental decisions in the

PAST IS PREDICTING THE FUTURE above investigation shifted towards termination
of pregnancy, meaning that a smaller number of
Fetal cardiology gained a tremendous advantage
infants and children with complex cardiac mal-
from 2D ultrasonography for postnatal diag-
formations would present in postnatal life69. In
nostics and treatment of congenital cardiac
another study, 1589 infants with CHD were
defects. About 20 years ago, the significance of
identified in a well-defined population70. The
prenatal diagnosis of a congenital heart defect
live-birth prevalence of CHD was 8.1/1000, of
(CHD) was considered very important for the
which only 6.1% were diagnosed prenatally. The
prognosis of the fetus, and the outcome of
percentage of prenatally diagnosed CHD increased
pregnancy, possibility of postnatal correction or
from 2.6 to 12.7% using echocardiography, and
life-saving intervention, and prediction of life
detection was lowest for atrial septal defect (4.7%)
quality of the newborn and the family. When
and highest for hypoplastic left heart syndrome
introduced, 3D and 4D echocardiography was a
(HLHS) (28%). Prenatally diagnosed CHD was
new and exciting possibility in fetal cardiology.
associated with a high incidence of infant mor-
Medications for rhythm disturbances of the fetal
tality (30.9%) and fetal wastage (17.5%). Fetal
heart have been used successfully for many years.
echocardiography has been used increasingly
Prenatal interventions, very rarely performed on a
in the prenatal diagnosis of congenital cardiac
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fetal heart, are becoming more available with the

development of new non-surgical methods of
cardiac defect repair. What direction will the
development of fetal cardiology take? If the
diagnosis of CHD is shifted towards earlier
gestation, this will result in an increase in the rate
of terminations of pregnancy. In those who
survive, prenatal interventions will be possible in
some cases, while in others prognoses will be
improved by early life-saving postnatal inter-
vention in cardiac tertiary centers.
Development of fetal echocardiography
In the 1980s, it was revealed that fetal echo-
cardiography could correctly predict structural
malformations of the heart, and it was concluded
that the technique was sufficiently reliable to give
an accurate prognosis in early pregnancy and
provide the basis for alterations in obstetric
management68. In a series of 1600 pregnancies, 34
cases of CHD were correctly identified by fetal
echocardiography, with confirmation of the
diagnosis by anatomical study. It was a great
success in that 14 pregnancies were terminated
electively. Twenty fetuses died subsequently,
owing either to the complexity of the congenital
heart disease or to associated extracardiac
abnormalities. Eight errors were reported in inter-
pretation of the fetal echocardiogram. There were
no reports concerning prenatal intervention with
regard to the fetal heart at that time. In another
study, the authors reported their experience with
fetal CHD since 1980, diagnosing the condition in
malformation, and the above study indicated
that survival of infants was not improved after
prenatal diagnosis with fetal echocardiography70.
There is some discussion concerning the respons-
ibility for prenatal screening of CHD: is the pedi-
atric cardiologist or the gynecologist responsible
for the screening71–73? There is a large discrepancy
in the study results of second-trimester ultrasound
screening for fetal malformations, owing to a
varying level of experience of the examiners. The
reported detection rates of fetal CHD were
0–60%71. Various screening concepts for more
effective detection of CHD are available, and the
most recent technique of early echocardiography
between 13 and 15 weeks of gestation was con-
sidered very useful, owing to easier termination of
pregnancy if necessary. It is the opinion of our
group that the gynecologist is responsible for
screening of CHD, and, if CHD is suspected, then
the pediatric cardiologist should examine the
patient and confirm or make the diagnosis74–77.
The gynecologist, pediatric cardiologist, geneti-
cist, psychologist and social-worker should be
involved in counselling.
Outcome after prenatal diagnosis of fetal
cardiac lesion
The prenatal diagnosis of structural CHD is associ-
ated with a poor prognosis74. A high mortality rate
of 79% has been reported in the study of 222
fetuses, infants and children in whom prenatal
diagnosis of CHD was made. Prenatal death

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Challenges for prenatal diagnosis
occurred in 57 fetuses, 87 died as neonates and 31
died in infancy and childhood. Among 47 survivors
only five have survived beyond 4 years. High
mortality was associated with the presence of
extracardiac anomalies in 32% and prenatal
cardiac failure in 13%74. Fetal echocardiography
has been a useful tool for prenatal detection of
CHD and other heart lesions, and in some cases for
the treatment of fetal arrhythmias78. As most
forms of heart disease occur in otherwise normal
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pregnancies with no high-risk features, detection
of these cases is dependent on the skill of the
ultrasonographer performing general obstetric
scanning78. Detection of even major malform-
ations seen in the four-chamber view is still less
than perfect78,79. It is expected that CHD will be
detected earlier in pregnancy, and that examin-
ation will include evaluation of the great artery
structure79. There is now evidence that prenatal
diagnosis of CHD improves perinatal morbidity
or mortality80. New information about the
molecular genetic basis of CHD will help in
management and counselling. If extracardiac mal-
formations are excluded, then in utero therapy
should be con- sidered for some malformations80.
It has been available for fetal arrhythmias, fetal
heart failure and in some cases for a very few struc-
tural CHDs81.
For personal use only.
The outcome after prenatal diagnosis of HLHS
in 30 fetuses was as follows. Four of 12 mothers
whose fetuses were diagnosed before 24 weeks of
gestation chose to terminate the pregnancy82.
Intention to treat was present in 24 mothers of the
remaining fetuses, of whom five were not offered
the Norwood stage 1 procedure because of trisomy
18, unfavorable cardiac anatomy or neurological
impairment. Of the 19 patients who were selected
for the operation, nine survived, which means that
the survival rate was 37.5% from an intention-
to-treat position. It was concluded that survival
rate of the patient with HLHS is poor and
discouraging82.
Survival after fetal aortic balloon valvuloplasty has
been reported, and seemed a very encouraging
approach to the treatment of fetal CHD83. Dis-
couraging world experience of percutaneous ultra-
sound-guided balloon valvuloplasty in human
fetuses with severe aortic valve obstruction was
reported in 12 fetuses between 27 and 33 weeks of
gestation84. The range between initial presenta-
tion and intervention was 3 days to 9 weeks.
Technically successful balloon valvuloplasties
were achieved in seven fetuses, none of whom had
atretic valve. Only one of these seven fetuses
survived, while the remaining six died postnatally
owing to cardiac dysfunction, or at surgery in the
early postnatal period. The conclusion was that
the experience with fetal ultrasound-guided
balloon valvuloplasty has been poor as a result of
17
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Kurjak, Stipoljev and Stanojevic
selection of severe cases and technical problems
during the procedure84.
Future of fetal echocardiography: reality or
illusion
Are improvements in the field of fetal echo-
cardiography possible? The answer should be
affirmative, because in the past two decades there
have been so many new facts concerning the
pathophysiology and management of cardiac
diseases. The shift from prenatal diagnosis of
structural cardiac anomalies and rhythm disturb-
ances towards fetal cardiac flow dynamics has
been possible because of the development of
sophisticated ultrasound techniques used by
skilled professionals85,86. Improvements from the
point of view of public health can be achieved if
better screening protocols are set up and widely
performed by more skilled professionals at earlier
gestational ages87. After the diagnosis of CHD,
appropriate multidisciplinary counselling should
be offered, and effective treatment developed.
Genetic counselling and gene treatment in some
CHD cases may be the future challenge of fetal
cardiology88. The past, that is the first prenatal
diagnoses of CHD, was a glimpse into the future:
dynamic growth of the challenging field of fetal
cardiology, with a promising perspective.
CONCLUSION
Recent advances in prenatal diagnosis have opened
many medical, moral, ethical and legal questions
that should be addressed and answered appropri-
ately to allow and support the further develop-
ment of these diagnostic tools. It is clear that new
developments will be necessary to meet so many
challenges, in particular the process of developing
novel, accurate, risk-free prenatal diagnostic tech-
niques using fetal cells isolated from the maternal
circulation, or the more recent development of
examining cell-free fetal DNA in maternal plasma
or serum by PCR.
As a possible new addition to screening, ultra-
sound investigations would be coupled with look-
ing at the fetal cells or free DNA as predictors for
fetal aneuploidies, prematurity and pre-eclampsia.
Mankind should use the same creativity and
serendipity that has allowed the gathering of
amazing knowledge on the human genome to
develop the medical, social, ethical, moral and
political strategies for the acceptable application of
this technology for the benefit of humanity.
Undoubtedly, the most important aspect of these
efforts is the need for properly trained individuals
to use this amazingly powerful technology appro-
priately. This is exactly what the present issue of
our journal is about.
The Ultrasound Review of Obstetrics and Gynecology 201
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Challenges for prenatal diagnosis
References
1. Kurjak A, Bekavac I. Perinatal problems in developing
countries: lessons learned and future challenges.
J Perinat Med 2001;29:179–87
2. Elejalde BR, de Elejalde MM. Molecular genetics in
fetal medicine. In Chervenak FA, Kurjak A, eds. The
Fetus as a Patient. Carnforth, UK: Parthenon Pub-
lishing, 1996:119–37
3. Stempfle N, Huten Y, Fredouille C, Brisse H,
Nessmann C. Skeletal abnormalities in fetuses with
The Ultrasound Review of Obstetrics and Gynecology Downloaded from informahealthcare.com by Universitaetsbibliothek Duisburg-Essen on 05/20/14
Down’s syndrome: a radiographic post-mortem
study. Pediatr Radiol 1999;29:682–8
4. Kjaer I, Keeling JW, Smith NM, Hansen BF. Pattern of
malformations in the axial skeleton in human triploid
fetuses. Am J Med Genet 1997;72:216–21
5. Kjaer I, Keeling JW, Hansen BF. Pattern of malform-
ations in the axial skeleton in human trisomy 18
fetuses. Am J Med Genet 1996;65:332–6
6. van Zalen-Sprock RM, Brons JT, van Vugt JM, van der
Harten HJ, van Geijn HP. Ultrasonographic and radio-
logic visualization of the developing embryonic
skeleton. Ultrasound Obstet Gynecol 1997;9:392–7
7. Guis F, Ville Y, Vincent Y, Doumerc S, Pons JC,
Frydman R. Ultrasound evaluation of the length of
the fetal nasal bones throughout gestation. Ultrasound
Obstet Gynecol 1995;5:304–7
8. Cicero S, Curcio P, Papageorghiou A, Sonek J,
Nicolaides K. Absence of nasal bone in fetuses
with trisomy 21 at 11–14 weeks of gestation: an
observational study. Lancet 2001;358:1665–7
For personal use only.
9. Cuckle H. Time for total shift to first-trimester
screening for Down’s syndrome. Lancet 2001;358:
1658–9
10. Baba K, Satoh K. Development of the system for
ultrasonic fetal three-dimensional reconstruction.
Acta Obstet Gynecol Jpn 1986;38:1385–91
11. Dyson RL, Pretorius DH, Budorick NE, et al.
Three-dimensional ultrasound in the evaluation of
fetal anomalies. Ultrasound Obstet Gynecol 2000;16:
321–9
12. Pretorius DH, Nelson TR. Fetal face visualization
using three-dimensional ultrasonography. J Ultra-
sound Med 1995;14:349–56
13. Pretorius DH, House M, Nelson TR, Hollenbach KA.
Evaluation of normal and abnormal lips in
fetuses: comparison between three- and two-
dimensional sonography. Am J Roentgenol 1995;165:
1233–7
14. Shih JC, Shyu MK, Lee CN, Wu CH, Lin GJ, Hsieh FJ.
Antenatal depiction of the fetal ear with three-
dimensional ultrasonography. Obstet Gynecol 1998;91:
500–5
15. Lin HH, Liang RI, Chang FM, Chang CH, Yu CH,
Yang HB. Prenatal diagnosis of otocephaly using
two-dimensional and three-dimensional ultrasono-
graphy. Ultrasound Obstet Gynecol 1998;11:361–3
16. Budorick NE, Pretorius DH, Johnson DD, Tartar MK,
Lou KV, Nelson TR. Three-dimensional ultrasound
examination of the fetal hands: normal and
abnormal. Ultrasound Obstet Gynecol 1998;12:227–34
17. Budorick NE, Pretorius DH, Johnson DD, Nelson TR,
Tartar MK, Lou KV. Three-dimensional ultrasono-
graphy of the fetal distal lower extremity: normal and
abnormal. J Ultrasound Med 1998;17:649–60
18. Bonilla-Musoles F, Machado LE, Osborne NG.
Multiple congenital contractures (congenital
202 The Ultrasound Review of Obstetrics and Gynecology
18
Z:\Customer\PARTHEN\Ultrasound Review\A4413 - UROG December 2002.vp
23 October 2002 14:14:23
Kurjak, Stipoljev and Stanojevic
multiple arthrogryposis). J Perinat Med 2002;30:
99–104
19. Grandjean H, Larroque D, Levi S and Eurofetus Study
Group. The performance of routine ultrasonic
screening of pregnancies in the Eurofetus Study. Am J
Obstet Gynecol 1999;181:446–54
20. Merz E, Weber G, Bahlmann F, Miric-Tesanic D.
Application of transvaginal and abdominal three-
dimensional ultrasound for the detection or exclusion
of malformations of fetal face. Ultrasound Obstet
Gynecol 1997;9:237–43
21. Pretorius DH, House M, Nelson TR, Hollenbach KA.
Evaluation of normal and abnormal lips in fetuses:
comparison between three and two dimensional
sonography. Am J Roentgenol 1995;165:12333–7
22. Bonilla-Musoles F, Machado LE, Bailao LA, Osborne
NG, Raga F. Abdominal wall defects: two- versus
three-dimensional ultrasonographic diagnosis.
J Ultrasound Med 2001;20:379–89
23. Berge SJ, Plath H, Van de Vondel PT, et al. Fetal cleft lip
and palate: sonographic diagnosis, chromosomal
abnormalities, associated anomalies and postnatal
outcome in 70 fetuses. Ultrasound Obstet Gynecol
2001;18:422–31
24. Nyberg DA, Sickler GK, Hegge FN, et al. Fetal cleft lip
with and without cleft palate: US classification and
correlation with outcome. Radiology 1995:195:677–84
25. Hall B. Mongolism in newborn infants. An examina-
tion of the criteria for recognition and some specula-
tions on the pathogenic activity of the chromosomal
abnormality. Clin Pediatr (Phila) 1966;5:4–12
26. Deter RL, Nazar R, Milner LL. Modified neonatal
growth assessment score: a multivariate approach to
the detection of intrauterine growth retardation in
the neonate. Ultrasound Obstet Gynecol 1995;6:400–10
27. Vintzileos AM, Campbell WA, Rodis JF, Bors-Koefoed
R, Nochimson DJ. Fetal weight estimation formulas
with head, abdominal, femur, and thigh circum-
ference measurements. Am J Obstet Gynecol 1987;157:
410–14
28. McLean F, Usher R. Measurements of liveborn fetal
malnutrition infants compared with similar gestation
and with similar birth weight normal controls. Biol
Neonate 1970;16:215–21
29. Catalano PM, Tyzbir ED, Allen SR, McBean JH,
McAuliffe TL. Evaluation of fetal growth by estima-
tion of neonatal body composition. Obstet Gynecol
1992;79:46–50
30. Liang RI, Chang FM, Yao BL, Chang CH, Yu CH, Ko
HC. Predicting birth weight by fetal upper-arm
volume with use of three-dimensional ultrasono-
graphy. Am J Obstet Gynecol 1997;177:632–8
31. Chang FM, Liang RI, Ko HC, Yao BL, Chang CH, Yu
CH. Three-dimensional ultrasound-assessed fetal
thigh volumetry in predicting birth weight. Obstet
Gynecol 1997;90:331–9
32. Hanaoka U, Yanagihara T, Tanaka H, Hata T.
Comparison of three-dimensional, two-dimensional
and color Doppler ultrasound in predicting the
presence of a nuchal cord at birth. Ultrasound Obstet
Gynecol 2002;19:471–4
33. Ploeckinger-Ulm B, Ulm MR, Lee A, Kratochwil A,
Bernaschek G. Antenatal depiction of fetal digits with
three-dimensional ultrasonography. Am J Obstet
Gynecol 1996;175:571–4
34. Campbell S. 4D, or not 4D: that is the question.
Ultrasound Obstet Gynecol 2002;19:1–4
 Color profile: Generic CMYK printer profile
Composite Default screen
Challenges for prenatal diagnosis
35. de Vries JI, Visser GH, Prechtl HF. The emergence of
fetal behaviour. I. Qualitative aspects. Early Hum Dev
1982;7:301–22
36. de Vries JI, Visser GH, Prechtl HF. The emergence of
fetal behavior. II. Quantitative aspects. Early Hum Dev
1985;12:99–120
37. Kurjak A, Vecek N, Hafner T, Bozek T, Funduk-Kurjak
B, Ujevic B. Prenatal diagnosis: what does four-
dimensional ultrasound add? J Perinat Med 2002;30:
57–62
The Ultrasound Review of Obstetrics and Gynecology Downloaded from informahealthcare.com by Universitaetsbibliothek Duisburg-Essen on 05/20/14
38. Okado N, Kojima T. Ontogenity of the central
nervous system: neurogenesis, fibre connection,
synaptogenesis and myelenisation in the spinal cord.
In Prechtl HFR, ed. Continuity of Neural Functions from
Prenatal to Postnatal Life. Oxford: Blackwell Scientific,
1984:46–64
39. Carrera M, Veiga A. Preimplantation diagnosis. In
Kurjak A, Chervenak FA, Carrera JM, eds. The Embryo
as a Patient. Carnforth, UK: Parthenon Publishing,
2001:129–38
40. Nyberg DA, Souter VL. Sonographic markers of fetal
trisomies. J Ultrasound Med 2001;20:655–74
41. Muller F, Dommergues M, Simon-Bouy B, et al.
Cystic fibrosis screening: a fetus with hyperechogenic
bowel may be the index case. J Med Genet 1998;
35:657–60
42. Stipoljev F, Sertic J, Kos M, et al. Incidence of
chromosomopathies and cystic fibrosis mutations in
second trimester fetuses with isolated hyperechoic
bowel. J Maternal Fetal Med 1999;8:44–7
For personal use only.
43. Levy HL, Guldberg P, Guttler F, et al. Congenital heart
disease in maternal phenylketonuria: report from
the Maternal PKU Collaborative Study. Pediatr Res
2001;49:636–42
44. Burglen L, Amiel J, Viollet L, et al. Survival motor
neuron gene deletion in the arthrogryposis multiplex
congenita–spinal muscular atrophy association. J Clin
Invest 1996;98:1130–2
45. Stiller RJ, Lieberson D, Herzlinger R, Siddiqui D, Iaifer
SA, Whetham JC. The association of increased fetal
nuchal translucency and spinal muscular atrophy
type I. Prenat Diagn 1999;19:587–9
46. Esplin MS, Hallam S, Farrington PF, Nelson L, Byrne J,
Ward K. Myotonic dystrophy is a significant cause of
idiopathic polyhydramnios. Am J Obstet Gynecol 1998;
179:974–7
47. Paladini D, Borghese A, Arienzo M, Teodoro A,
Martinelli P, Nappi C. Prospective ultrasound
diagnosis of Pallister–Killian syndrome in the second
trimester of pregnancy: the importance of the fetal
facial profile. Prenat Diagn 2000;20:996–8
48. Paladini D, Palmieri S, Lecora M, et al. Prenatal
ultrasound diagnosis of Roberts syndrome in a family
with negative history. Ultrasound Obstet Gynecol 1996;
7:208–10
49. Chitayat D, Toi A, Babul R, et al. Omphalocele in
Miller–Dieker syndrome expanding the phenotype.
Am J Med Genet 1997;69:293–8
50. Ranzini AC, Day-Salvatore D, Turner T, Smulian JC,
Vintzileos AM. Intrauterine growth and ultrasound
findings in fetuses with Beckwith–Wiedermann
syndrome. Obstet Gynecol 1997;89:538–42
51. Palomaki GE, Knight GJ, McCarthy JE, Haddow JE,
Donhowe JM. Maternal serum screening for Down
syndrome in the United States: a 1995 survey. Am J
Obstet Gynecol 1997;176:1046–51
52. De Vore GR, Romero R. Combined use of genetic
sonography and maternal serum triple-marker
19
Z:\Customer\PARTHEN\Ultrasound Review\A4413 - UROG December 2002.vp
23 October 2002 14:14:24
Kurjak, Stipoljev and Stanojevic
screening: an effective method for increasing the
detection of trisomy 21 in women younger than
35 years. J Ultrasound Med 2001;20:645–54
53. Spencer K, Souter V, Tul N, Snijders R, Nicolaides KH.
A screening program for trisomy 21 at 10–14 weeks
using fetal nuchal translucency, maternal serum free
β-human chorionic gonadotropin and pregnancy-
associated plasma protein-A. Ultrasound Obstet
Gynecol 1999;13:231–7
54. Kan YW, Golbus MS, Klein P, Dozy AM. Successful
application of prenatal diagnosis in a pregnancy at
risk for homozygous β-thalassemia. N Engl J Med
1975;292:1096–9
55. Holzgreve W, Garritsen HS, Ganshirt Ahlert D. Fetal
cells in the maternal circulation. J Reprod Med 1992;
37:410–18
56. Zhong XY, Byrk MR, Troeger C, Jackson LR,
Holzgreve W, Hahn S. Fetal DNA in maternal plasma
is elevated in pregnancies with aneuploid fetuses.
Prenat Diagn 2000;20:795–8
57. Di Naro E, Ghezzi F, Vitucci A, et al. Prenatal diagnosis
of β-thalassaemia using fetal erythroblasts enriched
from maternal blood by a novel gradient. Mol Hum
Reprod 2000;6:571–4
58. Zhong XY, Holzgreve W, Hahn S. Detection of fetal
rhesus D and sex from fetal DNA in maternal plasma
by multiplex PCR. Br J Obstet Gynaecol 2002;107:
766–9
59. Zhong XY, Hahn S, Holzgreve W. Prenatal identifi-
cation of fetal genetic traits using free fetal DNA in
maternal plasma: accurate enough for routine pre-
natal diagnosis? Lancet 2001;357–310–11
60. Aractingi S, Berkane N, Bertheau P, et al. Fetal DNA in
skin of polymorphic eruptions of pregnancy. Lancet
1998;352:1898–901
61. Holzgreve W, Ghezzi F, Di Naro E, Maymon E,
Gunshirt D, Hahn S. Disturbed fetomaternal cell
traffic in preeclampsia. Obstet Gynecol 1998;91:669–72
62. Al-Mufti R, Lees C, Albaiges G, Hambley H,
Nicolaides KH. Fetal cells in maternal blood of
pregnancies with severe fetal growth restriction. Hum
Reprod 2000;15:218–21
63. Holzgreve W, Hahn S. Novel molecular biological
approaches for the diagnosis of preeclampsia. Clin
Chem 1999;45:451–2
64. Holzgreve W, Li CJ, Steinborn A, et al. Erythroblasts in
maternal blood are elevated prior to the onset of
preeclampsia. Am J Obstet Gynecol 2001;184:165–8
65. Hamada H, Arinami T, Kubo T, Hamaguchi H,
Iwasaki H. Fetal nucleated cells in maternal peripheral
blood frequency and relationship to gestational age.
Hum Genet 1993;91:427–32
66. Oosterwijk JC, Mesker WE, Ouwerherk-Van Velzen
MCM, et al. Prenatal diagnosis of trisomy 13 on fetal
cells obtained from maternal blood after minor
enrichment. Prenat Diagn 1998;18:1082–5
67. Orsetti B, Lefort G, Boulot P, Andreo B, Pellestor F.
Fetal cells in maternal blood: the use of primed in situ
(prins) labelling technique for fetal cell detection and
sex assessment. Prenat Diagn 1998;18:1014–22
68. Allan LD, Crawford DC, Anderson RH, Tynan MJ.
Echocardiographic and anatomical correlations in
fetal congenital heart disease. Br Heart J 1984;52:
542–8
69. Allan LD, Sharland GK, Milburn A, et al. Prospective
diagnosis of 1006 consecutive cases of congenital
heart disease in the fetus. J Am Coll Cardiol 1994;
23:1452–8
The Ultrasound Review of Obstetrics and Gynecology 203
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70. Monatna E, Khoury MJ, Cragan JD, Sharma S, Dhar P,
Fyfe D. Trends and outcomes after prenatal diagnosis
of congenital cardiac malformations by fetal echo-
cardiography in a well defined birth population.
Atlanta, Georgia, 1990–1994. J Am Coll Cardiol 1996;
28:1805–9
71. Gembruch U. Prenatal diagnosis of congenital heart
disease. Prenat Diagn 1997;17:1283–98
72. Allan LD. Fetal congenital heart disease: diagnosis and
management. Curr Opin Obstet Gynecol 1994;6:45–9
The Ultrasound Review of Obstetrics and Gynecology Downloaded from informahealthcare.com by Universitaetsbibliothek Duisburg-Essen on 05/20/14
73. Tuzler G. Fetal cardiology. Curr Opin Pediatr 2000;
12:492–6
74. Sharland GK, Lockhart SM, Chita SK, Allan LD.
Factors influencing the outcome of congenital heart
disease detected prenatally. Arch Dis Child 1991;66:
284–7
75. Penny DJ, Weintraub RG. Fetal echocardiography.
J Pediatr Child Health 1995;31:371–4
76. Friedman AH, Kleinman CS, Copel JA. Diagnosis of
cardiac defects: where we’ve been, where we are and
we’re going. Prenat Diagn 2002;22:280–4
77. Allan LD. A practical approach to fetal heart scanning.
Semin Perinatol 2000;24:324–30
78. Mapp T. Fetal echocardiography and congenital heart
disease. Prof Care Mother Child 2000;10:9–11
79. Allan LD. The outcome of fetal congenital heart
disease. Semin Perinatol 2000;24:380–4
80. Todros T. Prenatal diagnosis and management of
fetal cardiovascular malformations. Curr Opin Obstet
Gynecol 2000;12:105–9
For personal use only.
204 The Ultrasound Review of Obstetrics and Gynecology
20
Z:\Customer\PARTHEN\Ultrasound Review\A4413 - UROG December 2002.vp
23 October 2002 14:14:24
View publication stats
Kurjak, Stipoljev and Stanojevic
81. Sharland G. Fetal cardiology. Semin Neonatol 2001;
6:3–15
82. Allan LD, Apfel HD, Printz BF. Outcome after pre-
natal diagnosis of the hypoplastic left heart
syndrome. Heart 1998;79:371–3
83. Allan LD, Maxwell DJ, Carminati M, Tynan MJ.
Survival after fetal aortic balloon valvuloplasty.
Ultrasound Obstet Gynecol 1995;5:90–1
84. Kohl T, Sharland G, Allan LD, et al. World experience
of percutaneous ultrasound-guided balloon valvulo-
plasty in human fetuses with severe aortic valve
obstruction. Am J Cardiol 2000;85:1230–3
85. Bega G, Kuhlman K, Lev-Toaff A, Kurtz A, Wapner W.
Application of three-dimensional ultrasonography in
the evaluation of the fetal heart. J Ultrasound Med
2001;20:307–13
86. Michailidis GD, Simpson JM, Karidas C, Economides
DL. Detailed three-dimensional fetal echocardio-
graphy facilitated by an internet link. Ultrasound
Obstet Gynecol 2001;18:325–8
87. Haak MC, Bartelings MM, Gittenberger-de Groot
AC, Van Vugt JMG. Cardiac malformations in first-
trimester fetuses with increased nuchal translucency:
ultrasound diagnosis and postmortem morphology.
Ultrasound Obstet Gynecol 2002;20:14–21
88. Saiki Y, Rebeyka IM. Fetal cardiac intervention and
surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg
Annu 2001;4:256–70